Conditions: Heart Failure With Preserved Ejection Fraction
Keywords: Cardiovascular Diseases Heart Failure Heart failure with Preserved Ejection Fraction NT-proBNP 6 MWT KCCQ SF-36 NYHA Class LCZ696 Enalapril Valsartan Angiotensin-Converting Enzyme Inhibitors (ACEi) Angiotensin II Type 1 Receptor Blockers (ARB) Renin Angiotensin System Inhibitors (RASi)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2572
Healthy volunteers: no

Brief summary:
The purpose of this study is to demonstrate the superiority of LCZ696 over individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF).

Detailed description:
This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF \> 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e.

enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.

Arms:
arm 1: All patients who fulfill the inclusion/exclusion criteria will be stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata will receive LCZ696 or enalapril. Patients in the ARB strata will receive LCZ696 or valsartan. Patients in the no RASi strata will receive LCZ696 or matching placebo.

Patients in the ACEi and ARB strata will take two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata will take only one tablet twice daily (LCZ696 or matching placebo).

In the LCZ696 arm, patients will receive active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally). arm 2: Patients randomized to the comparator arm will receive either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).

Patients in the ACE stratum randomized to comparator, will receive enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily).

Patients in the ARB stratum randomized to comparator will receive valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily).

Patients in the no RASi stratum randomized to comparator will receive LCZ696 matching placebo.

Interventions: intervention 1: sacubitril/valsartan intervention 2: Enalapril intervention 3: Valsartan intervention 4: Placebo to match sacubitril/valsartan intervention 5: Placebo to match enalapril intervention 6: Placebo to match valsartan
Intervention descriptions: intervention 1: Sacubitril/valsartan is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg, respectively in tablet form to be taken orally intervention 2: Enalapril is available as 2.5 mg, 5 mg, and 10 mg tablet form to be taken orally intervention 3: Valsartan is available as 40 mg, 80 mg, 160 mg tablet form to be taken orally intervention 4: Placebo to match LCZ696 50 mg, 100 mg, 200 mg tablet form to be taken orally intervention 5: Placebo to match enalapril 2.5 mg, 5 mg, 10 mg tablet form to be taken orally intervention 6: Placebo to match valsartan 40 mg, 80 mg, 160 mg tablet form to be taken orally

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
LCZ696/Entresto®
Clinical Trial Protocol CLCZ696D2302
A 24-week, randomized, double-blind, multi-center, parallel 
group, active controlled study to evaluate the effect of 
LCZ696 on NT-proBNP, exercise capacity, symptoms and
safety compared to individualized medical management of 
comorbidities in patients with heart failure and preserved 
ejection fraction
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2016-003410-28
Version number:
02 Clean
Clinical trial phase:
III
Release date:
12-Sep-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................11
Amendment 2 ...........................................................................................................................16
Amendment 1 ...........................................................................................................................17
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................20
2.1
Objectives and related endpoints...........................................................................20
3
Investigational plan ...........................................................................................................21
3.1
Study design...........................................................................................................21
3.2
Rationale for study design .....................................................................................26
3.2.1
Rationale for target study population....................................................26
3.2.2
Rationale for the primary endpoints......................................................26
3.2.3
Rationale for the secondary endpoints selection...................................28
3.3
Rationale for dose/regimen, route of administration and duration of treatment....29
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................30
3.6
Risks and benefits..................................................................................................30
4
Population..........................................................................................................................30
4.1
Inclusion criteria ....................................................................................................30
4.2
Exclusion criteria...................................................................................................31
5
Treatment...........................................................................................................................34
5.1
Study treatment......................................................................................................34
5.1.1
Investigational and control drugs..........................................................34
5.1.2
Additional treatment..............................................................................35
5.2
Treatment arms......................................................................................................35
5.3
Treatment assignment and randomization.............................................................35
5.4
Treatment blinding.................................................................................................35
5.5
Treating the patient................................................................................................36
5.5.1
Patient numbering .................................................................................36


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
5.5.2
Dispensing the study drug.....................................................................36
5.5.3
Handling of study and additional treatment..........................................37
5.5.4
Instructions for prescribing and taking study treatment........................37
5.5.5
Permitted dose adjustments and interruptions of study treatment ........38
5.5.6
Rescue medication ................................................................................40
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 .........................................................................................44
6.1
Information to be collected on screening failures..................................................48
6.2
Patient demographics/other baseline characteristics .............................................48
6.3
Treatment exposure and compliance .....................................................................48
6.4
Efficacy..................................................................................................................48
6.4.1
Primary efficacy assessment .................................................................48
6.4.2
Secondary efficacy assessment .............................................................49
6.4.3
Appropriateness of efficacy assessments..............................................49
6.5
Safety.....................................................................................................................49
6.5.1
Physical examination ............................................................................49
6.5.2
Vital signs..............................................................................................49
6.5.3
Height, weight and waist/hip circumference.........................................50
6.5.4
Laboratory evaluations..........................................................................50
6.5.5
Electrocardiogram (ECG) .....................................................................52
6.5.6
Pregnancy and assessments of fertility .................................................52
6.5.7
Angioedema ..........................................................................................52
6.5.8
Appropriateness of safety measurements..............................................53
6.6
Other assessments..................................................................................................53
6.6.1
Clinical outcome assessments...............................................................53
7
Safety monitoring..............................................................................................................55
7.1
Adverse events.......................................................................................................55
7.2
Serious adverse events...........................................................................................57


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
7.2.1
Definition of SAE .................................................................................57
7.2.2
SAE reporting........................................................................................58
7.3
Liver safety monitoring .........................................................................................59
7.4
Renal safety monitoring.........................................................................................60
7.5
Reporting of study treatment errors including misuse/abuse ................................60
7.6
Pregnancy reporting...............................................................................................61
8
Data review and database management.............................................................................61
8.1
Site monitoring ......................................................................................................61
8.2
Data collection.......................................................................................................62
8.3
Database management and quality control............................................................62
8.4
Data monitoring committee...................................................................................63
8.5
Adjudication committee.........................................................................................63
9
Data analysis......................................................................................................................64
9.1
Analysis sets ..........................................................................................................64
9.2
Patient demographics and other baseline characteristics.......................................64
9.3
Treatments .............................................................................................................64
9.4
Analysis of the primary variables..........................................................................65
9.4.1
Primary variables ..................................................................................65
9.4.2
Statistical model, hypothesis, and method of analysis..........................65
9.4.3
Handling of missing values/censoring/discontinuations.......................69
9.4.4
Sensitivity analyses ...............................................................................69
9.5
Analysis of secondary variables ............................................................................70
9.5.1
Efficacy variables..................................................................................70
9.5.2
Safety variables .....................................................................................74
9.6
Analysis of exploratory variables ..........................................................................74
9.6.1
NT-proBNP up to Week 24...................................................................74
9.6.2
Estimated glomerular filtration rate (eGFR).........................................75
9.7
Interim analyses.....................................................................................................75
9.8
Sample size calculation..........................................................................................75
10 Ethical considerations........................................................................................................77
10.1
Regulatory and ethical compliance........................................................................77
10.2
Informed consent procedures.................................................................................77
10.3
Responsibilities of the investigator and IRB/IEC..................................................78
10.4
Publication of study protocol and results...............................................................78
10.5
Quality Control and Quality Assurance.................................................................78
11 Protocol adherence ............................................................................................................79


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
11.1
Protocol amendments.............................................................................................79
12 References .........................................................................................................................79
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................85
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................86
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................88
16 Appendix 4 – Treatment guidelines for hyperkalemia (serum potassium* greater than 
5.3 mmol/L [mEq/L]) ........................................................................................................90
17 Appendix 5 – Guidelines for the management of hypotension .........................................92
18 Appendix 6 – Six-minute walk test ...................................................................................93
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 3-1
Definition of low and high total daily doses for commonly used 
ACEis and ARBs...................................................................................24
Table 3-2
Study drug dose levels during double-blind treatment epoch...............25
Table 3-3
Safety monitoring criteria requirements prior to study drug 
initiation and during up-titration...........................................................25
Table 5-1
Prohibited treatment..............................................................................41
Table 6-1
Assessment schedule.............................................................................45
Table 6-2
Complete laboratory evaluations...........................................................51
Table 7-1
Adverse events commonly seen in study population............................59
Table 7-2 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................61
Table 9-1
Sensitivity of power for at least 5-points deterioration in KCCQ 
clinical summary score to changes in assumptions for N = 2500.........76
Table 9-2
Sensitivity of power for at least 5-points improvement in KCCQ 
clinical summary score to changes in assumptions for N = 2500.........77
Table 14-1
Liver event and laboratory trigger definitions ......................................86
Table 14-2
Follow-up requirements for liver events and laboratory triggers..........86
Table 15-1
Specific renal alert criteria and actions.................................................88
List of figures
Figure 3-1
Study design..........................................................................................22
Figure 3-2
Study drug up-titration..........................................................................24
Figure 9-1
Graphical illustration of the sequentially rejective testing procedure...67


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
List of abbreviations
6MWD
six-minute walk distance
6MWT
six-minute walk test
ACE
angiotensin converting enzyme
ACEi
angiotensin converting enzyme inhibitor
ACR
Albumin-creatinine ratio
AE
adverse event
AF
atrial fibrillation and atrial flutter
ALB
albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANP
atrial natriuretic peptide
ARB
angiotensin receptor blocker
ARNI
angiotensin receptor neprilysin inhibitor
AST
aspartate aminotransferase
AT1
angiotensin type 1
AUC
area under curve
B6MWD
baseline six-minute walk distance
BCSS
baseline clinical summary score
bid
twice a day
BMI
body mass index
BNP
B-type natriuretic peptide
BP
blood pressure
bpm
beats per minute
BMSS
baseline SF-36 mental component summary score
BPSS
baseline SF-36 physical component summary score
BSBP
baseline systolic blood pressure
BUN
blood urea nitrogen
CABG
coronary artery bypass graft
CAD
coronary artery disease
CCB
calcium channel blocker
CFR
US Code of Federal Regulations 
cGMP
cyclic guanosine monophosphate
CNP
C-type natriuretic peptide
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
COX-2
cyclo-oxygenase-2
CPO
country pharma organization
CRF
case report/record form (paper or electronic)
CRO
contract research organization
CRT
cardiac resynchronization therapy 
CSR
clinical study report


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
CSS
clinical summary score
CV
cardiovascular
DBP
diastolic blood pressure
DM
diabetes mellitus
DMC
data monitoring committee
DS&E
drug safety & epidemiology
EC
ethics committee
ECG
electrocardiogram
echo
echocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EF
ejection fraction
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOS
end of study
ER
emergency room
ESC
European Society of Cardiology
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration 
GCP
Good Clinical Practice
HA
Health Authority
hCG
human chorionic gonadotropin
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HfrEF
heart failure with reduced ejection fraction
Hgb
hemoglobin
HTN 
hypertension
IA
interim analysis
IB
investigator brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
independent ethics committee
IN
investigator notification
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine system
iv
intravenous
KCCQ
Kansas City Cardiomyopathy Questionnaire
LA
left atrial 
LAE
left atrial enlargement


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
LFT
liver function test 
LVEF
left ventricular ejection fraction
LVH
left ventricular hypertrophy
MAR
missing at random
MCHC
mean corpuscular hemoglobin concentration
MCS
mental component summary
MCV
mean corpuscular volume
MDRD
Modification in Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities 
MI
myocardial infarction
MMRM
mixed model for repeated measures
MRA
mineralocorticoid antagonist
NEP
neprilysin
NEPi
neprilysin inhibitor
NP
natriuretic peptide
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PCI
percutaneous coronary intervention
PCR
protein-creatinine ratio
PCS
physical component summary
PDE-5
phosphodiesterase-5
PPS
per protocol set
PSD
premature study discontinuation
QoL
quality of life
RAS
renin angiotensin system
RASi
renin angiotensin system inhibitors
RBC
red blood cell
RDW
red blood cell distribution width
RoW
Rest of the World 
SAE
serious adverse event
SAF
safety
SBP
systolic blood pressure
SF-36
The Short Form (36) Health Survey
SUSAR
suspected unexpected serious adverse reactions
TBL
total bilirubin
ULN
upper limit of normal
US
United States
WHO
World Health Organization 
WoC
withdrawal of consent


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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)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
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 
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded data, such as paper or 
eSource.
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


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
Withdrawal of informed
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
Protocol summary
Protocol number
CLCZ696D2302
Full title
A 24-week, randomized, double-blind, multi-center, parallel group, active 
controlled study to evaluate the effect of LCZ696 on NT-proBNP, exercise 
capacity, symptoms and safety compared to individualized medical 
management of comorbidities in patients with heart failure and preserved 
ejection fraction
Brief title
A randomized, double-blind controlled study to evaluate the effect of 
LCZ696 compared to individualized medical therapy for comorbidities in 
HFpEF patients
Sponsor and clinical 
phase
Novartis, Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to demonstrate superiority of LCZ696 over 
individualized medical therapy for comorbidities in reducing N-terminal pro-
brain natriuretic peptide (NT-proBNP) and improving exercise capacity and 
symptoms and QOL in patients with heart failure with preserved ejection 
fraction (HFpEF).
Primary objective(s) 
The primary objectives of this study are

To demonstrate that LCZ696 is superior to individualized medical 
therapy for comorbidities in reducing NT-proBNP from baseline after 
12 weeks of treatment

To demonstrate that LCZ696 is superior to individualized medical 
therapy for comorbidities in improving exercise capacity as assessed 
by the six-minute walk test (6MWT) at Week 24 in a subset of 
patients
Secondary objectives
To compare LCZ696 to individualized medical therapy for comorbidities 
on:

Mean change from baseline in Kansas City Cardiomyopathy 
Questionnaire (KCCQ) clinical summary score (CSS) at Week 24

Proportion of patients with ≥5-points change in KCCQ clinical 
summary score at Week 24 (separate analyses for ≥5-points
improvement and ≥5-points deterioration)

Improvement in New York Heart Association (NYHA) functional class 
at Week 24

Improvement in symptoms as assessed by The Short Form (36) Health 
Survey (SF-36) physical component summary (PCS) score at Week 
24
Study design
This study is a 24-week, randomized, double-blind, multi-center, parallel 
group, active controlled study to evaluate LCZ696 compared to 
individualized medical therapy on NT-proBNP, exercise capacity, and 
symptoms in patients with HF and preserved left ventricular ejection 
fraction (LVEF >40%)


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
Population
Approximately 2500 patients ≥45 years with symptomatic HF (NYHA 
class II-IV), preserved ejection fraction (LVEF>40%), documented 
structural heart disease and KCCQ CSS < 75 will be randomized.
Key inclusion criteria
1.
Written informed consent must be obtained before any 
assessment is performed
2.
≥ 45 years of age, male, or female
3.
LVEF >40% by echocardiography performed within 6 months 
prior to Visit 1 or during the screening epoch
4.
Symptom(s) of HF requiring treatment with diuretic(s) (including 
loop or thiazide diuretics, or mineralocorticoid antagonist (MRAs) 
for at least 30 days prior to Visit 1
5.
Current symptom(s) of HF (NYHA class II-IV) at Visit 1
6.
Structural heart disease demonstrated by echocardiographic 
evidence of left atrial enlargement (LAE) or left ventricular 
hypertrophy (LVH) as defined below (any local measurement 
made during the screening epoch or within the 6 months prior to 
Visit 1):
a.
LAE defined by at least one of the following: LA width 
(diameter) ≥3.8 cm or LA length ≥5.0 cm or LA area ≥20 
cm2 or LA volume ≥55 mL or LA volume index ≥29 mL/m2
b.
LVH defined by septal thickness or posterior wall thickness 
≥1.1 cm
7.
Receiving evidence based therapy for relevant comorbidities as 
determined by the individual clinical profile of the patient (eg age 
and number and type of comorbidities) with stable doses for the 
previous four weeks prior to randomization
8.
NT-proBNP > 220 pg/mL for patients with no atrial 
fibrillation/atrial flutter (AF) or > 600 pg/mL for patients with AF 
on the Visit 1 electrocardiogram (ECG)
9.
KCCQ CSS < 75 at Visit 1
10. Patients on angiotensin converting enzyme inhibitor (ACEi) or 
angiotensin receptor blocker (ARB) therapy must have a history 
of HTN
Key exclusion criteria
1.
Any prior echocardiographic measurement of LVEF ≤40%, 
under stable conditions
2.
Acute coronary syndrome (including myocardial infarction [MI]), 
cardiac surgery, other major cardiovascular (CV) surgery, or 
urgent percutaneous coronary intervention (PCI) within the 
3 months prior to Visit 1 or an elective PCI within 30 days prior 
to Visit 1
3.
Any clinical event within the 6 months prior to Visit 1 that could 
have reduced the LVEF (eg MI, coronary artery bypass graft 
[CABG]), unless an echo measurement was performed after the 
event confirming the LVEF to be > 40%
4.
Current (within 30 days from visit 1) acute decompensated HF 
requiring augmented therapy with diuretics, vasodilators and/or 
inotropic drugs
5.
Current (within 30 days from visit 1) use of renin inhibitor(s), dual 
RAS blockade or LCZ696
6.
History of hypersensitivity to LCZ696 or its components


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Amended Clinical Trial Protocol (Version 02 Clean)                                   Protocol No. CLCZ696D2302
7.
Patients with a known history of angioedema
8.
Walk distance primarily limited by non-cardiac comorbid 
conditions at Visit 1
9.
Probable alternative diagnoses that in the opinion of the 
investigator could account for the patient’s HF symptoms 
(ie dyspnea, fatigue) such as significant pulmonary disease 
(including primary pulmonary HTN), anemia or obesity. 
Specifically, patients with the following are excluded:
a.
severe pulmonary disease including chronic obstructive 
pulmonary disease (COPD) (ie requiring home oxygen, 
chronic nebulizer therapy, chronic oral steroid therapy or 
hospitalized for pulmonary decompensation within 12 
months) or
b.
hemoglobin (Hgb) < 10 g/dL males and < 9.5 g/dL females
or
c.
body mass index (BMI) > 40 kg/m2
10. Patients with any of the following:
a.
systolic blood pressure (SBP) ≥180 mmHg at Visit 1, or
b.
SBP > 150 mmHg and < 180 mmHg at Visit 1 unless the 
patient is receiving 3 or more antihypertensive drugs. 
Antihypertensive drugs include, but are not limited to, a 
thiazide or other diuretic, MRA, ACEi, ARB, beta blocker 
and calcium channel blocker (CCB), or
c.
SBP < 110 mmHg or symptomatic hypotension at Visit 1
11. Patients with HbA1c > 7.5% not treated for diabetes
12. Patients with history of any dilated cardiomyopathy, including 
peripartum cardiomyopathy, chemotherapy induced 
cardiomyopathy, or viral myocarditis
13. Evidence of right sided HF in the absence of left-sided structural 
heart disease
14. Known pericardial constriction, genetic hypertrophic 
cardiomyopathy, or infiltrative cardiomyopathy
15. Clinically significant congenital heart disease that could be the 
cause of the patient’s symptoms and signs of HF
16. Presence of hemodynamically significant valvular heart disease 
in the opinion of the investigator
17. Stroke, transient ischemic attack, carotid surgery or carotid 
angioplasty within the 3 months prior to Visit 1
18. Coronary or carotid artery disease or valvular heart disease 
likely to require surgical or percutaneous intervention during the 
trial
19. Life-threatening or uncontrolled arrhythmia, including 
symptomatic or sustained ventricular tachycardia and atrial 
fibrillation or flutter with a resting ventricular rate > 110 beats per 
minute (bpm)
20. Patients with a cardiac resynchronization therapy (CRT) device
21. Patients with prior major organ transplant or intent to transplant 
(ie on transplant list)
22. Any surgical or medical condition, which in the opinion of the 
investigator, may place the patient at higher risk from his/her 


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participation in the study, or is likely to prevent the patient from 
complying with the requirements of the study or completing the 
study
23. Evidence of hepatic disease as determined by any one of the 
following: SGOT (AST) or SGPT (ALT) values exceeding 3 × the 
upper limit of normal (ULN), bilirubin > 1.5 mg/dl at Visit 1
24. Patients with eGFR < 30 mL/min/1.73 m2 as calculated by the 
Modification in Diet in Renal Disease (MDRD) formula at Visit 1
25. Patients with serum potassium > 5.2 mmol/L (or equivalent 
plasma potassium value) (mEq/L) at Visit 1
26. History or presence of any other disease with a life expectancy 
of < 3 years
27. History of malignancy of any organ system (other than localized 
basal or squamous cell carcinoma of the skin or localized 
prostate cancer), treated or untreated, within the past 1 year, 
regardless of whether there is evidence of local recurrence or 
metastases; as well as, patients with any planned treatment for 
malignancy
28. 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 human 
chorionic gonadotropin (hCG) laboratory test
Study treatment
LCZ696
50 mg bid (dose level 1), 100 mg bid (dose level 2), 200 mg bid (dose 
level 3)
Enalapril
2.5 mg bid (dose level 1), 5 mg bid (dose level 2), 10 mg bid (dose level 3)
Valsartan
40 mg bid (dose level 1), 80 mg bid (dose level 2), 160 mg bid (dose level 3)
Efficacy assessments

NT-proBNP

6MWT

KCCQ

NYHA functional classification

SF-36
Key safety 
assessments

Adverse event monitoring

Physical examinations

Laboratory values (including monitoring for hyperkalemia, renal 
dysfunction)

ECG changes

Angioedema surveillance
Data analysis
The following primary null hypotheses will be included in the testing 
strategy.

H1: LCZ696 is no better than the comparator in change from baseline 
in log(NT-proBNP) at Week 12 in the overall study population

H2: LCZ696 is no better than the comparator in change from baseline 
in 6MWD at Week 24 in patients with baseline six-minute walk 
distance (B6MWD) ranging from 100 meters to 450 meters.


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The following secondary null hypotheses will be included in the testing 
strategy.

H3: LCZ696 is no better than the comparator in change from baseline 
in KCCQ clinical summary score (CSS) at Week 24 in the overall 
study population.

H4: LCZ696 is no better than the comparator in NYHA change from 
baseline at Week 24 in the overall study population.
Each null hypothesis is tested against the one-sided alternative that 
LCZ696 is better than the comparator in the corresponding variable.
In order to control the family-wise type-I error rate at the one-sided 0.025 
significance level, a sequentially rejective multiple testing procedure 
based on the graphical presentation (Bretz et al 2009) will be employed, 
whereby the testing procedure is graphically illustrated in Figure 9-1.
Based on the above testing procedure, if applicable, H1, H2 and H3 will be 
tested based on the corresponding MMRM models (Section 9.4.2, 
Section 9.5.1.1), and H4 will be tested based on the longitudinal 
proportional cumulative odds model (Section 9.5.1.3).
If statistical significance had been established in the mean difference in 
change from baseline to Week 24 for KCCQ CSS, the following 
responders will be analyzed accordingly, based on the longitudinal binary 
logistic regression models (Section 9.5.1.1), to further illustrate the 
clinical relevance of the observed differences in terms of proportion of 
responders.

KCCQ CSS improvement (defined by at least 5 points improvement);

KCCQ CSS deterioration (defined by at least 5 points deterioration);
No multiplicity adjustment will be done for these supportive responder 
analyses (i.e., the tests for the responder analyses will be performed at 
nominal level of one-sided 0.025).
Key words
Heart failure with preserved ejection fraction, exercise capacity, symptoms, 
NT-proBNP, 6MWD, 6MWT, KCCQ, NYHA, SF-36


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Amendment 2
Amendment rationale
The completed study CLCZ696B2314 (PARADIGM-HF) targeted patients with HF and 
reduced ejection fraction (EF ≤40%). Two ongoing studies (PARAGON and PARALLAX), 
and one completed phase 2 study (PARAMOUNT) in patients with HF and preserved ejection 
fraction include patients with EF ≥45%. Therefore, this amendment will expand the EF 
inclusion criteria from current ≥45% to >40% in order to ensure that the LCZ696 clinical 
development program will cover the full EF spectrum.
Due to the increasing importance of generating exercise capacity data in the HFpEF population, 
this amendment elevates change in six-minute walk distance (6MWD) to a primary endpoint.
The primary analysis was selected to be performed in a sub-set of patients with baseline six-
minute walk distance (B6MWD) ranging from 100 meters to 450 meters. Similar criteria was 
used in other HF studies (Abraham et al 2002, Abraham et al 2015, Redfield et al 2015 and 
Palau et al 2016 ).
The amendment also includes a strategy for the multiplicity testing of the primary and secondary 
efficacy endpoints, as agreed with major Health Authorities.
An additional 300 patients will be enrolled to ensure that patients with LVEF >40% are 
represented in CLCZ696D2302 study population without jeopardizing or compromising any 
key study objective or assessment, which have previously been agreed upon with key external 
stakeholders.
Changes to the protocol
The main changes in this amendment are:
1. To expand the EF inclusion criteria from the current ≥45% to > 40% 
2. To increase sample size from current 2,200 to 2,500 patients.
3. To elevate change in 6MWD as a primary endpoint in a subset of patients and remove it as 
a secondary endpoint
4. To include a testing strategy of the primary and secondary efficacy variables in the 
multiple testing procedure to control the family-wise Type-I error rate.
5. To provide clarifications, both on the patient profile and the study design; as well as, 
making editorial changes.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities. In addition, if the changes herein affect 
the Informed Consent, sites are required to update and submit for approval of a revised 
Informed Consent that takes into account the changes described in this amended protocol.


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Amendment 1 
Amendment rationale 
The purpose of this amendment is to correct a typographic error in the original protocol 
(version 00). In the original protocol, the eGFR exclusion criteria appeared as eGFR < 15 
ml/min/1.73m2. The correct eGFR exclusion criteria for the study is eGFR < 30 ml/min/1.73m2. 
This has been corrected in this version of the protocol. In addition, minor clarifications have 
been added to List of abbreviations, Figure 3-1, Table 3-3 and the footnotes of Table 6-1.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
This version of the protocol will be used for submission to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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1
Introduction
1.1
Background
Heart failure (HF) is a major public health problem associated with a high mortality rate, 
frequent hospitalizations, and poor quality of life (QoL). Despite existing treatment options, HF 
remains a progressive syndrome with a high mortality rate, and an illness with an unmet need 
for new therapies to improve health outcomes (McMurray et al 2012).
Heart failure has been shown to occur with either reduced systolic function or preserved systolic 
function. HF with normal ejection fraction (EF) has been designated HF with preserved ejection 
fraction (HFpEF). HFpEF accounts for approximately half of HF cases, and is associated with 
substantial morbidity, mortality and deteriorated QoL (Lam et al 2011). Moreover, the 
prevalence of HFpEF, as well as, its relative prevalence compared with HF with reduced 
ejection fraction (HFrEF), has been increasing in recent years (Owan et al 2006, Borlaug and 
Paulus 2011). Compared with HFrEF, patients with HFpEF are older, predominantly female, 
more likely to have hypertension (HTN) and atrial fibrillation (AF), and less likely to have 
coronary artery disease (CAD) (Lenzen et al 2004).
Mechanisms implicated in HFpEF include abnormal diastolic function with resultant increase 
in ventricular filling pressures, increased vascular stiffness, and abnormal systolic function 
despite preserved EF (Tan et al 2009, Tartière-Kesri et al 2012). Recently, these individuals 
have also been shown to have an impaired natriuretic and renal endocrine response to acute 
volume expansion early in the development of this syndrome (McKie et al 2011).
Unlike HFrEF, there is no proven pharmacologic therapy for patients with HFpEF (McMurray 
et al 2012). All four major outcomes trials (PEP-CHF, perindopril; CHARM-Preserved, 
candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone) have failed to convincingly 
show a clinical benefit in HFpEF (Yusuf et al 2003, Cleland et al 2006, Massie et al 2008, Pitt 
et al 2014). Since no treatment has yet been shown convincingly to reduce morbidity or 
mortality in patients with HFpEF, the current focus is to alleviate symptoms and improve well-
being. This has been reiterated in the latest European Society of Cardiology (ESC) guidelines 
(Ponikowski et al 2016). Consequently, guidelines focus on treating symptoms with diuretics 
and treating comorbid conditions, such as diabetes mellitus (DM), HTN, renal insufficiency, 
AF and CAD, which are common in HFpEF patients (Hunt et al 2005, McMurray et al 2012).
LCZ696 is a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI). Neprilysin (NEP)
degrades biologically active natriuretic peptides (NPs), including atrial natriuretic peptide 
(ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). LCZ696, 
through its dual mode of action potentiates natriuretic peptides (NPs) via NEP inhibition while 
inhibiting the renin angiotensin system (RAS) via angiotensin type 1 (AT1) receptor blockade; 
both mechanisms are considered to act in a complementary and additive manner to improve 
survival in patients with chronic heart failure. Consistent with the theorized mechanism of 
action, LCZ696 was shown to be superior to enalapril in reducing cardiovascular deaths and 
hospitalization in patients with chronic heart failure with reduced ejection fraction in the 
completed PARADIGM-HF trial. In addition, as compared with enalapril, LCZ696 
significantly decreased the symptoms and physical limitations of heart failure assessed by 
Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS), and 


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reduced total HF hospitalization, all cause hospitalization and emergency room (ER) visit. 
LCZ696 is approved globally including the United States (US) and European Union (EU) for 
the treatment of HFrEF with the trade name ENTRESTO.
The mechanism of action of LCZ696 also suggests that LCZ696 may impact the suspected 
pathophysiology of HFpEF, in which it is believed that excessive fibrosis and myocyte 
hypertrophy lead to abnormal left ventricular diastolic filling, impaired diastolic distensibility 
and/or increased vascular stiffness, with consequent elevated cardiac filling pressures (Krum 
and Abraham 2009). It was recently reported that patients with HFpEF have lower levels of 
myocardial cyclic guanosine monophosphate (cGMP) concentration (and lower protein kinase 
G activity) compared with patients with HFrEF or patients with aortic stenosis (van Heerebeek 
et al 2012). Therefore, enhancing NP action seems a reasonable potential therapeutic option. 
By augmenting the active NPs, neprilysin inhibition increases the generation of cGMP, thereby, 
potentially, enhancing myocardial relaxation and reducing hypertrophy. Natriuretic peptides 
also stimulate natriuresis, and vasodilation, and may have additional antifibrotic and 
antisympathetic effects (Potter et al 2006, Gardner et al 2007).
PARAMOUNT-HF (CLCZ696B2214) was a recently completed, phase II proof of concept 
(therapeutic validation) trial in HFpEF comparing LCZ696 with valsartan. It consisted of a 
12 week core study period and a 24 week extension period (Solomon et al 2012). The study 
demonstrated a 23% greater reduction in NT-proBNP (p = 0.005) at 12 weeks (primary endpoint) 
for LCZ696 compared with valsartan. In addition, the study showed significant improvements 
in New York Heart Association (NYHA) classification along with greater reductions in all 
echocardiographic measures of left atrial (LA) size in the LCZ696 group compared with the 
valsartan group at 36 weeks. LCZ696 is currently being investigated in a phase III clinical 
outcomes study (PARAGON-HF) to confirm its efficacy in HF patients with preserved EF (left 
ventricular ejection fraction [LVEF] ≥45%). No therapy to date has convincingly been shown 
to reduce morbidity and mortality (Yusuf et al 2003, Cleland et al 2006, Massie et al 2008).
Since HFpEF patients are often elderly and highly symptomatic, and have a poor quality of life, 
a key goal of therapy is to alleviate symptoms (Ponikowski et al 2016). No therapy other than 
diuretics has been shown to improve symptoms in this population. This study will evaluate the 
effect of LCZ696 on NT-proBNP, exercise capacity and symptoms in a large population of 
HFpEF patients. LCZ696 will be compared to physician individualized therapy for 
comorbidities and allow patients in the comparator arm to continue on an angiotensin 
converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), based upon their 
prior renin angiotensin system inhibitors (RASi) therapy. This study in approximately 2500
patients will complement the PARAGON-HF outcomes study and represent the largest HF 
symptoms and exercise data set in HFpEF patients with EF > 40% and help further our 
understanding of what limits patients with this disease.
1.2
Purpose
The purpose of this study is to demonstrate superiority of LCZ696 over individualized medical 
therapy for comorbidities in reducing NT-proBNP and improving exercise capacity, symptoms
and QoL in patients with HFpEF.


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2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To demonstrate that LCZ696 is superior 
to individualized medical therapy for 
comorbidities in reducing NT-proBNP 
from baseline after 12 weeks of 
treatment 

To demonstrate that LCZ696 is superior 
to individualized medical therapy for 
comorbidities in improving exercise 
capacity as assessed by the six-minute 
walk test (6MWT) at Week 24 in a 
subset of patients
Endpoint(s) for primary objective(s)

Change from baseline in NT-proBNP
(in log scale) at Week 12

Change from baseline in six-minute 
walk distance (6MWD) at Week 24
Secondary Objective(s)

To compare LCZ696 to individualized 
medical therapy for comorbidities on 
mean change of KCCQ clinical 
summary score (CSS) at Week 24

To compare LCZ696 to individualized 
medical therapy for comorbidities on 
proportion of patients with ≥5-points 
change in KCCQ CSS at Week 24 
(separate analyses for ≥5-points
improvement and ≥5-points 
deterioration)

To compare LCZ696 to individualized 
medical therapy for comorbidities in 
improving NYHA functional class at 
Week 24

To compare LCZ696 to individualized 
medical therapy for comorbidities in 
improving symptoms as assessed by The 
Short Form (36) Health Survey (SF-36)
physical component summary (PCS) 
score at Week 24 
Endpoint(s) for secondary objective(s)

Mean change from baseline in KCCQ 
CSS at Week 24

Proportion of patients with ≥5-points 
deterioration in KCCQ CSS at Week 24

Proportion of patients with ≥5-points 
improvement in KCCQ CSS at Week 
24

Change from baseline in NYHA 
functional class at Week 24

Change from baseline in SF-36 PCS
score at Week 24
Exploratory Objective(s)

To compare LCZ696 to individualized 
medical therapy for comorbidities in 
reducing NT-proBNP at Week 24
Endpoint(s) for exploratory objective(s)

Change from baseline in NT-proBNP
(in log scale) at Week 24


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Objective(s)
Endpoint(s)

To explore the relative effect of LCZ696 
vs individualized medical therapy for 
comorbidities on renal function as 
assessed by eGFR at Week 24

To compare LCZ696 to individualized 
medical therapy for comorbidities on 
mean change of KCCQ overall summary 
score (OSS) at Week 24

To compare LCZ696 to individualized 
medical therapy for comorbidities on 
proportion of patients with ≥5 points 
change in KCCQ OSS at Week 24 
(separate analyses for ≥5-points
improvement and ≥5-points 
deterioration)

To evaluate safety of LCZ696 vs
individualized medical therapy for 
comorbidities

Rate of change (slope) in eGFR from 
baseline

Mean change from baseline in KCCQ 
OSS at Week 24

Proportion of patients with ≥5-points 
deterioration in KCCQ OSS at Week 24

Proportion of patients with ≥5-points 
improvement in KCCQ OSS at Week 
24

Frequency of adverse events (AEs), 
serious adverse events (SAEs), and 
laboratory abnormalities
3
Investigational plan
3.1
Study design
This study is a 24-week, randomized, double-blind, multi-center, parallel group, active 
controlled study to evaluate LCZ696 compared to individualized medical therapy on
NT-proBNP, exercise capacity, symptoms and QoL in patients with HF and preserved left
ventricular ejection fraction (LVEF > 40%) (Figure 3-1). Patients will be initially stratified into 
one of three strata according to prior treatment for comorbidities: ACEi, ARB or no RASi. 
Patients will then be randomized 1:1 to receive either LCZ or comparator. Patients in the ACEi 
strata will be randomized to receive either LCZ696 or enalapril. Patients in the ARB strata will 
be randomized to receive either LCZ696 or valsartan, and patients in the no RASi strata will be 
randomized to receive either LCZ696 or placebo. Patients in the ACEi and ARB strata must 
have a history of HTN. There will be no designated proportion of patients in each strata, the
strata will populate based upon the patient’s prior treatment regimen.
A screening epoch of up to 2 weeks will be used to assess eligibility. Patients on appropriate 
therapy for comorbidities will be eligible for the study. Patients will be required to have been 
on stable doses of baseline medications for at least four weeks prior to randomization. After 
randomization, patients will begin a 1 to 4 week study drug up-titration epoch followed by a 20
to 23 week maintenance epoch (Figure 3-1). Visits to assess safety and efficacy are scheduled 
at 4 to 6 week intervals during the maintenance epoch. The assessment to address the primary 
objective of reduction in NT-proBNP will be performed using data up to Week 12, and the 
primary objective of change in 6MWD and all secondary objectives will be performed using 
data up to Week 24. No interim analysis (IA) is planned.


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Figure 3-1
Study design
ACEi = angiotensin converting enzyme inhibitor
ARB = angiotensin receptor blocker
RASi = renin angiotensin system inhibitors
* Patients in the ACEi and ARB strata must have a history of HTN
Screening epoch
At screening (Visit 1), patients will sign the informed consent and be assessed for eligibility for 
study participation through review of study inclusion/exclusion criteria. Patients enrolled in the 
study will continue their baseline medication regimen and enter a screening epoch of up to 2 
weeks in order to allow adequate time for the completion of all qualifying screening and 
eligibility evaluations.
Screening NT-proBNP, complete lab evaluations, and pregnancy testing will be assessed by 
sending samples to the central lab. It may take up to 72 hours to obtain the results of the clinical 
laboratory assessments to evaluate the patient’s eligibility for the study.
Qualifying echocardiogram (echo) measurements will be based on locally obtained echoes 
performed within 6 months of Visit 1. If a qualifying echo within 6 months of Visit 1 is not 
available, the patient must enter the study based on a qualifying echo performed during the 
screening epoch before any study drug is dispensed to the patient. No imaging method other 
than echocardiography will be accepted for inclusion into the study.


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KCCQ questionnaire will be administered at screening to determine eligibility for study (CSS 
< 75). A 6MWT will be performed at screening in all patients to familiarize patients with the 
assessment.
A patient who enters screening but is determined not to be eligible will be considered a screen 
failure. The investigator may consider re-screening the patient at a later time if he/she believes 
that the patient’s condition has changed and they may potentially be eligible. A patient may be 
re-screened once. A minimum of 2 weeks must elapse between screen failure and re-screening.
Randomized treatment epoch
At the randomization visit (Visit 101), all patients who fulfill the inclusion/exclusion criteria 
will be stratified based upon prior therapy as described above. Subsequent to stratification, 
patients will be randomized into either the LCZ696 or the comparator treatment group at a 1:1 
ratio. Table 3-1 categorizes low and high total daily doses for commonly used ACEis and ARBs.
Study drug dose levels are outlined in Table 3-2 and study drug up-titration outlined in 
Figure 3-2. The goal of treatment is to ensure that each patient receives the maximal tolerated 
dose of study medication.
ACEis are required to be discontinued 36 hours prior to the randomization visit (Visit 101) to 
minimize potential risk of angioedema, and ARBs are required to be discontinued at the 
randomization visit. With the exception of ACEi, ARB or renin inhibitor, patients will continue 
on their prior medication for the treatment of comorbidities. All patients must be on stable doses 
of appropriate therapy for comorbidities for at least 4 weeks prior to enrollment.
For patients who are not currently treated with ACEi/ARB, the starting dose should be dose 
level 1 for LCZ696. Those patients previously treated with low dose of ACEi/ARB (Table 3-1)
should be initiated at dose level 1 for LCZ696, enalapril and valsartan. For patients previously 
treated with high dose RASi, the starting dose is dose level 2 for LCZ696, enalapril and 
valsartan. The target dose for LCZ696 is 200 mg bid, for enalapril is 10 mg bid and for valsartan 
160 mg bid (dose level 3). However, maximal doses for study medication will be determined 
by the investigator based upon the patient’s clinical status. It is recommended that patients 
remain at each dose level during up-titration for 1 to 2 weeks such that patients initiated at dose 
level 1 reach target dose in 2 to 4 weeks and those patients initiated at dose level 2 reach target 
dose in 1 to 2 weeks. In certain circumstances, longer up-titration periods may be required as 
deemed necessary by the investigator. Patients must meet the safety criteria (Table 3-3) before 
initiation of study drug and prior to any up-titration.
Patients will remain at the target dose (dose level 3) for the remainder of the study. If patients 
cannot tolerate the target dose of study medication (dose level 3), down titration to a lower dose 
is allowed (see Section 5.5.5). Patients should be re-challenged to the target dose of study 
medication when their condition permits up-titration based on their systolic blood pressure 
(SBP), eGFR, potassium values, and at the investigator’s discretion. However, patients can 
remain at low doses (level 1 or 2), based on their tolerability and clinical judgment of the 
investigator.
The duration of the double-blind treatment period is 24 weeks.


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Figure 3-2
Study drug up-titration
ACEi = angiotensin converting enzyme inhibitor
ARB = angiotensin receptor blocker
RASi = renin angiotensin system inhibitors
TD = study treatment discontinuation
PSD = premature study discontinuation
Table 3-1
Definition of low and high total daily doses for commonly used ACEis 
and ARBs
Study medication
Low RASi stratum
High RASi stratum
ACEis
Enalapril 
≤ 10 mg
> 10 mg
Benazepril
≤ 20 mg
> 20 mg
Captopril
≤ 100 mg
> 100 mg
Cilazapril
≤ 2.5 mg
> 2.5 mg
Delapril
≤ 30 mg
> 30 mg
Fosinopril
≤ 20 mg
> 20 mg
Imidapril
≤ 10 mg 
> 10 mg
Lisinopril
≤ 10 mg
> 10 mg
Moexipril
≤ 7.5 mg
> 7.5 mg
Perindopril
≤ 4 mg
> 4 mg


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Study medication
Low RASi stratum
High RASi stratum
Quinapril
≤ 20 mg
> 20 mg
Ramipril
≤ 5 mg
> 5 mg
Spirapril
≤ 6 mg
> 6 mg
Temocapril
≤ 2 mg
> 2 mg
Trandolapril
≤ 2 mg
> 2 mg
Zofenopril
≤ 30 mg
> 30 mg
ARBs
Azilsartan
≤ 80 mg
> 80 mg
Candesartan
≤ 16 mg
> 16 mg
Eprosartan
≤ 400 mg
> 400 mg
Irbesartan
≤ 150 mg
> 150 mg
Losartan
≤ 50 mg
> 50 mg
Olmesartan
≤ 10 mg
> 10 mg
Telmisartan
≤ 40 mg
> 40 mg
Valsartan
≤ 160 mg
> 160 mg
Table 3-2
Study drug dose levels during double-blind treatment epoch
Dose level
LCZ696
Enalapril
Valsartan
1
50 mg bid
2.5 mg bid
40 mg bid
2
100 mg bid
5 mg bid 
80 mg bid
3
200 mg bid
10 mg bid 
160 mg bid
Table 3-3
Safety monitoring criteria requirements prior to study drug initiation 
and during up-titration
Parameter
Study drug initiation 
(Visit 101)
Study drug up-titration (Any 
visit with up-titration or re-
initiation)
Serum potassium
(or equivalent plasma potassium 
value)
*K ≤5.2 mmol/L (mEq/L) 
K ≤5.4 mmol/L (mEq/L)
Kidney function
*eGFR ≥30 mL/min/1.73m2
eGFR ≥25 mL/min/1.73m2
eGFR reduction < 35% 
compared to Visit 101
Blood pressure
SBP ≥110 mmHg 
No symptomatic hypotension as 
determined by the investigator 
and SBP ≥100 mmHg


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Parameter
Study drug initiation 
(Visit 101)
Study drug up-titration (Any 
visit with up-titration or re-
initiation)
AEs or conditions
No conditions that preclude 
continuation according to the 
investigator’s judgment
No postural symptoms or any 
AEs that preclude continuation 
according to the investigator’s 
judgment
*Laboratory values from the screening visit (Visit 1) may be used for study drug initiation
3.2
Rationale for study design
3.2.1
Rationale for target study population
The study population will consist of patients ≥45 years of age with a LVEF > 40% and evidence 
of structural heart disease (left atrial enlargement [LAE] and/or left ventricular hypertrophy 
[LVH]), current symptoms of HF (NYHA class II-IV), use of diuretics within the prior 30 days, 
NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or > 600
pg/mL for patients with AF, and KCCQ CSS < 75. Eligible patients will be on appropriate 
medical therapy for comorbidities in the opinion of the investigator.
Structural heart disease (LAE and LVH) is a key diagnostic criterion for HFpEF in the most 
recent guidelines (Ponikowski et al 2016). Left atrial (LA) size (an integrative measure of left 
ventricular diastolic pressure) is independently associated with an increased risk of morbidity 
and mortality (Zile et al 2011). Including echocardiographic evidence of structural heart disease 
consistent with HFpEF will help facilitate homogeneity of the study population. Both TOPCAT 
(Pitt et al 2014) and I-Preserve (Massie et al 2008) used an EF lower boundary threshold of 
45%. This is also the threshold used in PARAGON-HF, an ongoing large outcomes study (4600 
patients) comparing valsartan 160 mg bid to LCZ696 200 mg bid in HFpEF. Elevated NT-
proBNP levels aid in the diagnosis of HFpEF. Current guidelines include NT-proBNP > 125 
pg/mL as one of the criteria to be used for the diagnosis of HFpEF (Ponikowski et al 2016). In 
this symptoms study, we have chosen a threshold for NT-proBNP of 220 pg/mL which is 
consistent with prior guidelines (Paulus et al 2007) to increase the likelihood that patients’
symptoms at baseline are related to HF rather than their comorbid conditions. NT-proBNP was
the strongest independent predictor of mortality and subsequent HF hospitalizations in the I-
PRESERVE study (Solomon et al 2007, Komajda et al 2011) and was used as an inclusion 
criterion in TOPCAT. Patients with baseline AF are required to have higher NT-proBNP levels, 
as AF is strongly associated with higher levels of NT-proBNP (McKelvie et al 2010). The 
number of patients with EF < 45% will be targeted to approximately 300 patients and the 
number of AF patients will be limited to approximately one-third in the current study (based on 
the Visit 1 electrocardiogram [ECG]) so that the proportion of patients with EF < 45% and AF 
in the study will be representative of the HFpEF population (Massie et al 2008, Steinberg et al 
2012, West et al 2011, Tsuji et al 2017, Lund et al 2018).
3.2.2
Rationale for the primary endpoints
The study has two primary endpoints: NT-proBNP and 6MWD.
NT-proBNP: One of the primary endpoints of this study is the change from baseline in NT-
proBNP (in log scale) at Week 12. In a prior study in over 300 HFpEF patients, LCZ696 showed 


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a significantly greater reduction in NT-proBNP at Week 12 as compared to valsartan (Solomon 
et al 2012). Aggregate clinical data have demonstrated that NT-proBNP not only provides value 
for the diagnosis, and helps the management of patients with HF, but also predicts clinical 
outcome (mortality and morbidity). Studies suggest that NT-proBNP levels strongly correlate 
with adverse clinical outcomes in HF patients including death and hospital admission for 
chronic HF (Hartmann et al 2004, Hunt et al 2005, Masson et al 2008, McMurray et al 2014).
Across all stages of HF, elevated BNP/NT-proBNP concentration are the most robust 
prognostic predictor of mortality and cardiovascular events compared to other traditional 
outcome predictors (peak oxygen consumption, blood urea nitrogen (BUN), SBP and 
pulmonary capillary wedge pressure) with increasing BNP/NT-proBNP concentration 
predicting worse prognosis in a linear fashion (Sachdeva et al 2010).
In this short term study in patients with HF, change of NT-proBNP is considered an appropriate 
surrogate endpoint for clinical outcomes of HF. We will use this data to determine the treatment 
effect of LCZ696 compared to individualized medical therapy for comorbidities on the risk and 
clinical status of the population. In addition, the NT-proBNP data from this study can be used 
as a bridge to the PARAGON-HF study where NT-proBNP is also measured.
Six-minute walk distance (6MWD): The other primary endpoint is change from baseline in 
6MWD which is derived from a simple, inexpensive, and reproducible test (6MWT) for the 
assessment of exercise capacity. It evaluates the global and integrated responses of all the 
systems involved during exercise including the pulmonary and cardiovascular systems. The 
6MWD correlates well with results using formal treadmill exercise testing and has been shown 
to predict outcomes in patients with HF, particularly, in patients with more advanced HF 
(Pollentier et al 2010).
Many different studies have investigated whether the distance walked during the walking test 
is a prognostic indicator in heart failure patients. The 6MWD correlates with changes in 
symptoms after HF therapy, suggesting that it may be useful as a measure of symptom benefit 
(Olsson et al 2005). Lower levels of exercise capacity (a distance < 300 meters during 6MWT)
have proven to be predictive of mortality (total or cardiovascular) and morbidity 
(hospitalization for worsening HF) both in patients with mild to moderate (Bittner et al 1993, 
Roul et al 1998, Zugck et al 2000) and advanced HF (Cahalin et al 1996, Shah et al 2001). In 
the SOLVD study, a 6MWD ≥ 450 meters indicated low mortality risk (Bittner et al 1993). 
Furthermore, it has been demonstrated that a 6MWD < 450 m constitutes impaired exercise 
capacity (Abraham et al 2015). More recently, 6MWT has been used in prior studies to assess 
the effect of therapeutic interventions in HFpEF patients (Kamp et al 2009, Kitzman et al 2010, 
Redfield et al 2015). 
The primary analysis was selected to be performed in a sub-set of patients with baseline six-
minute walk distance (B6MWD) ranging from 100 meters to 450 meters. The selected cut-off 
was chosen a) by expert opinion b) since < 450 meters indicates exercise impairment and c) 
because previous studies have used similar cutoffs (Abraham et al 2002, Abraham et al 2015, 
Redfield et al 2015 and Palau et al 2016).


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3.2.3
Rationale for the secondary endpoints selection
KCCQ: KCCQ is a valid, reliable and responsive health status measure for patients with heart 
failure and may serve as a clinically meaningful outcome in cardiovascular research, patient 
management and quality assessment (Green et al 2000). The KCCQ instrument includes a 
clinical summary score (CSS) that encompasses the physical limitation score and the total 
symptom score. The CSS is a combined score based upon the clinical symptoms and physical 
function domains of the questionnaire. CSS specifically, has been shown both to be predictive 
of outcomes and has been used to measure response to therapy in patients with HFrEF (Ekman 
et al 2011). Further, KCCQ has been shown to be a valid and reliable tool to measure health 
status and predict outcomes in patients with HFpEF (Joseph et al 2013).
Data from HF-ACTION suggest that a 5-points change in the KCCQ overall score corresponds 
to clinically significant changes in measures of exercise capacity (peak oxygen consumption 
and 6MWT) (Flynn et al 2012). Importantly, analysis of KCCQ scores in 1, 358 patients 
enrolled in the EPHESUS study showed a linear correlation with both all-cause mortality and 
the combined endpoint of cardiovascular mortality and hospitalizations, for each 5-points
decrease in KCCQ CSS (Kosiborod et al 2007). The proposed study will evaluate not only mean 
change from the baseline but also proportion of patients with ≥5-points change including both 
improvement and deterioration at the end of the study.
NYHA: NYHA classification is an assessment of a patient’s functional capacity and 
symptomatic status of HF; it is a well-established and internationally recognized prognostic 
indicator of outcomes. NYHA classification reflects the limitations that the patient with HF has 
to cope with on a daily basis because of his/her symptoms. Further, NYHA is used in daily 
clinical practice and clinical studies to record the patient’s current functional status and provide 
important information on disease progression in HF patients. In the recently issued draft 
guideline on drug development for the treatment of HF, the European Medicines Agency (EMA)
recognized the importance of the NYHA classification in the assessment of symptoms in 
patients with HF, and emphasized that NYHA class as an established standard that should be 
included to allow comparisons across trials (European Medicines Agency, 2016).
SF-36: SF-36 is a generic health-related quality of life (HRQOL) instrument which comprises 
of 36 questions across 8 domains: 1) limitations in physical activities because of health 
problems; 2) limitations in social activities because of physical or emotional problems; 
3) limitations in usual role activities because of physical health problems; 4) bodily pain; 
5) general mental health (psychological distress and well-being); 6) limitations in usual role 
activities because of emotional problems; 7) vitality (energy and fatigue); 8) general health 
perceptions (Ware and Sherbourne 1992). The SF-36 is considered to be a valid, reliable, 
concise generic measure of state of health and has demonstrated to detect clinical treatment 
benefits across medical conditions including chronic disorders such as HF (Ware and Gandek 
1998, Frendl and Ware 2014, Nolte et al 2015, Karlström 2016).


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3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
LCZ696 200 mg twice daily is the dose that has been used across all HF studies in the LCZ696 
program. Biomarker analysis and modeling indicate that this dose of LCZ696 delivers 
approximately 90% of its maximal NEP inhibition. In addition, LCZ696 200 mg delivers similar 
valsartan exposure (assessed by area under curve [AUC]) as Diovan® (valsartan) 160 mg twice 
daily. Twice daily dosing schedule is considered necessary for sustained NEP inhibition over a 
24-hour period and it is anticipated to reduce the incidence of hypotension in HF patients. The 
primary endpoint of change in NT-proBNP (in log scale) will be assessed at Week 12, consistent 
with the effect of LCZ696 seen in HFpEF in the PARAMOUNT-HF study (Solomon et al 2012).
The primary endpoint of change in 6MWD and all secondary endpoints (including symptoms, 
and QoL) will be evaluated at Week 24, which has been shown to be sufficient time to 
demonstrate changes in HF status using these measures (Green et al 2000).
3.4
Rationale for choice of comparator
Presently, there is no evidence-based, guideline-recommended, pharmacologic therapy for 
HFpEF patients. However, there are guideline recommendations for the treatment of the 
comorbidities that are prevalent in HFpEF, such as HTN, DM, and CAD (Ponikowski et al 
2016). ACEi and ARB are commonly used for treatment of comorbidities. Patients will be 
stratified into three strata based upon their prior RASi use (ACEi, ARB or no RASi) and then 
randomized to active therapy with LCZ696 or comparator. In the comparator arm, patients 
previously treated with an ACEi will receive enalapril. Patients previously treated with an ARB 
will receive valsartan. Patients not previously treated with RASi will not receive RASi. Only 
patients with a history of HTN will be included in the ACEi and ARB strata. Background
therapy for comorbidities (eg beta blockers, calcium channel blockers) will be optimized in all 
patients throughout the study; diuretics will be adjusted to manage the symptoms of heart failure 
as needed during the study.
Enalapril is chosen as the angiotensin converting enzyme (ACE) comparator as it is a 
commonly prescribed ACEi in patients with HFpEF for treating prevalent comorbidities. The 
enalapril dose of 10 mg bid (total daily dose of 20 mg) is selected as the comparator target dose 
for this study because it is the recommended maintenance dose for hypertension (Enalapril 
SmPC 2003). Data from the EU HF registry indicates that the median dose of enalapril for HF 
in real world practice is about 10 mg/day with approximately only 46% of the patients achieving 
the target dose of 20 mg/day (Maggioni et al 2010).
Valsartan is chosen as the ARB comparator as it is the ARB component of LCZ696. Valsartan 
is an orally active, potent and specific competitive type 1 angiotensin II receptor (AT1) receptor 
antagonist. The exposure delivered by LCZ696 200 mg bid is similar to valsartan 160 mg bid
(320 mg total daily dose), which is the Food and Drug Administration (FDA) and EMEA 
approved maximal and guideline recommended dose strength for the treatment of HTN. Thus,
the target dose of valsartan chosen for the comparator arm is 160 mg bid. The same dosing 
regimen of valsartan is also used in the PARAGON-HF study.


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3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits
Patients will be instructed not to take any other RAS blockade medications (ACEi, ARB or 
renin inhibitor) except study drug (LCZ696, enalapril, or valsartan) to avoid excess RAS 
blockade and minimize potential risk of angioedema. Washout of prior RAS agents is ensured 
by the discontinuation of prior ACEis at least 36 hours prior to randomization and 
discontinuation of prior ARBs on the day of randomization. If the patient is to be started on 
open-label ACEi during the study, study drug will be stopped ≥36 hours prior to initiating 
ACEi treatment. All patients will continue other individualized medical therapy for 
comorbidities as directed by the investigator. The risk to patients in this trial will be minimized 
by compliance with the eligibility criteria, study procedures, and close clinical monitoring (eg
hypotension).
In women of child-bearing potential, a possible risk of developmental toxicity cannot be 
excluded. Women of child-bearing potential should therefore, use a highly effective method of 
contraception during dosing and for 7 days after stopping of study medication. If there is any 
question that the patient will not reliably comply, they should not be entered in the study. All 
patients in this study will be ≥45 years of age and therefore the risk of pregnancy during the 
trial is minimal.
Clinical trial data in adults demonstrate that LCZ696 has an overall safety profile generally 
comparable to other RASi agents. For patients participating in this study: the risks common to 
LCZ696, enalapril and valsartan include hypotension, hyperkalemia, worsening renal function 
and angioedema. Potential risks of LCZ696 also include hepatotoxicity, effects on bone growth 
and mineralization, and changes in amyloid beta in the central nervous system (CNS).
Participating patients will benefit from careful monitoring and follow-up during the entire study 
duration regardless of whether they are receiving the study medication.
4
Population
The study population will consist of patients ≥45 years of age with a LVEF > 40% and evidence 
of structural heart disease (LAE and/or LVH), current symptoms of HF (NYHA class II-IV), 
use of diuretics within the prior 30 days, NT-proBNP > 220 pg/mL for patients with no AF or >
600 pg/mL for patients with AF, and KCCQ CSS < 75. Eligible patients will be on appropriate 
medical therapy for comorbidities in the opinion of the investigator.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. ≥ 45 years of age, male, or female
3. LVEF > 40% by echocardiography performed within 6 months prior to Visit 1 or during the 
screening epoch


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4. Symptom(s) of HF requiring treatment with diuretics (including loop, or thiazide diuretics, 
or mineralocorticoid antagonist [MRAs]) for at least 30 days prior to Visit 1
5. Current symptom(s) of HF (NYHA class II-IV) at Visit 1
6. Structural heart disease demonstrated by echocardiographic evidence of left atrial 
enlargement (LAE) or left ventricular hypertrophy (LVH) as defined below (any local 
measurement made during the screening epoch or within the 6 months prior to Visit 1):
a. left atrial enlargement defined by at least one of the following: LA width (diameter) 
≥3.8 cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 mL or LA 
volume index ≥29 mL/m2
b. left ventricular hypertrophy defined by septal thickness or posterior wall thickness 
≥1.1 cm
7. Receiving evidence based therapy for relevant comorbidities as determined by the 
individual clinical profile of the patient (eg age and number and type of comorbidities) with 
stable doses for the previous four weeks prior to randomization
8. NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or > 600 
pg/mL for patients with AF on the Visit 1 ECG
9. KCCQ clinical summary score < 75 at Visit 1
10. Patients on ACEi or ARB therapy must have a history of HTN
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Any prior echocardiographic measurement of LVEF ≤40%, under stable conditions
2. Acute coronary syndrome (including myocardial infarction [MI]), cardiac surgery, other 
major cardiovascular (CV) surgery, or urgent percutaneous coronary intervention (PCI) 
within the 3 months prior to Visit 1 or an elective PCI within 30 days prior to Visit 1
3. Any clinical event within the 6 months prior to Visit 1 that could have reduced the LVEF 
(eg MI, coronary artery bypass graft [CABG]), unless an echo measurement was 
performed after the event confirming the LVEF to be > 40%
4. Current (within 30 days from Visit 1) acute decompensated HF requiring augmented therapy 
with diuretics, vasodilators and/or inotropic drugs
5. Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or 
LCZ696
6. History of hypersensitivity to LCZ696 or its components
7. Patients with a known history of angioedema
8. Walk distance primarily limited by non-cardiac comorbid conditions at Visit 1
9. Probable alternative diagnoses that in the opinion of the investigator could account for the 
patient’s HF symptoms (ie dyspnea, fatigue) such as significant pulmonary disease 
(including primary pulmonary HTN), anemia or obesity. Specifically, patients with the 
following are excluded:


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a.
severe pulmonary disease including chronic obstructive pulmonary disease (COPD) 
(ie requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy or 
hospitalized for pulmonary decompensation within 12 months) or
b. hemoglobin (Hgb) < 10 g/dL males and < 9.5 g/dL females or
c.
body mass index (BMI) > 40 kg/m2
10. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives 
of enrollment, whichever is longer
11. Patients with any of the following:
a.
systolic blood pressure (SBP) ≥180 mmHg at Visit 1, or
b. SBP > 150 mmHg and < 180 mmHg at Visit 1 unless the patient is receiving 3 or 
more antihypertensive drugs. Antihypertensive drugs include, but are not limited to, a 
thiazide or other diuretic, MRA, ACEi, ARB, beta blocker and calcium channel 
blocker (CCB), or
c.
SBP < 110 mmHg or symptomatic hypotension at Visit 1
12. Patients with HbA1c > 7.5% not treated for diabetes
13. Patients with history of any dilated cardiomyopathy, including peripartum cardiomyopathy, 
chemotherapy induced cardiomyopathy, or viral myocarditis
14. Evidence of right sided HF in the absence of left-sided structural heart disease
15. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative 
cardiomyopathy
16. Clinically significant congenital heart disease that could be the cause of the patient’s 
symptoms and signs of HF
17. Presence of hemodynamically significant valvular heart disease in the opinion of the 
investigator
18. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3 months 
prior to Visit 1
19. Coronary or carotid artery disease or valvular heart disease likely to require surgical or 
percutaneous intervention during the trial
20. Life-threatening or uncontrolled arrhythmia, including symptomatic or sustained ventricular 
tachycardia and atrial fibrillation or flutter with a resting ventricular rate > 110 beats per 
minute (bpm)
21. Patients with a cardiac resynchronization therapy (CRT) device
22. Patients with prior major organ transplant or intent to transplant (ie on transplant list)
23. Any surgical or medical condition, which in the opinion of the investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the patient 
from complying with the requirements of the study or completing the study
24. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of study drugs, including but not limited to any of the 
following:

any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic 
function/injury within the last 5 years


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25. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or 
SGPT (ALT) values exceeding 3 × the upper limit of normal (ULN), bilirubin > 1.5 mg/dl
at Visit 1
26. Patients with eGFR < 30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal 
Disease (MDRD) formula at Visit 1
27. Presence of known functionally significant bilateral renal artery stenosis
28. Patients with serum potassium > 5.2 mmol/L (or equivalent plasma potassium value) 
(mEq/L) at Visit 1
29. History or presence of any other disease with a life expectancy of < 3 years
30. History of non-compliance to medical regimens and patients who are considered potentially 
unreliable
31. History or evidence of drug or alcohol abuse within the last 12 months
32. Persons directly involved in the execution of this protocol
33. History of malignancy of any organ system (other than localized basal or squamous cell 
carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 1 
year, regardless of whether there is evidence of local recurrence or metastases; as well as, 
patients with any planned treatment for malignancy
34. Patients taking medications prohibited by the protocol (see Section 5.5.8)
35. 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 human 
chorionic gonadotropin (hCG) laboratory test
36. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 7 days after stopping of study medication. Highly effective contraception 
methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (eg calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) 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

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

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception

In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug

In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the informed consent form (ICF)


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
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 (eg 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
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The sponsor will provide the following study drugs:
Randomized treatment period
LCZ696 is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg sacubitril/valsartan, and 
will be subsequently referred to as LCZ696 50 mg, 100 mg, and 200 mg in this study protocol 
for simplicity.
At the randomization visit (Visit 101), all patients who fulfill the inclusion/exclusion criteria 
will be stratified based upon prior therapy as described above. Subsequent to stratification, 
patients will be randomized into either the LCZ696 or the comparator treatment group at a 1:1 
ratio. Table 3-1 categorizes low and high total daily doses for commonly used ACEis and ARBs.
Study drug initiation is dependent on prior RASi dose. Study drug dose levels during up-
titration are outlined in Table 3-2. The goal of treatment is to ensure that each patient receives 
the maximal tolerated dose of study medication up to the target dose of LCZ69 200 mg bid, 
enalapril 10 mg bid and valsartan 160 mg bid (dose level 3). Background therapy for 
comorbidities will be optimized in all patients throughout the study; diuretics will be adjusted 
to manage the symptoms of heart failure as needed during the study.
Patients in the ACEi and ARB strata will receive two study medications and patients in the no 
RASi strata will receive one study medication. The following study drugs will be provided:

LCZ696 50 mg, 100 mg and 200 mg tablets

Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets

Enalapril 2.5 mg, 5 mg and 10 mg tablets

Placebo to match enalapril 2.5 mg, 5 mg, and 10 mg tablets

Valsartan 40 mg, 80mg, 160 mg tablets

Placebo to match valsartan 40 mg, 80 mg, 160 mg tablets
All study medications will be supplied in bottles or blister cards. Sufficient medication will be 
provided for the treatment according to study protocol, including additional medication to allow 
for delayed visits. Medication labels will be in the local language and comply with the legal 


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requirements of the country. They will include storage conditions for the drug and the 
medication number, but no information about the patient.
5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
At the randomization visit (Visit 101), all patients who fulfill the inclusion/exclusion criteria 
will be stratified based upon prior therapy (Figure 3-1). Subsequent to stratification, patients 
will be randomized within one of the three strata to either the LCZ696 or the comparator group
at a 1:1 ratio.

LCZ696

Comparator

Enalapril

Valsartan

No RASi
5.3
Treatment assignment and randomization
At Visit 101, all eligible patients will be stratified via Interactive Response Technology (IRT) 
into one of three strata based upon prior RASi use and subsequently randomized to either 
LCZ696 or comparator (Figure 3-1). In addition, randomization will be stratified by region. The 
investigator or his/her delegate will contact the IRT after confirming that the patient fulfills all 
the inclusion and none of the 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 investigational treatment to be dispensed to the 
patient. The randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
5.4
Treatment blinding
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods:


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
Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone involved in the study with the following exceptions:

The independent unblinded statistician, programmer and data personnel who are 
involved in preparing safety reports for the Data Monitoring Committee (DMC).
These personnel will not be involved in any other trial conduct related activities

The program level DMC members who will review safety data in an unblinded 
manner

The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, labeling, schedule of administration, appearance, taste 
and odor.

A double-dummy design is used for the two RASi strata because the identity of the 
investigational treatment cannot be disguised due to their different forms. A single dummy 
will be used for the no RASi strata.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study.
The appropriate personnel from the site and Novartis will assess whether study drug should be 
permanently discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
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 site number 
assigned by Novartis and a sequential number assigned by the investigator. 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 requested 
identifying information for the patient to register them into the IRT. The site must select the 
CRF book with a matching Subject Number from the electronic data capture (EDC) system to 
enter data.
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening epoch 
Study Disposition eCRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 2 treatment arms (LCZ696 vs comparator)
and a dose level. Investigator staff will identify the study drug package(s) to dispense to the 


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patient by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the package to the patient, 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.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
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 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 additional treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
Novartis will supply the investigators with all study medications required 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. In 
order to adequately blind the study, patients in the ACEi and ARB strata will be required to take 
a total of two tablets: one tablet from the LCZ696/matching placebo pack and one tablet from 
the enalapril/matching placebo or valsartan/matching placebo pack, twice a day for the duration 
of the study. Patients in the no RASi strata will be required to take one tablet from the 
LCZ696/matching placebo pack twice a day for the duration of the study. There will be three 
dose levels for LCZ696, enalapril and valsartan; and three dose levels for each corresponding 
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Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 am) 
and their evening study drug dose at approximately 19:00 (7 pm). The study drugs should be 
taken with water, with or without food. If the patient misses taking any study drug dose, he/she 
should take it as soon as possible, unless it is almost time for the following scheduled dose. In 
this case, the patient should skip the missed dose and return back to his/her regular study drug 
administration schedule.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF. All kits of study treatment assigned 
by the IRT will be recorded/databased in the IRT.
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.
5.5.5
Permitted dose adjustments and interruptions of study treatment
For patients who are unable to tolerate the protocol-specified dosing scheme, dose level
adjustments and interruptions of study treatment are permitted in order to keep the patient on 
study drug. The following guidelines should be followed:

Every attempt should be made to maintain patients at the target study drug dose level 
throughout the trial. If the patient does not tolerate the target study drug dose level, the 
investigator can adjust or stop concomitant background medications for comorbid 
conditions to rectify the situation, before considering to down-titrate to the next lower 
study drug dose level.
Adjustment of study drug dose level
If despite adjustment of concomitant medications per the guidance provided the situation is not 
rectified, the investigator may consider down-titrating study drug dose level. As outlined
previously, patients in the ACEi and ARB strata take two study medications while patients in 
the non RASi strata take one study medication. In the ACEi and ARB strata, both study 
medications must be adjusted simultaneously.
During the randomized treatment epoch, down titration of study drug at any time based on the 
judgment of the investigator will be allowed according to the safety and tolerability criteria 
defined in Appendix 3, Appendix 4, and Appendix 5. If down-titration is necessary, the patient 
should be down titrated to the next lower study drug dose level. If down-titration occurs due to 
an (S)AE (Section 7.1 and 7.2), then the appropriate reporting guidelines must be followed 
(Section 7.2.2). The patient may continue receiving the lower dose level for a recommended 
period of 1 to 4 weeks before being re-challenged at the next higher dose level. For example, a 
patient who encounters tolerability problems at the target study drug dose level (dose level 3),
should receive study drug at dose level 2 for 1 to 4 weeks at the discretion of the investigator. 
Then, he/she should be re-challenged with up-titration back to dose level 3. The maximal dose 
for study medication will be determined by the investigator based upon the patient’s individual 
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If the tolerability issues are not alleviated despite down titration by one dose level, the 
investigator may down titrate further to the next lower study drug dose level for 1 to 4 weeks, 
up to temporary discontinuation of the study drug. Again, once stable, the patient should be re-
challenged with up-titration to the next higher dose level every 1 to 4 weeks in an attempt to 
bring back the patient gradually to the target study drug dose level (dose level 3). The 
investigator may choose the next dose level for down- or up-titration according to his or her 
judgment. As discussed in Section 5.5.4, the IRT system should be contacted to register any 
changes in the patient’s study drug dose level, including in cases of temporary and permanent 
discontinuation of the study drug, and to obtain the medication numbers of the study drug 
supplies required for the new study drug dose level.
In some instances, according to the safety and tolerability criteria and the investigator’s 
judgment, dose level 1 or 2 could be maintained if he/she considers that the patient’s condition 
would not allow any further up titration to the target dose level of study drug (dose level 3). In
this case, it would be acceptable to maintain the patient at dose level 1 or level 2, whichever is 
the higher and tolerated dose level by the patient.
Study drug restart after temporary treatment interruption
Study drug should be reintroduced in those patients who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator.
Once the investigator considers the patient’s condition appropriate for receiving the study drug, 
the investigator should re-start the patient on the study drug at the most appropriate and 
allowable dose level per his/her medical judgment. If tolerated, the patient should be up-titrated 
a dose level every 1 to 4 weeks to the target dose level 3, as per the investigator’s judgment. 
Should the patient not tolerate the re-start study drug dose level, he/she may be down titrated 
again (if appropriate) or temporarily discontinue the study medication again and a new attempt 
to up-titrate or reintroduce the study drug could be considered by the investigator as soon as 
medically justified in his/her judgment.
The use of an open-label ACEi, ARB or a renin inhibitor is prohibited while the patient is taking 
study drug. Should the patient receive open-label RASi or renin inhibitor during the study, study 
drug must be withdrawn and the patient continued to be followed within the study. Patients 
must wait 36 hours after last study drug administration prior to initiating open label ACEi. 
Whenever possible, as dictated by clinical status, patients should resume study drug. Study drug 
re-initiation should be at the dose level deemed appropriate by the investigator and up-titration 
to target dose undertaken as described above. Patients who received open label ACEi should 
wait 36 hours before resuming study medication. These changes must be recorded on the 
Dosage Administration Record eCRF.
In case of pregnancy discovered during the screening epoch, the patient will be excluded from 
the study. In case of pregnancy discovered during the randomization epoch, the patient should 
be instructed to immediately discontinue study drug and encouraged to continue to attend 
scheduled study visits.
See Section 7.6 for further details on pregnancies and reporting guidelines.


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5.5.6
Rescue medication
Guidance on handling renal dysfunction, hyperkalemia, and hypotension are provided to 
investigators in Appendix 3, Appendix 4, and Appendix 5, respectively.
Use of rescue medication must be recorded on the Concomitant Medications eCRF.
5.5.7
Concomitant medication
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded. 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.
Diuretics will be adjusted in all patients to manage the symptoms of heart failure as needed 
during the study. Changes in diuretic dose must be recorded in the Concomitant Medications 
eCRF.
Management of comorbidities
The patient should be receiving evidence based medical therapy for relevant comorbidities such 
as but not limited to HTN, DM, AF, dyslipidemia, COPD and CAD (including diuretics, beta 
blockers, calcium channel blockers as appropriate). Medical management of comorbidities 
should be individualized based upon the clinical profile of the patient, taking into consideration 
age and the number and type of comorbidities. 
During the course of the study, investigators should continue to optimize background 
medications for comorbidities based upon the patient’s clinical situation. Elevations in BP
during the study should be treated by initiation or adjustment of non RASi therapies. Should 
the investigator feel that addition of open label RASi or renin inhibitor is required, study drug 
must be discontinued as outlined above in section 5.5.5 (initiation of open label ACEi should 
be deferred for 36 hours after discontinuation of study drug). Patients who have discontinued 
study medication for this reason will continue to be followed within the study and study drug 
reinitiated as deemed appropriate by the investigator. HbA1c and lipid profile will be performed 
pre-randomization and during the course of the study; diabetes and lipid management should 
be optimized during the course of the study as appropriate. All changes in medical therapy for 
the treatment of comorbidities during the study will be recorded in the eCRF. Additional 
information will be collected from the investigator for those patients with poorly controlled 
blood pressure, diabetes and lipids, as to whether medications were adjusted and if not, the 
reason why no changes in medical therapy were made. 
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements, MRAs and any other medications known 
to raise potassium levels should be used with caution while the patient is receiving the study 
drug due to the increased possibility of occurrence of hyperkalemia. The investigator is 


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encouraged to assess patients’ potassium levels regularly, especially in those who are receiving 
these medications.
Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of the occurrence of hypotension.
Neseritide 
The concomitant administration of LCZ696 with neseritide has not been studied. In the event a 
study patient requires the concomitant administration of neseritide with the study medications, 
the investigator should consider starting them at a lower dose or a slower infusion rate while 
monitoring the patient’s BP carefully.
HMG-CoA reductase inhibitors
Caution is recommended when co-administering LCZ696 with atorvastatin or other statins 
(eg simvastatin, pravastatin) that are substrates of OATP1B1 and OATP1B3 because of the 
potential to raise plasma statin levels.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of study drug due 
to safety reasons, unless the actions specified are taken.
Table 5-1
Prohibited treatment
Medication
Action to be taken
Any ACEI
Temporarily discontinue study drug while on ACEi. The open label ACEi 
treatment must be stopped for ≥36 hours prior to re-initiation of study drug.
Any ARB
Temporarily discontinue study drug while on ARB. The open label ARB 
treatment must be stopped prior to re-initiation of study drug.
Any renin inhibitor
Temporarily discontinue study drug while on renin inhibitor. The open label 
renin inhibitor must be stopped prior to re-initiation of study drug.
ACEIs, ARBs and renin inhibitors
The concomitant use of open-label ACEis, ARBs or a renin inhibitor is strictly prohibited while 
the patient is receiving study drug. Should an investigator wish to give open label RASi during 
the study, study drug will be withdrawn and the patient will continue to be followed within the 
study. If the patient is to be started on open-label ACEi, study drug must be stopped ≥36 hours 
prior to initiating ACEi treatment. Study drug may be resumed after discontinuation of open 
label ACEis, ARBs or a renin inhibitor as described above.
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 drug 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 


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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 Study Lead or designee that 
the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to IRT at any time in case of emergency. The investigator will provide:

protocol number

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 unblinding 
can be performed at any time.
An assessment will be done by the appropriate site personnel and the Medical Lead (or designee) 
after an emergency treatment code break and the patient must discontinue the study treatment.
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. The study will be completed when the last patient enrolled has 
completed their last visit (24 weeks after randomization). Patients will continue to be followed 
in the study regardless of study drug discontinuation.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from study drug, or must refer them for appropriate ongoing care. An open-label 
extension study may be available through the sponsor dependent on the results of the 
PARAGON-HF study.
5.6.2
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time. However, study 
treatment discontinuation does not constitute withdrawal from the study, does not constitute 
withdrawal of consent and should not lead to the patient being withdrawn from the study. 
Patients who have discontinued study drug should be encouraged to attend all the protocol 
specified study visits and perform all measurements as stipulated in the visit schedule (Table 6-
1) and remain in follow up for the duration of the trial.
If they fail to return for these assessments for unknown reasons, every effort should be made to 
contact them. The investigator must also contact the IRT to register the patient’s interruption 
from study treatment and record it on the Dosage Administration Record.
If the patient does not attend the study visits, follow-up should continue according to the 
specified schedule by telephone to determine if any AEs pre-specified in the protocol have 


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occurred, except in the case that the patient specifically refuses such follow-up and withdraws 
his/her consent.
The emergence of the following circumstances will require permanent study drug 
discontinuation:

Withdrawal of informed consent

Investigator thinks that continuation would be detrimental to the patient’s well-being

Suspected occurrence of angioedema (Section 6.5.7). A patient with any signs or symptoms 
of clinically significant angioedema should be thoroughly evaluated by the investigator

Pregnancy and post-pregnancy during lactation period (Section 6.5.6 and Section 7.6)
The emergence of the following circumstances will require temporary or permanent 
discontinuation (study drug may be restarted once these circumstances no longer exist):

Use of an open label ACE inhibitor, ARB, or renin inhibitor (Section 5.5.8)

Any laboratory abnormalities that in the judgment of the investigator warrant 
discontinuation of study drug after taking into consideration the patient’s overall status
(Section 6.5.4)
Study drug may be discontinued at the investigator’s discretion if any of the following occurs:

Any severe suspected drug-related AE (Section 7.1)

Any other protocol deviation that results in a significant risk to the patient’s safety
The appropriate personnel from the site and Novartis will assess whether study drug should be 
permanently discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
5.6.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator must make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject 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 subject’s study withdrawal should be made as detailed in the 
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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and Rest of the World (RoW): All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
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 discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study (EOS) visit has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 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.
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at which 
time all of the assessments listed for the final visit will be performed. At this final visit, all 
dispensed investigational treatment should be reconciled; all the AEs and concomitant 
medications also should be reconciled on the eCRFs.
Patients who have discontinued study drug should be encouraged to attend all the protocol 
specified study visits and perform all measurements as stipulated in the visit schedule (Table 6-
1) and remain in follow up for the duration of the trial. Visit 101 will be considered the reference 
visit for all study visits during the treatment epoch. Regardless of the occurrence of any 
unscheduled visits, scheduled visits should be performed within the specified timeframe in 
relation to Visit 101 as outlined in Table 6-1. If a visit is completed earlier than scheduled or 
postponed, it should not result in the next visit being brought forward or postponed.


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Table 6-1
Assessment schedule
Epoch
Screen
Double-blind treatment
Visit
1
101
102
103
104
105
106
107
199 and/or 
PSD
Week(w)
-2
0
2
4
8
12
16
20
24
Day
-14
1
14
28
56
84
112
140
168
Obtain informed consent*
X
Inclusion/exclusion criteria
X
S
Medical history/demography
X
Heart failure and diabetes 
history
X
Cardiovascular medical history
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Alcohol & smoking history
X
Complete physical exam
S
S
Short physical exam
S
S
S
S
S
S
S
Vital signs (BP and pulse)
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Waist/hip circumference
X
X
X
12-lead ECG assessment
X
X
X
Echocardiography1
X
NYHA classification (HF 
signs/symptoms)
X
X
X
X
X
X
X
X
X
KCCQ questionnaire
X
X
X
X
X
X
Six-minute walk test
X
X
X
X
SF-36
X
X
X


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Epoch
Screen
Double-blind treatment
Visit
1
101
102
103
104
105
106
107
199 and/or 
PSD
Week(w)
-2
0
2
4
8
12
16
20
24
Management of comorbidities 
(Blood Pressure)
x
x
x
x
x
x
x
x
x
Management of comorbidities 
(Diabetes, Lipids)
x
x
x
x
Management of comorbidities 
(Arrhythmias)
x
x
x
Complete laboratory 
evaluations2
X
X
X
X
Abbreviated laboratory 
evaluations3
X
X
X
X
X
FSH4
X
Serum/urine pregnancy test5
X
X
X
X
X
X
X
X
X
Plasma NT-proBNP6
X
X
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
Dispense study medication
X
X
X
X
X
X
X
Screening disposition
X
Treatment compliance
X
X
X
X
X
X
X
Treatment disposition
X
Study completion form
X
PSD = Premature Subject Discontinuation
X = assessment to be recorded on clinical data base
S = assessment to be recorded on source documentation only
*IC obtained prior to all study specific screening procedures


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1 Qualifying LVEF measurements/documentation of structural heart disease will be based on locally obtained echocardiograms (echo) performed within 6 
months of Visit 1. If a locally performed echo within 6 months of Visit 1 is not available, an echo must be performed during the screening epoch.
2 Complete laboratory evaluations including urinalysis will be sent to the central lab at all specified visits.
3 Abbreviated laboratory evaluations will be sent to the central lab and include: BUN, creatinine, potassium, and eGFR, and may additionally be performed 
in the local lab as needed and include: creatinine, potassium, and eGFR. Lab results must be available and assessed before any study drug up-titration 
(see table 3-3)
4 Not required for males or pre-menopausal women.
5 Not required for males or post-menopausal women. Serum pregnancy test performed at Visit 1 and 199/PSD. Urine pregnancy test performed at all other 
study visits.
6 Only the Visit 1 NT-proBNP results will be reported to the investigator and the sponsor. Local measurements of BNP or NT-proBNP during the course 
of the study is strongly discouraged.


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6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
SAE data collected. Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data.
Re-screening
A patient who enters screening but is determined not to be eligible will be considered a screen 
failure. The investigator may consider re-screening the patient at a later time if he/she believes 
that the patient’s condition has changed and they may potentially be eligible. In this case, a new 
patient number will be allocated to the subject and he/she will need to re-perform all Visit 1 
procedures. A patient may be re-screened once. A minimum of 2 weeks must elapse between 
screen failure and re-screening. The patient must provide new written informed consent before 
they are re-screened.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: year 
of birth, age, sex, race, ethnicity and source of patient referral. A detailed medical history 
(including HF, CV and other conditions relevant to the study population to be enrolled) and 
current medical conditions present before the signing of the informed consent will be collected.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
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 or care giver. This information should be 
captured in the Study Treatment Compliance eCRF at each visit. The investigator and/or study 
personnel should counsel the patient if compliance is below 80% at any time during the study. 
Study drug accountability will be determined by the site monitor while performing routine site 
visits and at the completion of the study. All study treatment dispensed and returned must be 
recorded in the Drug Accountability Log.
The duration of randomized treatment exposure will be calculated based upon the start and stop 
dates recorded in the Dosage Administration Record eCRFs.
6.4
Efficacy
6.4.1
Primary efficacy assessment
The primary efficacy variables are change from baseline in NT-proBNP (in log scale) at Week 
12 and change from baseline in six-minute walk distance (6MWD) at Week 24.


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6.4.2
Secondary efficacy assessment
The secondary efficacy variables include:

KCCQ CSS at Week 24

NYHA functional classification at Week 24

SF-36 PCS score at Week 24
6.4.3
Appropriateness of efficacy assessments
Rationale for the choice of endpoints for the study has been outlined previously (Section 3.2.2
and 3.2.3). The primary efficacy assessments, NT-proBNP and 6MWT, are key clinical 
measures in this patient population for response to therapy, exercise capacity improvement and 
assessment of overall risk. The secondary efficacy assessments (KCCQ, SF-36 and NYHA) are 
validated measures of symptoms and quality of life in patients with HFpEF.
6.5
Safety
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety profile 
of the study drugs. Such information may include diagnostic procedure reports, discharge 
summaries, autopsy reports, and other relevant information that may help in assessing the 
reported AE. All additional information will be de-identified prior to collection by Novartis or 
its agents.
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. Complete physical 
examination will be performed at Visit 1 and 199/PSD.
A short physical exam will include the examination of general appearance and vital signs (BP 
[SBP and DBP] and pulse). A short physical exam will be conducted at all visits starting from 
Visit 101 except where a complete physical examination is required (see Table 6-1).
Information from all physical examinations must be included in the source documentation at 
the study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the eCRF. Significant findings made after signing the 
informed consent which meet the definition of an AE must be recorded on the AE section of 
the eCRF.
6.5.2
Vital signs
Vital signs include BP and pulse measurements. BP will be measured in the sitting position 
after 5 minutes of rest using an automated validated device (eg OMRON) or a standard 
sphygmomanometer with an appropriately sized cuff on the non-dominant arm. Vital signs will 
be performed at each study visit.


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6.5.3
Height, weight and waist/hip circumference
Height in centimeters (cm) will be measured at Visit 1. Body weight (to the nearest 0.1 kilogram 
[kg] in indoor clothing, but without shoes) will be measured at each study visit.
Waist/hip circumference (to the nearest centimeter [cm] in indoor clothing) will be measured at 
Visit 1, 105, and 199/PSD.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collection, 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.
Complete laboratory evaluations such as hematology and blood chemistry (Table 6-2) for the 
assessment of safety in this study will be performed at Visits 1, 101, 105 and 199/PSD.
Abbreviated laboratory evaluations will be performed as indicated in Table 6-1. Abbreviated 
central laboratory includes: BUN, creatinine, potassium, and eGFR.
In addition to the required central laboratory assessments, a local laboratory may be used for 
the assessment of creatinine, potassium and eGFR during the up-titration period as indicated in 
Table 6-1. The results from the local laboratory during the up-titration period will be allowed 
to be used for decision making regarding the eligibility of the patient to continue on in the study 
and will be recorded on the appropriate eCRF. In addition, local laboratory assessments may be 
performed on an as-needed basis to monitor tolerability to study drug at unscheduled visits 
during the randomized treatment period and will be recorded in the appropriate eCRF.
Laboratory values that exceed the boundaries of a notable laboratory abnormality (Appendix 1) 
must be commented on by the investigator in the patient’s eCRF and additional laboratory 
evaluations should be performed, as judged appropriate by the investigator. If the laboratory 
abnormality induces clinical signs or symptoms, or requires therapeutic intervention, then the 
diagnosis or medical condition must be entered on the AE eCRF. If the laboratory abnormality 
is the primary reason for an unforeseen hospitalization or otherwise fulfills the seriousness 
category of an AE, then the procedure for rapid notification of SAEs must be followed. If the 
laboratory abnormality leads to study drug discontinuation (temporarily or permanently), the 
patient must be followed until the abnormality resolves or until it is judged to be permanent. 
The 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.
All central laboratory results will be communicated to the investigators and the sponsor, with 
the exception of NT-proBNP of which only the Visit 1 NT-proBNP will be reported 
(Section 6.6.1.4).


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Table 6-2
Complete laboratory evaluations
Hematology
Biochemistry
Urine measurements
Hematocrit
Alanine aminotransferase (ALT)
Urinalysis
Hemoglobin
Albumin (Alb)
Platelet count
Alkaline phosphatase (ALP)
Red blood cell count (RBC)
Aspartate aminotransferase 
(AST)
White blood cell count (WBC)
Blood urea nitrogen (BUN)*
WBC differential
Calcium
Red blood cell distribution width 
(RDW)
Chloride
Mean corpuscular volume 
(MCV)
Creatinine*
Mean corpuscular hemoglobin 
concentration (MCHC)
eGFR*
Glucose
Hemoglobin A1C
Lipid profile (total cholesterol, 
LDL, HDL, and triglycerides)
Phosphate
Potassium*
Serum pregnancy test
Sodium
Total bilirubin (TBL)
Fractionated bilirubin (if total 
bilirubin > 2 x ULN)
Total protein
Uric acid
*Laboratory assessments for the abbreviated laboratory evaluation at visits where the complete 
laboratory evaluation is not performed
6.5.4.1
Hematology
Hemoglobin, hematocrit, RBC, RDW, MCHC, MCV, WBC with differential, and platelet count 
will be measured.
6.5.4.2
Clinical chemistry
Blood urea nitrogen (BUN), creatinine, total bilirubin (TBL), fractioned bilirubin (if total 
bilirubin > 2 x ULN), AST, ALT, alkaline phosphatase, sodium, glucose (plasma), hemoglobin 
A1C, lipid profile, potassium, phosphate, chloride, calcium, total protein, albumin, and uric acid 
will be measured. Potassium, BUN, creatinine, and eGFR will be obtained at study visits where 
abbreviated central laboratory evaluations are scheduled.


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6.5.4.3
eGFR
Estimated eGFR will be calculated by the central or local laboratory using the following MDRD 
formula (Stevens et al 2006):
Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154 × (age in years)-0.203 
× (0.742 if female) × (1.212 if black), where SCr is the standardized serum creatinine value.
6.5.4.4
Urinalysis
Urinalysis with dipstick measurements for specific gravity, pH, total protein, bilirubin, ketones, 
leukocytes and blood will be performed by central lab. If a dipstick is positive, a qualitative 
microscopic determination, of WBC and RBC sediments will also be measured.
6.5.5
Electrocardiogram (ECG)
A standard 12-lead ECG will be performed locally at Visit 1, 105 and Visit 199/PSD. 
Interpretation of the tracing must be made by a qualified health care provider and documented 
on the ECG section of the eCRF. Each ECG tracing should be labeled with the study and subject 
number, date, and kept in the source documents at the study site. Clinically significant 
abnormalities should also be recorded on the Medical History/AE eCRF page.
6.5.6
Pregnancy and assessments of fertility
Serum FSH will be performed at Visit 1 in post-menopausal women.
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
Visit 1 and Visit 199/PSD. Additional pregnancy testing might be performed if requested by 
local requirements. A urine dip-stick pregnancy test will be performed locally at all other visits. 
The urine dip-stick pregnancy test is not required for post-menopausal women. A positive urine 
pregnancy test requires immediate interruption of study drug. A positive urine test needs to be 
confirmed with serum pregnancy test. If positive, the patient must discontinue study drug.
6.5.7
Angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise.
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an Angioedema-
like Event form (provided by Novartis) to summarize the event, its treatment, and its ultimate 
outcome. This report along with the requisite medical documentation must be submitted 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. In addition, all appropriate angioedema eCRFs should be 
completed.
For suspected and confirmed angioedema, the study medication should be discontinued.


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The investigator may be also be contacted by Novartis regarding AEs that may resemble an 
angioedema-like event. A list of terms that are considered “angioedema-like” (eg periorbital 
swelling) will be provided to sites in a manual. The investigator or his/her delegated staff must 
complete the required forms and provide the required medical records for all 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.
Information regarding this committee is outlined in Section 8.5. Details on the procedures for 
reporting angioedema events will be provided to investigators in a manual.
6.5.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments
6.6.1
Clinical outcome assessments
6.6.1.1
Clinician reported outcomes (ClinRO)
NYHA classification is a subjective assessment of patient’s functional capacity and 
symptomatic status and can change frequently over time. It is a well-established prognostic 
indicator of outcomes. Further, NYHA is used in daily clinical practice and research to record 
the patient’s current functional status and provide important information on disease progression 
in HF patients. NYHA assessment will be performed by a delegated and trained health care 
professional at every study visit.
6.6.1.2
Patient Reported Outcomes (PRO)
The Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It 
contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy 
and knowledge, and QoL.
The CSS is a combined score based upon the clinical symptoms and physical function domains
of the questionnaire. The CSS specifically, has been shown both to be predictive of outcomes 
and has been used to measure response to therapy in patients with HF (Ekman et al 2011). In 
addition, the overall summary score (OSS) is derived from the physical function, symptom 
(frequency and severity), social function and quality of life domains (Green et al 2000). Scores 
are transformed to a range of 0 - 100, in which higher scores reflect better health status.
A 5-points change in the KCCQ corresponds to clinically significant changes in measures of 
exercise capacity (Flynn et al 2012). Further, KCCQ scores show a linear correlation with all-
cause mortality for each 5-points decrease in KCCQ CSS (Kosiborod et al 2007). The proposed 
study will evaluate not only mean change from the baseline but also the proportion of patients 
with ≥5-points change including both improvement and deterioration at the end of the study.


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KCCQ will be performed at Visit 1 as part of study screening. Patients with CSS < 75 will be 
included in the study. In addition, KCCQ will be performed during the study at Visit 101, 103,
105, 106, 199/PSD.
SF-36 Version 2
The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy patients and patients with acute and 
chronic conditions. It consists of eight subscales that can be scored individually: physical 
functioning, role-physical, bodily pain, general
health, vitality, social functioning, 
role-emotional, and mental health (Ware et al 1993). Two overall summary scores, the physical 
component summary (PCS) and the mental component summary (MCS) also can be computed 
(Ware et al 1994). The SF-36 has proven useful in monitoring general and specific populations, 
comparing the relative burden of different disease, differentiating the health benefits produced 
by different treatments, and in screening individual patients. In this study the four week recall 
questionnaire will be used. 
Patients will require approximately 5 to 10 minutes to complete this form.
SF-36 will be completed at Visit 101, 106 and 199/PSD.
Completion of Questionnaires
All questionnaires will be completed in the language most familiar to the respondent, at the 
scheduled study visit prior to the patient seeing the investigator for any clinical assessment or 
evaluation. 
The patient should be given sufficient instruction, space, time and privacy to complete the 
questionnaire. The study coordinator should check the responses to the questionnaire for 
completeness and encourage the patient to complete any missing responses.
Under special circumstances, such as but not limited to illiteracy and poor vision, the 
completion of the questionnaires can be done with assistance, by a caregiver or a study 
coordinator not directly involved in the care of the patient, if a patient is unable to complete it 
on their own. This situation should be clearly noted both in source documents and as an 
investigator notification in the eCRF
All patients will complete the PRO questions via an electronic tablet. If patients experience any 
difficulties with submission after they complete the Patient Reported Outcome (PROs), the 
study staff should assist them with submitting their responses. Attempts should be made to 
collect responses to all PROs for all patients, including from those who prematurely discontinue 
prior to the study evaluation completion visit; however, if patients refuse to complete PROs,
(after screening visit), this should be documented in study source records. Patient’s refusal to 
complete study PROs are not protocol deviations and do not require the patient be discontinued 
from the trial.
Completed questionnaires will be reviewed and examined by the investigator for responses that 
may indicate potential AEs or SAEs. If AEs or SAEs are confirmed, then the physician must 
record the events as per instructions given in Section 7.1 and Section 7.2 of the protocol.


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6.6.1.3
Performance Outcomes
Six-minute walk test (6MWT)
The 6MWT is a simple, inexpensive, and reproducible method for the assessment of exercise 
capacity. The 6MWT has good reliability and a significant ability to predict functional capacity 
in patients with HF (Pollentier et al 2010). Scoring is based on the total distance walked. Lower 
levels of exercise capacity (a distance < 300 m during 6MWT) have proven to be predictive of 
mortality and morbidity in HF (Bittner et al 1993, Roul et al 1998, Zugck et al 2000). The 
6MWT also correlates with changes in symptoms after HF therapy, suggesting that it may be 
useful as a measure of symptom benefit (Olsson et al 2005).
The 6MWT will be performed in accordance with the guidelines of the American Thoracic 
Society 2002 (American Thoracic Society, 2002). A detailed description of the 6MWT is 
provided in Appendix 6.
Patients will perform 6MWT at Visit 1, 101, 106 and 199/PSD.
6.6.1.4
Other Clinical Outcome Assessments
NT-proBNP
Change from baseline in NT-proBNP (in log scale) at Week 12 is one of the two primary 
endpoints for this study. NT-proBNP provides value for the diagnosis, and helps in the 
management of patients with heart failure and predicts clinical outcome (mortality and 
morbidity).
NT-proBNP measurements will be performed by the central lab in all patients at Visits 1, 101, 
103, 105, and 199/PSD. Only the Visit 1 NT-proBNP results will be reported to the investigator 
and the sponsor. All other measurements will be blinded to the site and the Novartis clinical 
study team. Any, local measurements of BNP or NT-proBNP during the course of the study is 
strongly discouraged.
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 they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.


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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 
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 eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

no action taken (e.g. further observation only)

[investigational] treatment dosage increased/reduced

[investigational] treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

non-drug therapy given

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 
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 (IN)
or an Aggregate Safety Finding. New information might require an update to the informed 
consent and has then to be discussed with the patient.


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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 (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the 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 (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.


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7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent until either screen failure or until 30 days after the last study visit
must be reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs 
experienced after the 30 day period after the last study visit should only be reported to Novartis 
safety if the investigator suspects a causal relationship to study treatment.
At a minimum, randomized patients will be contacted for safety evaluations during the 30 days 
following the last study visit or following the last administration of study drug, including a final 
contact at the 30-day point. Documentation of attempts to contact the patient should be recorded 
in the source documentation. Furthermore, under this category, SAEs experienced after the 30 
days period 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, complete the SAE Report Form in English, and submit the 
completed form within 24 hours to Novartis. Detailed instructions regarding the submission 
process and requirements for signature are to be found in the investigator folder provided to 
each site.
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the 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
(DS&E) Department associate may urgently require further information from the investigator 
for health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees (EC) in accordance 
with EU Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries.
7.2.2.1
Adverse events that are commonly seen in the study population
Investigators will report AEs or SAEs that are commonly seen in the study population (Table 
7-1) but these will not be unblinded and will not be reported as SUSARs to regulatory agencies, 
ECs, or investigators during the study. These events will be unblinded and presented in the 


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clinical study report (CSR) after unblinding at the end of the study, and any SUSARs will be 
reported also at the end of the study.
If specifically requested by a local Health Authority (HA), pre-specified AEs commonly 
observed in the study population (Table 7-1) that also meet the criteria for SUSARs:

Will be expedited to the requesting HA as blinded reports without issuing INs, or

Pre-specified AEs commonly observed in the study population that occur in patients under 
the jurisdiction of the requesting HA will be expedited to the HA as unblinded reports; INs 
will be issued for these events.
Table 7-1
Adverse events commonly seen in study population
Cardiovascular events
Non-cardiovascular events
Unstable angina
Generalized edema
Arthralgia/Arthritis
COPD (including 
bronchitis and 
emphysema)
Arrhythmia (excluding 
AF)
Hypertension
Constipation
Cough
Transient ischemic 
attack
Hypotension
Diarrhea
Fatigue
Renal impairment
Peripheral edema
Headache
Sepsis
Chest pain
Syncope
Nausea
Nasopharyngitis
Dizziness/vertigo
Angina pectoris
Anemia
Pneumonia
Cerebrovascular 
accident
Dyspnea
Upper respiratory 
infection/insufficiency
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion of 
the standard base liver eCRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.


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These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are associated 
with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution.
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate eCRF pages, including the liver 
event overview eCRF pages.
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:

Serum events are outlined in detail in Appendix 3; surveillance situation (decrease in 
eGFR ≥25% from randomization) and action situation (decrease in eGFR ≥40% 
from randomization) are described

Urine event

new onset (≥1 +) proteinuria; confirmed by doubling in the urinary 
albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio (PCR) (if 
applicable)

new onset (≥1 +), hematuria or glycosuria
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site.
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.


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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.
Table 7-2
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration 
(DAR) eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
7.6
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 DS&E Department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study 
treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and Good Clinical Practice (GCP) compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of patient records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 


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organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
The trial will be conducted in a fully validated Data Capture system which conforms to US CRF 
21 Part 11 requirements. Investigator site staff will not be given access to the system until they 
have been trained. Designated investigator staff will enter the data required by the protocol into 
the Data Capture system. Automatic validation programs within the system check for data 
discrepancies in the eCRFs and by generating appropriate error messages, allow the data to be 
confirmed or corrected by the investigator staff. The investigator staff must certify that the data 
entered 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
Novartis staff (or contract research organization [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. If the electronic query system is not 
used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign 
the faxed copy and fax it back to Novartis staff that will make the correction to the database. 
The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the World Health 
Organization (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 
Novartis (or a designated CRO).


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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 database will be sent 
electronically to Novartis (or 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 to be 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 
Development management.
8.4
Data monitoring committee
An established program level Data Monitoring Committee (DMC) independent of Novartis that 
reviews safety data from LCZ696 studies will be used for this study. The DMC will review 
SAEs in an unblinded manner on a regular basis and determine if it is safe to continue the study. 
Any major recommendation from the DMC will be communicated to the Executive Committee 
and must be reviewed and ratified by the Executive Committee in consultation with Novartis 
prior to its enactment.
The membership of the DMC and the responsibilities of the DMC and Novartis will be defined 
in a separate document entitled the “Data Monitoring Committee Charter”. The DMC Charter 
will include information about data flow, purpose and timing of DMC meetings, guidance in 
the decision making process, communication strategy, procedures for ensuring confidentiality, 
procedures to address conflicts of interest and statistical monitoring guidelines.
8.5
Adjudication committee
Angioedema adjudication committee
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis). Details 
on the process of reporting angioedema and angioedema-like events are outlined in a manual 
provided to investigators.
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
If an angioedema-like event satisfies the definition of an SAE, the investigator must submit an 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event.
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites. The project-level angioedema 
adjudication committee will be used for this trial.


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9
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
9.1
Analysis sets
The following analysis sets will be used for the statistical analyses:
The full analysis set (FAS) will consist of all randomized patients with the exception of those 
patients who have not been qualified for randomization and have not received study drug, but 
have been inadvertently randomized into the study, and the exception of those patients who 
have been inadvertently randomized within a wrong stratum (ACEi, ARB, No RASi) and have 
not received study drug. 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 (SAF) set will consist of all randomized patients who received at least one dose of 
study drug. Patients will be analyzed according to the treatment actually received. The SAF will 
be used for the analyses of safety variables.
The per protocol set (PPS) 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 randomized treatment epoch. 
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 drug unless specified otherwise.
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years), sex, 
race, ethnicity, weight, height, body mass index (BMI), category of prior CV medication, prior 
HF hospitalization, NYHA class, NT-proBNP, BNP, and vital signs. BMI will be calculated as 
weight (kg) / height2 (m2) from the collected height and weight at Visit 1 (screening). 
Continuous variables will be summarized using n, mean, standard deviation, median, minimum, 
and maximum. Categorical variables will be summarized using frequencies and percentages.
The FAS will be used for the above analyses.
9.3
Treatments
The overall duration on the randomized study drug will be summarized by treatment group 
using mean, standard deviation, median, minimum, and maximum. Additionally, the number 
and percentage of patients will be summarized by treatment group for duration category. Mean 
doses and dose levels will be summarized by treatment group and visit.


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Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date respectively, will be summarized by therapeutic class, preferred term, and 
treatment group for the SAF.
The number and percentage of patients on different
CV background medications 
(eg mineralocorticoid receptor antagonist, β-blockers, diuretics, and digoxin) will be tabulated 
by treatment at baseline and during the randomized treatment epoch.
The FAS will be used for the above analyses unless otherwise specified.
9.4
Analysis of the primary variables
The primary objectives are to demonstrate that LCZ696 is superior to individualized medical 
therapy for comorbidities in reducing NT-proBNP from baseline after 12 weeks of treatment, 
and/or in improving exercise capacity as assessed by the 6MWT at Week 24 in a subset of 
patients with B6MWD ranging from 100 meters to 450 meters.
9.4.1
Primary variables
The primary efficacy variables are the change from baseline in log(NT-proBNP) at Week 12, 
and the change from baseline in six-minute walk distance (6MWD) at Week 24.
For patients who have died, the 6MWD after the death will be defined as zero.
For patients who permanently discontinue from study treatment, assessment values collected
after permanent discontinuation will generally be included in the analysis.
9.4.2
Statistical model, hypothesis, and method of analysis
Testing strategy
The following primary null hypotheses will be included in the testing strategy.

H1: LCZ696 is no better than the comparator in change from baseline in log(NT-proBNP) 
at Week 12 in the overall study population

H2: LCZ696 is no better than the comparator in change from baseline in 6MWD at Week 
24 in patients with B6MWD ranging from 100 meters to 450 meters.
The following secondary null hypotheses will be included in the testing strategy.

H3: LCZ696 is no better than the comparator in change from baseline in KCCQ CSS at 
Week 24 in the overall study population.

H4: LCZ696 is no better than the comparator in NYHA change from baseline at Week 24 
in the overall study population.
Each null hypothesis is tested against the one-sided alternative that LCZ696 is better than the 
comparator in the corresponding variable.
In order to control the family-wise type-I error rate at the one-sided 0.025 significance level, a 
sequentially rejective multiple testing procedure based on the graphical presentation (Bretz et 
al 2009) will be employed, whereby H1 and H2 will be tested first at initially assigned level of 
one-sided (9/10) × α = 0.0225 and one-sided (1/10) × α = 0.0025, accordingly. If H1 and/or H2
are rejected, the alpha for the rejected null hypotheses will be propagated to H3, such that, H3


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will be tested at the updated alpha level (one-sided 0.025 if both H1 and H2 are rejected; one-
sided 0.0225 if H1 is rejected but H2 is not rejected; one-sided 0.0025 if H2 is rejected but H1 is 
not rejected); if H3 is rejected, the alpha will be propagated to H2 or H4 based on the initial step 
rejection status.

With H1 rejected but H2 not rejected at the initial step, if H3 is rejected at one-sided 
0.0225, the alpha will be propagated to H2, such that, H2 will be tested again at one-sided 
0.025; if H2 is rejected at one-sided 0.025, the alpha will be further propagated to H4. 
Otherwise, the testing procedure will stop.

With H2 rejected but H1 not rejected at the initial step, if H3 is rejected at one-sided 
0.0025, the alpha will be propagated to H4, such that, H4 will be tested at one-sided 
0.0025. Otherwise, the testing procedure will stop.

With both H1 and H2 rejected at the initial step, if H3 is rejected at one-sided 0.025, the 
alpha will be propagated to H4, such that, H4 will be tested at full alpha (one-sided 0.025). 
Otherwise, the testing procedure will stop.
Figure 9-1 provides graphical illustration of the sequentially rejective testing procedure.


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Figure 9-1
Graphical illustration of the sequentially rejective testing procedure
Based on the above testing procedure, if applicable, H1, H2 and H3 will be tested based on the 
corresponding MMRM models (Section 9.4.2, Section 9.5.1.1), H4 will be tested based on the 
longitudinal proportional cumulative odds model (Section 9.5.1.3)
If statistical significance had been established in the mean difference in change from baseline 
to Week 24 for KCCQ CSS, the following responders will be analyzed accordingly, based on 
the longitudinal binary logistic regression models (Section 9.5.1.1), to further illustrate the 
clinical relevance of the observed differences in terms of proportion of responders.

KCCQ CSS improvement (defined by at least 5 points improvement);

KCCQ CSS deterioration (defined by at least 5 points deterioration);
No multiplicity adjustment will be done for these supportive responder analyses (i.e., the tests 
for the responder analyses will be performed at nominal level of one-sided 0.025).


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NT-proBNP analyses
The changes from baseline in log(NT-proBNP) will be analyzed using a mixed model for 
repeated measures (MMRM), in which, the response variable will be the changes from baseline 
in log(NT-proBNP); stratum (defined by prior ACEi/ARB medication usage [ACEi, ARB, 
None]), region, treatment (LCZ696, individualized medical therapy), visit and treatment-by-
visit interaction will be included as fixed-effect factors; baseline log(NT-proBNP), stratum-by-
baseline and visit-by-baseline interactions will be included as covariates; the within-patient 
covariance will be modeled using an unstructured covariance matrix (a common matrix for the 
two treatment groups). The analysis will include all post-baseline scheduled visits up to Week 
12 (Week 4, Week 12) and will be performed based on the likelihood method with an 
assumption of missing at random (MAR) for missing data (Siddiqui et al 2009, National 
Research Council 2010).
Based on the MMRM model, the primary null hypothesis, H1, will be tested based on the testing 
strategy, the estimates and the two-sided 95% confidence intervals will be provided for the 
adjusted geometric means for the ratio to baseline in NT-proBNP at Week 12 in each of the two 
treatment groups (LCZ696 and individualized medical therapy), and for the ratio of the adjusted 
geometric means (LCZ696 over individualized medical therapy).
The FAS will be used for the above primary analyses.
As a supportive analysis, the same approach will also be performed on the PPS.
6MWD analyses
The changes from baseline in 6MWD will be analyzed using a MMRM model, in which, the 
response variable will be the changes from baseline in six-minute walk distance; stratum 
(defined by prior ACEi/ARB medication usage [ACEi, ARB, None]), region, treatment 
(LCZ696, individualized medical therapy), visit and treatment-by-visit interaction will be 
included as fixed-effect factors; baseline six-minute walk distance (B6MWD), baseline systolic 
blood pressure (BSBP), stratum-by-B6MWD, stratum-by-BSBP and visit-by-B6MWD 
interactions will be included as covariates; the within-patient covariance will be modeled using 
an unstructured covariance matrix (a common matrix for the two treatment groups). The 
analysis will include all patients with B6MWD ranging from 100 meters to 450 meters, and all 
post-baseline scheduled visits up to Week 24 (Week 16 and Week 24), and will be performed 
based on the likelihood method with an assumption of MAR for missing data (other than due 
to death).
Based on the MMRM model, the primary null hypothesis, H2, will be tested based on the testing 
strategy, the estimates and the two-sided 95% confidence intervals will be provided for the 
adjusted means for the change from baseline in 6MWD at Week 24 in each of the two treatment 
groups (LCZ696 and individualized medical therapy), and for the adjusted mean difference 
(LCZ696 minus individualized medical therapy) at Week 24.
All patients in the FAS with B6MWD ranging from 100 meters to 450 meters will be used for 
the above primary analysis.
As a supportive analysis, the same approach will also be performed on the FAS with all patients 
included, regardless of B6MWD values, and on the PPS.


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9.4.3
Handling of missing values/censoring/discontinuations
Missing data will be handled with the likelihood method with the assumption that they are MAR 
in the primary analyses.
9.4.4
Sensitivity analyses
In order to explore the robustness of the MAR assumption on the primary analysis, a sensitivity 
analysis will be carried out which assesses the situation where the data are missing not at 
random (MNAR); In particular, the sensitivity analysis will assume that LCZ696 patients who 
discontinue due to adverse events, death or lack of efficacy will not have adhered to therapy if 
they had stayed in the study.
A controlled multiple imputation approach based on pattern mixture models will be applied 
(Carpenter and Kenward 2013), whereby all missing data of patients in the LCZ696 group who 
permanently discontinue study treatment due to: adverse events, death or lack of efficacy, will 
be assumed to behave like patients in the control group (individualized medical therapy) after 
permanent discontinuation and will be imputed based on the data from patients in the control 
group (individualized medical therapy) according to the stratum (defined by prior ACEi/ARB 
medication usage [ACEi, ARB, None]).
All other missing data will be considered as MAR within each arm and will be imputed using a 
multiple imputation approach (Carpenter and Kenward 2013) based on observed data within 
each arm according to the stratum. Of note, patients who permanently discontinue study 
treatment, are not considered discontinued from the study. It is planned to continue to collect 
and use data at scheduled visits even after permanent discontinuation of study treatment.
Furthermore, the missing data patterns in the change from baseline in log(NT-proBNP) and the 
change from baseline in 6MWD will be explored via by-treatment-group box plots for patients 
who permanently discontinue from study treatment due to adverse events, death or lack of 
efficacy, for patients who permanently discontinue from study treatment due to any other 
reasons, for patients who did not permanently discontinue from study treatment, and for patients 
who take open label LCZ696 after permanent discontinuation from study treatment.
As additional supportive analyses, the primary analyses for the primary variables (the change 
from baseline in log[NT-proBNP] at Week 12, and the change from baseline in 6MWD at Week
24) described in Section 9.4.1 will be performed for the following data as applicable:

Data where the 6MWD after the death were set to missing for patients who died.

Data where the last observation carry forward (LOCF) approach was performed for missing 
data.

Data where the responses after the first dose of open-label RASi or open-label LCZ696 after 
permanent discontinuation of the study treatment will be set to missing and considered 
MAR. (This is called on-treatment analysis.)
The FAS will be used for the above analyses.


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9.5
Analysis of secondary variables
9.5.1
Efficacy variables
All secondary efficacy variables will be analyzed using the FAS, unless otherwise specified.
9.5.1.1
KCCQ clinical summary score change from baseline
For patients who have died, the KCCQ CSS after the death will be imputed as zero. For patients 
who permanently discontinue study treatment, values collected after permanent discontinuation
will generally be included in the analysis.
The changes from baseline in KCCQ CSS will be analyzed using a MMRM model, in which, 
the response variable will be the changes from baseline in KCCQ clinical summary score; 
stratum (defined by prior ACEi/ARB medication usage [ACEi, ARB, None]), region, treatment 
(LCZ696, individualized medical therapy), visit and treatment-by-visit interaction will be 
included as fixed-effect factors; baseline KCCQ clinical summary score (BCSS), baseline 
systolic blood pressure (BSBP), stratum-by-BCSS, stratum-by-BSBP, and visit-by-BCSS
interactions will be included as covariates; the within-patient covariance will be modeled using 
an unstructured covariance matrix (a common matrix for the two treatment groups). If the model 
fitting procedure does not converge, the AR(1) covariance structure will be used. The analysis 
will include all post-baseline scheduled visits up to Week 24 (Week 4, Week 12, Week 16 and 
Week 24) and will be performed based on the likelihood method with an assumption of MAR 
for missing data (other than due to death).
Based on the MMRM model, the secondary null hypothesis, H3, will be tested (if applicable) 
based on the testing strategy, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted means for the change from baseline in KCCQ CSS at Week 24 in each 
of the two treatment groups (LCZ696 and individualized medical therapy), and for the adjusted 
mean difference (LCZ696 minus individualized medical therapy) at Week 24.
In addition, the improvement and the deterioration in KCCQ CSS will be analyzed separately 
using longitudinal binary logistic regression models, in which, the response variables will be, 
accordingly, the KCCQ CSS improvement (event defined by at least 5-points improvement in 
KCCQ CSS) and the KCCQ CSS deterioration (event defined by at least 5-points deterioration 
in KCCQ clinical summary score); stratum (defined by prior ACEi/ARB medication usage 
[ACEi, ARB, None]), region, treatment (LCZ696, individualized medical therapy), visit and
treatment-by-visit interaction will be included as fixed-effect factors; BCSS, BSBP, stratum-by-
BCSS, stratum-by-BSBP and visit-by-BCSS interactions will be included as covariates; patient-
specific intercepts will be included as random effects. The analysis will include all post-baseline 
scheduled visits up to Week 24 (Week 4, Week 12, Week 16 and Week 24) and will be 
performed based on the likelihood method with an assumption of MAR for missing data (other 
than due to death).
Based on the longitudinal binary logistic regression models, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted odds ratios (LCZ696 over individualized 
medical therapy) at Week 24.
Besides, the KCCQ clinical summary score and the change from baseline in KCCQ CSS
summary score will be summarized by visit and treatment group using n, mean, standard 


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deviation, min, Q1, median, Q3 max; the improvement and the deterioration in KCCQ CSS of 
at least 5-points will be summarized by visit and treatment group using frequencies and 
percentages.
The FAS will be used for the above analyses.
9.5.1.2
KCCQ overall summary score change from baseline
As an exploratory analysis, the same analyses as KCCQ CSS will also be performed for KCCQ 
OSS, except that the baseline KCCQ CSS in the models will be replaced by baseline KCCQ 
OSS.
The FAS will be used for the above analyses.
9.5.1.3
NYHA class change
The NYHA class change is a three-category ordinal variable with levels: “improved”, 
“unchanged”, and “worsened”, defined by at least one class improvement, no change, at least 
one class worsening, in NYHA class, respectively. For patients who died, the NYHA class 
change after the death will be categorized into “worsened”. For patients who permanently 
discontinue study treatment, values collected after permanent discontinuation will generally be 
included in the analysis.
The NYHA class change will be analyzed using a longitudinal proportional cumulative odds 
model, in which, the response variable will be the NYHA class change (order defined by 
“improved” < “unchanged” < “worsened”); stratum (defined by prior ACEi/ARB medication 
usage [ACEi, ARB, None]), region, treatment (LCZ696, individualized medical therapy), visit, 
treatment-by-visit interaction, baseline NYHA class, stratum-by-baseline and visit-by-baseline 
interactions will be included as fixed-effect factors; BSBP and stratum-by-BSBP interaction 
will be included as covariates; patient-specific intercepts will be included as random effects. 
The analysis will include all post-baseline scheduled visits up to Week 24 (Week 2, Week 4, 
Week 8, Week 12, Week 16, Week 20 and Week 24) and will be performed based on the 
likelihood method with an assumption of MAR for missing data (other than due to death).
Based on the longitudinal proportional cumulative odds model, the secondary null hypothesis, 
H4, will be tested (if applicable) based on the testing strategy, the estimate and the two-sided 
95% confidence interval will be provided for the adjusted odds ratio (LCZ696 over 
individualized medical therapy) at Week 24.
In addition, the improvement and deterioration in NYHA class will be analyzed separately using 
longitudinal binary logistic regression models, in which, the response variables will be,
accordingly, the NYHA class improvement (event defined by NYHA class change of level 
“improved”) and the NYHA class deterioration (event defined by NYHA class change of level 
“worsened”); stratum (defined by prior ACEi/ARB medication usage [ACEi, ARB, None]),
region,
treatment (LCZ696, individualized medical therapy), visit, treatment-by-visit 
interaction, baseline NYHA class, stratum-by-baseline and visit-by-baseline interactions will 
be included as fixed-effect factors; BSBP and stratum-by-BSBP interaction will be included as 
covariates; patient-specific intercepts will be included as random effects. The analysis will 
include all post-baseline scheduled visits up to Week 24 (Week 2, Week 4, Week 8, Week 12, 


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Week 16, Week 20 and Week 24) and will be performed based on the likelihood method with 
an assumption of MAR for missing data (other than due to death).
Based on the longitudinal binary logistic regression models, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted odds ratios (LCZ696 over individualized 
medical therapy) at Week 24.
Besides, the NYHA class and the NYHA class change will be summarized by visit and 
treatment group using frequencies and percentages.
The FAS will be used for the above analyses.
9.5.1.4
SF-36 physical component summary score
For patients who have died, the SF-36 PCS score after the death will be imputed as zero. For 
patients who permanently discontinue from study treatment, values collected after permanent
discontinuation will generally be included in the analysis.
The changes from baseline in SF-36 PCS score will be analyzed using a MMRM model, in 
which, the response variable will be the changes from baseline in SF-36 physical component 
summary score; stratum (defined by prior ACEi/ARB medication usage [ACEi, ARB, None]),
region, treatment (LCZ696, individualized medical therapy), visit and treatment-by-visit 
interaction will be included as fixed-effect factors; baseline SF-36 physical component 
summary score (BPSS), BSBP, stratum-by-BPSS, stratum-by-BSBP and visit-by-BPSS 
interactions will be included as covariates; the within-patient covariance will be modeled using 
an unstructured covariance matrix (a common matrix for the two treatment groups). The 
analysis will include all post-baseline scheduled visits up to Week 24 (Week 16 and Week 24) 
and will be performed based on the likelihood method with an assumption of MAR for missing 
data (other than due to death).
Based on the MMRM model, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted means for the change from baseline in SF-36 PCS score at Week 24 
in each of the two treatment groups (LCZ696 and individualized medical therapy), and for the 
adjusted mean difference (LCZ696 minus individualized medical therapy) at Week 24.
In addition, the SF-36 PCS score will be summarized by visit and treatment group using n, mean, 
standard deviation, min, Q1, median, Q3 max.
The FAS will be used for the above analyses.
9.5.1.5
SF-36 mental component summary score
The same analyses as SF-36 PCS score will also be performed for SF-36 MCS score, except 
that the BPSS in the models will be replaced by baseline SF-36 MCS score (BMSS), stratum-
by-BPSS and visit-by-BPSS interactions in the analysis models will be replaced by stratum-by-
BMSS and visit-by-BMSS interactions.
The FAS will be used for the above analyses.


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9.5.1.6
Missing data handling in the secondary endpoint analyses
In the analyses described in Sections 9.5.1.1 to 9.5.1.5, death is considered the worst possible 
outcome and hence scheduled visits after death will be imputed accordingly. Other missing data 
is assumed to be MAR.
As a sensitivity analysis, the controlled multiple imputation approach based on pattern mixture 
models will be applied (Carpenter and Kenward 2013), whereby all missing data of patients in 
the LCZ696 group who permanently discontinue study treatment due to: adverse events or lack 
of efficacy, will be assumed to behave like patients in the control group (individualized medical 
therapy) after permanent discontinuation and will be imputed based on the data from patients 
in the control group (individualized medical therapy) according to the stratum (defined by prior 
ACEi/ARB medication usage [ACEi, ARB, None]).
All other missing data will be considered as MAR within each arm and will be imputed using a 
multiple imputation approach (Carpenter and Kenward 2013) based on observed data within 
each arm according to the stratum. Of note, patients who permanently discontinue study 
treatment, are not considered discontinued from the study. It is planned to continue to collect 
and use data at scheduled visits even after permanent discontinuation of study treatment.
Furthermore, the missing data patterns in the secondary endpoint variables will be explored via 
by-treatment-group box plots or bar plots as appropriate for patients who permanently 
discontinue from study treatment due to adverse events or lack of efficacy, for patients who 
permanently discontinue study treatment due to any other reasons, for patients who did not 
permanently discontinue study treatment and for patients who take open label LCZ696 after 
permanent discontinuation from study treatment.
As additional supportive analyses, the main analyses for the secondary endpoints described in 
Sections 9.5.1.1 to 9.5.1.5 will be performed for the following data.

Data where the responses after the death were set to missing for patients who died.

Data where the LOCF approach was performed for missing data.

Data where the responses after the first dose of open-label RASi or open-label LCZ696 
after permanent discontinuation of study treatment will be set to missing and considered 
MAR. (This is called on-treatment analysis.)
9.5.1.7
Subgroup analyses
Subgroup analyses will be performed utilizing the corresponding analysis model used for 
primary and secondary endpoints, after adding the factors of subgroup and subgroup-treatment 
interaction to the model, to assess the consistency of the treatment effects across key clinically 
relevant subgroups listed below. The estimated treatment effect, two-sided 95% confidence 
interval, and the interaction p-value will be provided for each of the subgroups.

Stratum (defined by prior ACEI/ARB medication usage [ACEi, ARB, None])

Age group (< 65 years, ≥ 65 years; < 75 years, ≥ 75 years)

Sex

Region

Baseline NYHA (Class I-II, Class III-IV)


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
Diabetes (Yes [history of diabetes mellitus or HbA1c at screening ≥6.5%], No[no history 
of diabetes mellitus and HbA1c at screening < 6.5%])
9.5.2
Safety variables
The safety and tolerability assessments are listed below:

Identified and potential risks (including angioedema, hyperkalemia, hypotension, renal 
dysfunction, liver)

AEs and SAEs

Sitting systolic, diastolic BP, and pulse pressure

Heart rate

Symptomatic hypotension

Angioedema

Hyperkalemia

Renal dysfunction

Other relevant laboratory values

ECG changes
The assessment of safety will be based primarily on the frequencies of AEs, SAEs, and 
laboratory abnormalities. Other safety data will be summarized as appropriate.
The incidence of treatment-emergent AEs (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.
The incidence of AEs related to the identified and potential risks will be summarized by SMQ 
preferred terms.
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data 
and change from baseline values (mean, medians, standard deviations, ranges) and by the 
flagging of notable values in data listings. LFT categorical analysis will also be provided.
Data from other tests (eg ECG or 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 SAF. There will be no formal statistical 
inference analysis.
9.6
Analysis of exploratory variables
9.6.1
NT-proBNP up to Week 24
The changes from baseline in log(NT-proBNP) will be analyzed using a MMRM model, in 
which, the response variable will be the changes from baseline in log-transformed NT-proBNP; 
stratum (defined by prior ACEi/ARB medication usage [ACEi, ARB, None]), region, treatment 
(LCZ696, individualized medical therapy), visit and treatment-by-visit interaction will be 


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included as fixed-effect factors; baseline log-transformed NT-proBNP, stratum-by-baseline and
visit-by-baseline interactions will be included as covariates; the within-patient covariance will 
be modeled using an unstructured covariance matrix (a common matrix for the two treatment 
groups). If the model fitting procedure does not converge, the AR(1) covariance structure will 
be used. The analysis will include all post-baseline scheduled visits up to Week 24 (Week 4, 
Week 12 and Week 24) and will be performed based on the likelihood method with an 
assumption of MAR for missing data.
Based on the MMRM model, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted geometric means for the ratio of NT-proBNP over baseline NT-
proBNP in each of the two treatment groups (LCZ696 and individualized medical therapy) at 
Week 24; and for the adjusted geometric mean ratio (LCZ696 over individualized medical 
therapy) at Week 24.
The FAS will be used for the above analyses
9.6.2
Estimated glomerular filtration rate (eGFR)
For the rate change in eGFR, the eGFR slope will be estimated from a mixed model, in which, 
the response variable will be the eGFR; stratum (defined by prior ACEi/ARB medication usage 
[ACEi, ARB, None]), region, and treatment (LCZ696, individualized medical therapy) will be 
included as fixed-effect factors; time (in month) and treatment-by-time interaction will be 
included as covariates; a patient level random intercept and a patient level random slope (time) 
will be included as random effects with a unstructured covariance matrix (a common matrix for 
the two treatment groups). Here, the time is computed as (date of assessment – date of 
randomization + 1)/30.4375. The analysis will include all assessments from central lab at all 
visits up to Week 24 (Baseline to Week 24, scheduled or unscheduled) and will be performed 
based on the likelihood method with an assumption of MAR for missing data.
Based on the mixed model, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted mean slope in each of the two treatment groups (LCZ696 and 
individualized medical therapy), and for the adjusted mean difference (LCZ696 minus 
individualized medical therapy).
In addition, the eGFR and the change from baseline in eGFR will be summarized by visit and 
treatment group.
The FAS will be used for the above analyses.
9.7
Interim analyses
No efficacy interim analysis is planned.
9.8
Sample size calculation
The sample size (2500 randomized patients) has been chosen in order to provide adequate power
to evaluate both primary and secondary endpoints.
With an alpha of one-sided 0.0225, the power for the NT-proBNP will range from 92% to more 
than 99%, to detect a relative reduction ranging from 11% to 24% in change from baseline to 
Week 12 in NT-proBNP, assuming a standard deviation of 0.81 for change from baseline in the


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log-transformed NT-proBNP (based on PARAMOUNT-HF data of patients with baseline 
KCCQ CSS < 75) and an overall drop-out rate of 10%.
With an alpha of one-sided 0.0025, the power for the 6MWD will range from 90% to 99%, to 
detect a mean difference ranging from 22 meters to 30 meters in change from baseline to Week 
24 in 6MWD, assuming a standard deviation of 120 meters (Ingle et al 2005), an overall drop-
out rate of 10%, and an overall proportion of 88% for patients with B6MWD ranging from 100 
meters to 450 meters.
With an alpha of one-sided 0.0225, the power for the KCCQ CSS will range from 87% to 99%, 
to detect a mean difference ranging from 2 points to 3 points in change from baseline to Week 
24 in KCCQ CSS, assuming a standard deviation of 15.52 points for change from baseline in 
the KCCQ CSS (based on PARAMOUNT-HF data of patients with baseline KCCQ CSS < 75) 
and an overall drop-out rate of 5%.
All alpha levels in the following sample size calculations will be one-sided 0.025.
This sample size of 2500 randomized patients aims to provide a power of approximately 90%, 
with the one-sided alpha level of 0.025, to demonstrate a 5% responder advantage in at least 5-
point deterioration for patients who are treated with LCZ696 over individualized medical 
therapy when assuming the proportion of patients with at least 5-point deterioration from 
baseline to Week 24 in the individualized medical therapy group is 20% (based on 
PARAMOUNT-HF data of patients with baseline KCCQ CSS < 75) and an overall 5% dropouts.
With the same assumption of the dropout rate, this sample size will also provide a power of 69% 
to detect a 5% responder advantage in at least 5-points improvement in the KCCQ clinical 
summary score for patients who are treated with LCZ696 over individualized medical therapy 
when assuming the proportion of patients with at least 5-points improvement from baseline to 
Week 24 in the individualized medical therapy group is 55% (based on PARAMOUNT-HF data 
of patients with baseline KCCQ CSS < 75).
The sensitivity of power for at least 5-points deterioration in the KCCQ clinical summary score 
to changes in assumptions is outlined in Table 9-1.
Table 9-1
Sensitivity of power for at least 5-points deterioration in KCCQ clinical 
summary score to changes in assumptions for N = 2500
Assumed probability of at
least 5-points deterioration
Power for at least
5-points deterioration
(one-sided alpha = 0.025)
Individualized
medical
therapy
LCZ696
Difference
With 5%
drop-out rate
With 10%
drop-out rate
With 15%
drop-out rate
With 20%
drop-out rate
20%
15%
-5%
90%
88%
86%
84%
35%
30%
-5%
74%
72%
69%
67%
The sensitivity of power for at least 5-points improvement in the KCCQ CSS to changes is 
outlined in Table 9-2.


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Table 9-2
Sensitivity of power for at least 5-points improvement in KCCQ 
clinical summary score to changes in assumptions for N = 2500
Assumed probability of at
least 5-points improvement
Power for at least
5-points improvement
(one-sided alpha = 0.025)
Individualized
medical
therapy
LCZ696
Difference
With 5%
drop-out rate
With 10%
drop-out rate
With 15%
drop-out rate
With 20%
drop-out rate
55%
60%
5%
69%
67%
65%
62%
41%
46%
5%
69%
67%
64%
62%
The assumed dropout rates (Table 9-1 and Table 9-2) are for the purpose of power sensitivity 
analysis. During the conduct of the study, all efforts will be made to reduce missing data.
For other secondary endpoints, this sample size will provide adequate powers for reasonable 
effect size assumptions: power of 90% for NYHA class change, assuming 14% of the patients 
in the comparator and 19% of the patients in the LCZ696 group are improved in NYHA class 
change, 6% of the patients in the comparator and 5% of the patients in the LCZ696 group are 
worsened in NYHA class change (based on Week 24 PARAMOUNT-HF data of patients with 
baseline KCCQ CSS < 75); and power of approximately 90% to detect a between treatment 
group mean difference of 1.4 points or more in change from baseline in SF-36 physical 
component summary score, assuming a standard deviation of 10-points (Edelmann et al 2013).
East 6.3 was used for the sample size calculations.
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 may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable 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.
[*] For Germany only, the first paragraph will read as follows:
Eligible patients may only be included in the study after providing written (witnessed, where 


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required by law or regulation) IRB/IEC-approved informed consent. He/she should indicate 
assent by personally signing and dating the written informed consent document.  Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should 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 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 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, 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.


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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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients 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.
12
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van Heerebeek L, Hamdani N, Falcão-Pires I, et al (2012) Low myocardial protein kinase g 
activity in heart failure with preserved ejection fraction. Circulation; 126(7):830-9.
Ware J, Kosinki M, Gandeck B (1993, 1994) SF-36 Health Survey manual and interpretation 
guide. Boston: The Health Institute, New England Medical Center.
Ware JE Jr, Gandek B (1998) Overview of the SF-36 health survey and the international quality 
of life assessment (IQOLA) project. J Clin Epidemiol; 51(11): 903–912.
Ware JE Jr, Sherbourne, CD (1992) The MOS 36-Item Short-Form Health Survey (SF-36): I. 
Conceptual Framework and Item Selection. Med Care; 30:473-483.


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West R, Liang L, Fonarow GC, et al (2011) Characterization of heart failure patients with 
preserved ejection fraction: a comparison between ADHERE-US registry and ADHERE-
International registry. Eur J of Heart Fail; 13:945-952.
Yusuf S, Pfeffer MA, Swedberg K, et al (2003) Effects of candesartan in patients with chronic 
heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. 
Lancet; 362:777-781.
Zile MR, Gottdiener JS, Hetzel SJ, et al (2011) Prevalence and significance of alterations in 
cardiac structure and function in patients with heart failure and a preserved ejection fraction. 
Circulation; 124:2491-2501.
Zugck C, Krüger C, Dürr S et al (2000) Is the 6-minute walk test a reliable substitute for peak 
oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J; 21(7):540-9.


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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:
Hematology
Hematocrit
> 50% increase, > 20% decrease
Hemoglobin
> 50% increase, > 20% decrease
Platelet count
> 75% increase, > 50% decrease
RBC Count
> 50% increase, > 20% decrease
WBC count
> 50% increase, > 50% decrease
Blood Chemistry
Alkaline phosphatase > 100% increase
ALT (SGPT)
> 150% increase
AST (SGOT)
> 150% increase
BUN
> 50% increase
Calcium
> 10% increase, > 10% decrease
Chloride
> 10% increase, > 10% decrease
Creatinine
> 50% increase
Potassium
> 20% increase, > 20% decrease
Total bilirubin
> 100% increase
Uric acid
> 50% increase


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow-up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific renal alert criteria and actions
Serum Event
See detailed guidance below
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Confirm value after 24 to 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.
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 drug. 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 randomization (Visit 101) 
(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 creatinine

Volume decrease, including that resulting from excessive dosing of diuretics

Urinary infection

Urinary tract obstruction

Study drug


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Action situation
If a patient’s eGFR decreases by ≥40% from randomization (Visit 101) (or if serum creatinine 
concentration rises above 3 mg/dL (265µmol/L), the investigator will check for potentially 
reversible causes of renal dysfunction (see above).
The investigator may consider down-titration of study drugs. If the investigator judges that 
study drugs have 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 drug was stopped, every effort will be 
done to restart it again, according to clinical conditions.


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16
Appendix 4 – Treatment guidelines for hyperkalemia (serum 
potassium* greater than 5.3 mmol/L [mEq/L])
General principles
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken.
Any patient with a serum potassium* > 5.3 mmol/L (mEq/L) at any time after randomization 
requires the Investigator to confirm the potassium concentration in a non-hemolyzed sample 
via an immediate repeat lab sample to both the clinic local lab and the study central lab. Regular, 
repeated checks of potassium concentration (beyond that prescribed in the protocol) should 
continue until it is clear that the potassium concentration is stable and not rising into the range 
of concern (≥ 5.5 and < 6.0 mmol/L [mEq/L]) or potential danger (≥ 6.0 mmol/L [mEq/L]).
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below. Hyperkalemia should be followed until resolution.
Corrective action for management of hyperkalemia
Serum potassium* greater than 5.3 and less than or equal to 5.5 mmol/L 
(mEq/L)
1. Confirm potassium concentration in a non-hemolyzed sample
2. Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(eg orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
tomatoes, coffee, etc.)
3. Correct metabolic acidosis if necessary.
4. 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:

MRAs (if they are believed to be the most likely cause of hyperkalemia)

Potassium-sparing diuretics (eg amiloride and triamterene) including in combination 
products with thiazide or loop diuretics

Potassium supplements, eg 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


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5. Assess patient for dehydration or any condition that could lead to dehydration (e.g., 
diarrhea, vomiting) and/or hypovolemia and initiate appropriate corrective measures of 
rehydration.
6. Repeat serum potassium* measurement within 3 to 5 days

If serum potassium* remains > 5.3 and ≤ 5.5 mmol/L (mEq/L), regularly monitor 
serum potassium* levels to ensure stability (suggested once monthly)

Consider down-titration of study drugs, according to investigator’s medical judgment.
Serum potassium* greater than 5.5 and less than 6.0 mmol/L (mEq/L)

Confirm potassium concentration in a non-hemolyzed sample

Consider down-titration or temporarily discontinue study drugs according to investigator 
medical judgment.

Apply all measures outlined for serum potassium* > 5.3 and ≤ 5.5 mmol/L

Repeat serum potassium* measurement after 2-3 days

If serum potassium* < 5.5 mmol/L, consider resumption of study drugs at lower dose with 
repeat potassium within 5 days
Serum potassium* greater than or equal to 6.0 mmol/L (mEq/L)

Immediately discontinue study drugs

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 mmol/L (mEq/L)
No resumption of study drugs without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee.
* or equivalent plasma potassium value


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17
Appendix 5 – Guidelines for the management of 
hypotension
Guidelines
1. Investigator should monitor BP closely
2. If symptomatic hypotension occurs:
a. Correct any treatable cause, eg hypovolemia
b. If hypotension persists, any antihypertensive drug such as diuretics, calcium channel 
blockers (CCBs), nitrates, beta blockers, aldosterone antagonists and α-blockers, 
should be down-titrated or stopped first before down-titration of the study drugs are 
considered. Any non-antihypertensive drug (such as nitrates) should be considered for 
down-titration prior to study drug as determined by the best judgment of the 
investigator.
c. If hypotension persists, the study drugs should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medications adjust guidelines described in 
Section 5.5.5 should be adhered to as much as possible.


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18
Appendix 6 – Six-minute walk test
A standardized 6MWT will be performed in accordance with the guidelines of the American 
Thoracic Society 2002. All patients will undergo the 6MWT at Visit 1 (screening), 101, 106 & 
199.
The 6MWT is preferably performed indoors along a long, flat, straight, enclosed corridor with 
a hard surface that is seldom traveled. The walking course must be 25-30 meters in length; 
therefore, a corridor of at least 30 meters is required for the test. The beginning and end of the 
course should be marked with a cone. The patient will be asked to walk as far as possible for 6 
minutes timed on a stop watch. The number of complete course lengths walked will be recorded 
as well as any partial length walked. If the patient discontinues the test prematurely, the time, 
distance and reason for discontinuation will be recorded in the eCRFs. During the study, the 
6MWT should be performed about the same time of day on each occasion.
Prior to the test, the patient should sit at rest in a chair, located near the starting position for at 
least 10 minutes and resting baseline heart rate and blood pressure measured. Then, have the 
patient stand and rate their baseline dyspnea and overall fatigue using the Borg scale. Heart rate, 
blood pressure, dyspnea and overall fatigue using the Borg scale should be repeated 
immediately after completion of the test.
REQUIRED EQUIPMENT
1. Countdown timer (or stopwatch)
2. Two small cones or similar item to mark the turnaround points
3. A chair that can be easily moved along the walking course
4. Sphygmomanometer
5. Automated electronic defibrillator
6. Source Document Worksheet
PATIENT PREPARATION
1. At screening visit assess eligibility as per Exclusion Criterion #8 and refer to the provided 
eligibility check list.
2. Comfortable clothing should be worn
3. Appropriate shoes for walking should be worn
4. Patients should use their usual walking aids during the test (cane, walker, etc.)
5. The patient's usual medical regimen should be continued
6. A light meal is acceptable before early morning or early afternoon tests
7. Patients should not have exercised vigorously within 2 hours of beginning the test


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MEASUREMENTS
1. Testing should be performed about the same time of day to minimize intraday variability
2. A "warm-up" period before the test should not be performed
3. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, and make 
sure that clothing and shoes are appropriate. 
4. Measure and record baseline heart rate and blood pressure with the patient resting on a 
chair for at least 10 minutes
5. Have the patient stand and rate their baseline dyspnea and overall fatigue using the Borg 
scale 
6. Move to the starting point
Instruct the patient as follows:
"The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You 
will probably get out of breath or become exhausted. You are permitted to slow down, to stop, 
and to rest as necessary. You may lean against the wall while resting, but resume walking as 
soon as you are able.
You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I'm going to show you. Please 
watch the way I turn without hesitation."
Demonstrate by walking one length yourself. Walk and pivot around a cone briskly.
"Are you ready to do that? 
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or 
jog.
Start now, or whenever you are ready."
7. Position the patient at the starting line. You should also stand near the starting line 
during the test. Do not walk with the patient. As soon as the patient starts to walk, start 
the timer.
8. Do not talk to anyone during the walk. Use an even tone of voice when using the 
standard phrases of encouragement. Watch the patient. Do not get distracted and lose 
count of the lengths. Each time the participant reaches a turnaround point, mark the 
completed length on the source document worksheet. 
After the first minute, tell the patient the following (in even tones): 
"You are doing well. You have 5 minutes to go."
When the timer shows 4 minutes remaining, tell the patient the following: 
"Keep up the good work. You have 4 minutes to go."


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When the timer shows 3 minutes remaining, tell the patient the following: 
"You are doing well. You are halfway done."
When the timer shows 2 minutes remaining, tell the patient the following: 
"Keep up the good work. You have only 2 minutes left."
When the timer shows only 1 minute remaining, tell the patient: 
"You are doing well. You have only 1 minute to go."
Do not use other words of encouragement (or body language to speed up).
If the patient stops walking during the test and needs a rest, say this: 
"You can lean against the wall if you would like; then continue walking whenever you feel 
able." Do not stop the timer. If the patient sits down, the test is over or if the patient stops 
before the 6 minutes are up and refuses to continue (or you decide that they should not 
continue), wheel the chair over for the patient to sit on, discontinue the walk, and note on the 
worksheet the distance, the time stopped, and the reason for stopping prematurely.
When the timer is 15 seconds from completion, say this: 
"In a moment I'm going to tell you to stop. When I do, just stop right where you are and I 
will come to you."
When the timer rings (or buzzes), say: "Stop!" Walk over to the patient. Consider taking the 
chair if they look exhausted. Mark the spot where they stopped by placing a bean bag or a piece 
of tape on the floor.
9. Post-test: Immediately after completion of the test, record the post walk Borg dyspnea 
and fatigue levels and ask: 
“What if anything, kept you from walking farther (faster)?”
10. Measure and record heart rate and blood pressure while the patient is sitting
11. Record the number of lengths walked
12. Calculate the total distance walked, rounding to the nearest meter, and record it on the 
worksheet.
13. Congratulate the patient on good effort and offer a drink of water.
Reference: American Thoracic Society, 2002

SAP_001.pdf: 
Clinical Development
LCZ696/Entresto®
CLCZ696D2302
A 24-week, randomized, double-blind, multi-center, parallel 
group, active controlled study to evaluate the effect of 
LCZ696 on NT-proBNP, exercise capacity, symptoms and 
safety compared to individualized medical management of 
comorbidities in patients with heart failure and preserved 
ejection fraction
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
;
Document type:
SAP Documentation
Document status:
Release date:
Number of pages:
57
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CLCZ696D2302
Document History – Changes compared to previous final version of SAP
Date
Time point
Updates
Section
impacted (Current)
25JUN2017
Prior to DBL
31OCT2018
Prior to DBL
Updated per protocol amendment 2
All sections
29OCT2019
Prior to DBL
Add back-up strategy for model non-
convergence
Add additional sub-group of interest
Add additional sub-group analyses
Update safety topics
Update laboratory analyses
Update per protocol set definition
Section 2.1
Section 2.2.1
Section 2.5.5
Section 2.6.5
Section 2.8.1
Section 2.8.3
Section 5.2


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions..................................................................................9
2.2
Analysis sets ..........................................................................................................11
2.2.1
Subgroup of interest ..............................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.3.2
Background and demographic characteristics.......................................15
2.3.3
Medical history......................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior and concomitant therapies............................................................21
2.4.3
Comorbidity management.....................................................................22
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoints .................................................................................23
2.5.2
Statistical hypothesis, model, and method of analysis..........................24
2.5.3
Handling of missing values/censoring/discontinuations.......................27
2.5.4
Supportive and sensitivity analyses ......................................................27
2.5.5
Subgroup analyses.................................................................................29
2.6
Analysis of secondary efficacy objective(s)..........................................................30
2.6.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) .........................30
2.6.2
NYHA class change ..............................................................................35
2.6.3
Short Form Health Survey (SF-36).......................................................37
2.6.4
Handling of missing values/censoring/discontinuations.......................38
2.6.5
Subgroup analyses.................................................................................41
2.7
Analysis of the exploratory objectives ..................................................................42
2.7.1
NT-proBNP up to Week 24...................................................................42
2.7.2
Estimated glomerular filtration rate (eGFR).........................................43
2.8
Safety analyses.......................................................................................................44
2.8.1
Adverse events (AEs)............................................................................44


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2.8.2
Death .....................................................................................................48
2.8.3
Laboratory data .....................................................................................48
2.8.4
Other safety data ...................................................................................52
2.9
Pharmacokinetic endpoints....................................................................................53
2.10
PD and PK/PD analyses.........................................................................................53
2.11
Patient-reported outcomes .....................................................................................53
2.12
Biomarkers.............................................................................................................53
2.13
Other Exploratory analyses....................................................................................53
2.14
Interim analysis......................................................................................................53
53
3
Sample size calculation .....................................................................................................54
4
Change to protocol specified analyses ..............................................................................55
5
Appendix ...........................................................................................................................55
5.1
Imputation rules.....................................................................................................55
5.2
Rule of exclusion criteria of analysis sets..............................................................55
6
Reference...........................................................................................................................56


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List of abbreviations
6MWD
six-minute walking distance
6MWT
six-minute walking test
ACEi
angiotensin converting enzyme inhibitor
AE
adverse event
AF
atrial fibrillation/atrial flutter
Alb
albumin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
AST
aspartate aminotransferase
ATC
anatomical therapeutic classification
bid
twice a day
BMI
body mass index
bpm
beats per minute
B6MWD
baseline six-minute walking distance
BCSS
baseline KCCQ CSS
BLNTBNP
baseline log(NT-proBNP)
BMSS
baseline SF-36 MCS score
BOSS
baseline KCCQ OSS
BPSS
baseline SF-36 PCS score
BSBP
baseline systolic blood pressure
BUN
blood urea nitrogen
CAD
coronary artery disease
CRF
case report form
CSR
clinical study report
CSS
clinical summary score
CV
coefficient of variation
DBP
diastolic blood pressure
DMC
data monitoring committee
FAS
full analysis set
ECG
electrocardiogram
echo
echocardiogram
eGFR
estimated glomerular filtration rate
EOS
end of study
GCP
good clinical practice
HFpEF
heart failure with preserved ejection fraction
HTN
Hypertension
IA
interim analysis
IMT
individualized medical therapy
INR
international normalized ratio
IRT
interactive response technology
KCCQ
Kansas City Cardiomyopathy Questionnaire


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LDL
low-density lipoprotein
LLOQ
lowest limit of quantitation
LVEF
left ventricular ejection fraction
MAR
missing at random
MCS
mental component summary
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MCV
mean corpuscular volume
MCHC
mean corpuscular hemoglobin concentration
MMRM
mixed model for repeated measures
MNAR
missing not at random
NT-proBNP
N-terminal pro-brain natriuretic peptide
OSS
overall summary score
PPS
per-protocol set
PCS
physical component summary
PRO
patient-reported outcomes
PT
preferred term
QoL
quality of life
RASi
renin angiotensin system inhibitors
RBC
red blood cell count
RDW
red blood cell distribution width
SAE
serious adverse event
SAP
statistical analysis plan
SF-36
short form health survey
SOC
system organ class
TBL
total bilirubin
TEAE
treatment emergent adverse event
TESAE
treatment emergent serious adverse event
TFLs
tables, figures, listings
ULN
upper limit of normal range
ULOQ
upper limit of quantitation
WBC
white blood cell count
WHO
World Health Organization


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1
Introduction
The statistical analysis plan (SAP) describes the detailed methodology and implementation of 
the planned statistical analyses outlined in the study protocol v02 for CLCZ696D2302. The 
analysis results will be summarized in the clinical study report (CSR).
1.1
Study design
This is a 24-week, randomized, double-blind, multi-center, parallel group, active controlled 
study to evaluate LCZ696 compared to individualized medical therapy (IMT) on N-terminal 
pro-brain natriuretic peptide (NT-proBNP), exercise capacity, symptoms and quality of life
(QoL) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) 
(left ventricular ejection fraction [LVEF] > 40%) (Figure 1-1).
Figure 1-1
Study design
Approximately 2500 patients will be randomized in this study.
Patients will be initially stratified into one of three strata according to prior renin-angiotensin 
system inhibitor (RASi) treatment for comorbidities: angiotensin converting enzyme inhibitor
(ACEi), angiotensin receptor blocker (ARB) or no RASi. Patients will then be randomized at a 
1:1 ratio to receive either LCZ696 or comparator (i.e., IMT). Patients in the ACEi stratum will 
be randomized to receive either LCZ696 or enalapril. Patients in the ARB stratum will be 
randomized to receive either LCZ696 or valsartan. Patients in the no RASi stratum will be 
randomized to receive either LCZ696 or placebo. Patients in the ACEi and ARB strata must 
have a history of hypertension (HTN). There will be no designated proportion of patients in 


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each stratum, the strata will populate based upon the patient’s prior treatment regimen. In 
addition, randomization will be stratified by region.
For the purpose of blinding, the corresponding placebos are also dispended to the patients. Table 
1-1 summarizes the study medications for each treatment group and each stratum (ACEi, ARB, 
No RASi).
Table 1-1
Study Medications
Stratum
Study Medications
LCZ696
IMT
ACEi
LCZ696 Active + Enalapril Placebo
LCZ696 Placebo + Enalapril Active
ARB
LCZ696 Active + Valsartan Placebo
LCZ696 Placebo + Valsartan Active
No RASi
LCZ696 Active
LCZ696 Placebo
No interim analysis (IA) for efficacy is planned.
1.2
Study objectives and endpoints
Table 1-2 presents the objectives and related endpoints
Table 1-2
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
To demonstrate that LCZ696 is superior to 
IMT for comorbidities in reducing NT-proBNP 
from baseline after 12 weeks of treatment
To demonstrate that LCZ696 is superior to 
IMT for comorbidities in improving exercise 
capacity as assessed by the six-minute walk 
test (6MWT) at Week 24 in a subset of 
patients
Endpoint(s) for primary objective(s)
Change from baseline in NT-proBNP (in log 
scale) at Week 12
Change from baseline in six-minute walk 
distance (6MWD) at Week 24
Secondary Objective(s)
To compare LCZ696 to IMT for comorbidities
on mean change of Kansas City 
Cardiomyopathy Questionnaire (KCCQ)
clinical summary score (CSS) at Week 24
To compare LCZ696 to IMT for comorbidities
on proportion of patients with ≥5-points 
change in KCCQ CSS at Week 24 (separate 
analyses for ≥5-points improvement and ≥5-
points deterioration)
To compare LCZ696 to IMT for comorbidities 
in improving NYHA functional class at Week 
24
To compare LCZ696 to IMT for comorbidities
in improving symptoms as assessed by the
Short Form Health Survey (SF-36) physical 
component summary (PCS) score at Week 
24 
Endpoint(s) for secondary objective(s)
Mean change from baseline in KCCQ CSS 
at Week 24
Proportion of patients with ≥5-points 
deterioration in KCCQ CSS at Week 24
Proportion of patients with ≥5-points 
improvement in KCCQ CSS at Week 24
Change from baseline in NYHA functional 
class at Week 24
Change from baseline in SF-36 PCS score 
at Week 24


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Objective(s)
Endpoint(s)
Exploratory Objective(s)
To compare LCZ696 to IMT for comorbidities
in reducing NT-proBNP at Week 24
To explore the relative effect of LCZ696 vs 
IMT for comorbidities on renal function as 
assessed by estimated glomerular filtration 
rate (eGFR) at Week 24
To compare LCZ696 to IMT for comorbidities
on mean change of KCCQ overall summary 
score (OSS) at Week 24
To compare LCZ696 to IMT for comorbidities
on proportion of patients with ≥5 points 
change in KCCQ OSS at Week 24 (separate 
analyses for ≥5-points improvement and ≥5-
points deterioration)
To evaluate safety of LCZ696 vs IMT for 
comorbidities
Endpoint(s) for exploratory objective(s)
Change from baseline in NT-proBNP (in log 
scale) at Week 24
Rate of change (slope) in eGFR from 
baseline
Mean change from baseline in KCCQ OSS
at Week 24
Proportion of patients with ≥5-points 
deterioration in KCCQ OSS at Week 24
Proportion of patients with ≥5-points 
improvement in KCCQ OSS at Week 24
Frequency of adverse events (AEs), serious 
adverse events (SAEs), and laboratory 
abnormalities
2
Statistical methods
The following section contain important information on detailed statistical methodology used 
for analysis and reporting purposes.
2.1
Data analysis general information
Unless otherwise specified, data will be analyzed by DATAMAP according to the protocol for 
CLCZ696D2302, using SAS 9.4 or higher. Further details on planned statistical analyses will 
be presented in the following section and in CSR Appendix 16.1.9.
An established program level data monitoring committee (DMC) independent of Novartis that 
reviews safety data from LCZ696 studies will be used for this study. The DMC will review 
patient safety data in an unblinded manner approximately every six months and determine if it 
is safe to continue the study. Any major recommendation from the DMC will be communicated 
to the Executive Committee and must be reviewed and ratified by the Executive Committee in 
consultation with Novartis prior to its enactment.
In general, the continuous variables will be summarized using number of observations, mean, 
standard deviation, median, quartiles, minimum and maximum; the categorical variables will 
be summarized using frequencies and percentages.
The analysis will be conducted on all data at the end of trial.
2.1.1
General definitions
Randomized Treatment Epoch
The randomized treatment epoch is defined as the period from the date of randomization to the 
end of the study, inclusive.


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Baseline assessment and study day
Unless otherwise specified, the baseline assessment is defiend as below.

For efficacy variables, if the scheduled assessment at randomization (nominal visit) is 
performed and the assessment value is non-missing, the baseline assessment is defined as 
the scheduled assessment at randomization (nominal visit).

For efficacy variables, if the scheduled assessment at randomization (nominal visit) is not 
performed or the assessment value is missing, the baseline assessment is defined as the 
last non-missing assessment (scheduled or unscheduled) prior to or on the randomization
date.

For safety variables, the baseline assessment is defined as the last non-missing assessment 
(scheduled or unscheduled) prior to or on the first dose date of the study drug.
Specifically, the baseline systolic blood pressure (BSBP) is included in some efficacy analysis 
model as a covariate, in this case, the baseline assessment for the systolic blood pressure will 
be defined using the above criteria for efficacy variables.
In the listings, the study day will be displayed, as applicable.

In the listings of efficacy data, the study day is defined as the date of assessment 
(event/visit) minus the date of randomization plus one day, i.e., Day 1 is the 
randomization date.

In the listings of safety data, the study day is defined as the date of assessment 
(event/visit) minus the date of first dose plus one day, i.e., Day 1 is the first dose date.
Post-baseline assessment
Unless otherwise specified, for efficacy variables, the post-baseline assessments are defined as 
those assessments taken later than the date of randomization; for safety variables, the post-
baseline assessments are defined as those assessments taken later than the first dose date of the 
study drug.
Region and stratum (ACEi, ARB, No RASi)
Unless otherwise specified, the region and the stratum (ACEi, ARB, No RASi) will be loaded 
from the randomization data, where the region is defined based on country according to Table 
2-1, which may be updated according to the final enrollment plan prior to the database lock, 
and the stratum is defined based on the usage of the RASi (ACEi/ARB) medication prior to the 
randomization.
Table 2-1
Region mapping criteria
Region
Countries
North America
Canada, United States
Latin America
(including Central America)
Argentina, Brazil, Colombia, Guatemala, Mexico, Peru
Europe
Austria, Belgium, Bulgaria, Czech Republic, Denmark, Estonia, 
France, Germany, Hungary, Italy, Latvia, Lithuania, Netherlands,
Portugal, Romania, Russia, Serbia, Slovakia (Slovak Republic), Spain, 
Turkey, United Kingdom


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Region
Countries
Asia/Pacific and other
India, Israel, Thailand
Visit 199 mapping
For patients who completed the randomized treatment epoch, Visit 199 will be Week 24.
For patients who discontinued from the study during the randomized treatment epoch, Visit 199 
will be mapped to the next scheduled visit of the last attended scheduled visit prior to visit 199
(Table 2-2).
Table 2-2
Visit 199 mapping crietria
Randomized Treatment Epoch
Patient Status
Last Attended Scheduled
Visit Prior to Visit 199
Mapped Visit for Visit 199
Visit Number
Visit Name
Visit Number
Visit Name
Discontinued
101
Randomization
102
Week 2
Discontinued
102
Week 2
103
Week 4
Discontinued
103
Week 4
104
Week 8
Discontinued
104
Week 8
105
Week 12
Discontinued
105
Week 12
106
Week 16
Discontinued
106
Week 16
107
Week 20
Discontinued
107
Week 20
108
Week 24
Completed
---
---
108
Week 24
- For each patient, the last attended scheduled visit prior to visit 199 is defined as the visit with 
maximal visit number among all scheduled visit ( visit 101 to visit 107) in the visit panel.
Data collected at Visit 199 will be included in by-visit summaries and longitudinal modelling, 
if an assessment were scheduled at the mapped visit for Visit 199.
Unscheduled assessments
Unscheduled assessments will be included in over period minimum/maximum, and in over 
period shift table, but will not be included in by-visit summary and longitudinal modelling.
Model non-convergence
For all regression models, if the model fitting procedure does not converge, covariates could be 
removed from the model sequentially, as applicable, with the following order: visit-by-baseline
interaction, stratum-by-BSBP interaction, stratum-by-baseline interaction, BSBP, baseline, 
region and stratum (ACEi, ARB, No RASi).
2.2
Analysis sets
The following analysis sets will be used for the statistical analyses.

Screened set (SCR) – All patients who signed the informed consent for CLCZ696D2302. 
The SCR includes only unique screened patients, i.e., in the case of re-screened patients 
only the chronologically last screening data is counted.


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
Randomized set (RAN) – All patients in the SCR who received a randomization number, 
regardless of receiving study drug.

Full analysis set (FAS) – All randomized patients with the exception of those patients who 
have not been qualified for randomization and have not received study drug, but have been 
inadvertently randomized into the study, and the exception of those patients who have been 
inadvertently randomized within a wrong stratum (ACEi, ARB, No RASi) and have not 
received study drug. Further exclusions from the FAS may only be justified in exceptional 
circumstances (e.g., serious GCP violations). 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.

Per protocol set (PPS) – A subset of the FAS which will consist of the patients who do 
not have major deviations from the protocol procedures in the randomized treatment 
epoch. 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.

Safety set (SAF) – All randomized patients who received at least one dose of study drug. 
Patients will be analyzed according to the treatment actually received. The SAF will be 
used for the analyses of safety variables. The treatment actually received will be 
considered identical to the randomized treatment if the patient has received at least one 
dose of the randomized treatment.
Patients without valid written informed consent will be excluded from all analysis sets. Further 
exclusions from the FAS are only justified in exceptional circumstances (e.g., site closed down 
for GCP reasons). The determination of which patients were excluded from the FAS is made in 
a blinded manner before the database lock.
Rules leading to exclusion from the analysis sets are given in Appendix 5.2.
2.2.1
Subgroup of interest
Table 2-3 specifies the subgroups to be used in sub-group analyses.
Table 2-3
Subgroup specifications
Subgroups
Source
Data Source
Variable
Visit/Time 
Point
Region

North America;

Latin America
(including Central America)

Europe;

Asia/Pacific and other
Randomization
Region
Randomization
Stratum (ACEi, ARB, No RASi)

ACEi;

ARB;

No RASi;
Randomization
Stratum
Randomization


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Subgroups
Source
Data Source
Variable
Visit/Time 
Point
Age group (< 65 years, ≥ 65 years)

< 65 years;

≥ 65 years;
CRF page: 
Demography
Age
Screening
Age group (< 75 years, ≥ 75 years)

< 75 years;

≥ 75 years;
CRF page:
Demography
Age
Screening
Sex

Female;

Male;
CRF page:
Demography
Sex
Screening
Baseline NYHA class group

Class I/II

Class III/IV
CRF page:
Signs and
Symptoms of 
Heart Failure
including New 
York Heart 
Association 
Classification
NYHA
Classification
Randomization
(Baseline)
Diabetes (history or HbA1c ≥ 6.5%)*

Yes

No
CRF page:
Heart failure 
and Diabetes 
History
Central 
laboratory
result
Diabetes mellitus history
HbA1c
Screening
LVEF group (<= 60%, > 60%)

<= 60 %

> 60 %
CRF page:
Heart failure 
and Diabetes 
History
LVEF
Screening
Prior heart failure hospitalization

Yes

No
CRF page:
Heart failure 
and Diabetes 
History
Prior heart failure
hospitalization
Screening
NOTE: Baseline NYHA class is defined using the baseline criteria for efficacy variables (Section 
2.1.1)
NOTE *: Diabetes (history or HbA1c ≥ 6.5%) is defined as No if the patient has no history of diabetes 
mellitus and HbA1c at screening < 6.5%; Diabetes (history or HbA1c ≥ 6.5%) is defined as Yes if the 
patient has history of diabetes mellitus or HbA1c at screening ≥ 6.5%.
Table 2-4 summarizes the subgroup analyses in this study.
Table 2-4
Subgroup analyses
Subgroup Variable
Primary/Secondary
Efficacy Analysis
Selected 
Safety Analysis
Region
X
X
Stratum (ACEi, ARB, No RASi)
X
X
Age group (< 65 years, ≥ 65 years)
X
X


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Subgroup Variable
Primary/Secondary
Efficacy Analysis
Selected 
Safety Analysis
Age group (< 75 years, ≥ 75 years)
X
X
Sex
X
X
Baseline NYHA class group
X
X
Diabetes (history or HbA1c ≥ 6.5%)
X
X
LVEF group (<= 60%, > 60%)
X
X
Prior heart failure hospitalization
X
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Disposition for the screening epoch
The number and percentage of patients who completed the screening epoch will be provided. 
Besides, the primary reason for not completing the screening epoch will be summarized, using 
the number and percentage of patients not qualifying for such reasons. For any patient who was 
screened more than once, the data from the last screening will be used in the summary.
The SCR will be used for the above analyses.
Disposition for the randomized treatment epoch
The patient status for the randomized treatment epoch will be summarized by treatment group
for overall and for each stratum (ACEi, ARB, No RASi), using the number of patients who 
were randomized, the numbers and percentages of patients who completed the epoch and who 
discontinued from the study during the epoch; the primary reason for discontinuation from the 
study during the randomized treatment epoch will be summarized by treatment group for overall 
and for each stratum (ACEi, ARB, No RASi), using the number and percentage of patients
discontinued for such reasons.
The RAN will be used for the above analyses.
Disposition for the study treatment
The numbers and percentages of patients who took at least one dose of the study drug, who 
completed the study treatment and who permanently discontinued from the study treatment will 
be provided by treatment group, for overall and for each stratum (ACEi, ARB, No RASi); the 
primary reason for permanent discontinuation from the study drug will be summarized by 
treatment group, for overall and for each stratum (ACEi, ARB, No RASi), using the number 
and percentage of patients discontinued for such reasons.
The RAN will be used for the above analyses.


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Protocol deviations
The protocol deviations will be summarized by treatment group and protocol deviation category, 
for overall and for each stratum (ACEi, ARB, No RASi), using the numbers and percentages of 
patients with at least one protocol deviation within the protocol deviation category.
The RAN will be used for the above analyses.
Analysis set dispositions
The numbers and percentages of patients within each analysis set will be provided by treatment 
group, for overall and for each stratum (ACEi, ARB, No RASi).
In addition, the number and percentage of patients satisfying each criteria leading to exclusion 
from analysis sets will be provided by treatment group, for overall and for each stratum (ACEi, 
ARB, No RASi).
2.3.2
Background and demographic characteristics
For overall and for each stratum (ACEi, ARB, No RASi), summary statistics will be provided 
by treatment group for demographics and baseline characteristics, including age, age group (<
65 years, ≥65 years), age group (< 75 years, ≥75 years), sex, race, ethnicity, category of prior 
cardiovascular medication, prior heart failure hospitalization, height, weight, body mass index 
(BMI), body surface area (BSA), waist circumference, hip circumference, sitting pulse, sitting 
systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), LVEF, atrial fibrillation, 
atrial flutter, atrial fibrillation/atrial flutter (AF), NT-proBNP, 6MWD, HbA1c, HbA1c group 
(< 6.5%, ≥6.5%), history of diabetes mellitus, diabetes (history or HbA1c ≥ 6.5%), history of 
hypertension, history of coronary heart disease, NYHA class, KCCQ CSS, region, and stratum 
(only for overall), where BMI will be calculated as weight (kg) / height2 (m2) from height and 
weight at screening. If an above variable is scheduled at screening, the scheduled assessment at 
screening (nominal visit) will be summarized for this variable. If an above variable is scheduled 
at randomization, the baseline assessment, defined using baseline criteria for efficacy variables 
(Section 2.1.1), will be summarized for this variable. If an above variable is scheduled at both 
screening and randomization, both the assessment at screening (nominal visit) and the baseline 
assessment, will be summarized for this variable.
Continuous variables will be summarized using number of observations, mean, standard 
deviation, median, minimum, the first quartile (Q1), the third quartile (Q3), and maximum.
Categorical variables will be summarized using frequencies and percentages.
The FAS will be used for the above analyses.
2.3.3
Medical history
Any condition entered on the relevant medical history/current medical conditions CRF will be 
coded using the MedDRA dictionary. Medical history includes heart failure history and other 
medical history in this study, which are collected at screening. The number and percentage of 
patients with each medical condition will be provided by treatment group, system organ class 
(SOC), and preferred term (PT), for overall and for each stratum (ACEi, ARB, No RASi).
The FAS will be used for the above analyses.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The study drug administration will be recorded on the CRF page: “Dosage Administration 
Record – Double-blind Medication” using start date, end date and dispensing level of the study 
drug. Each pair of start date and end date will be considered as a dosing interval.
For each patient, the dosing intervals will be sorted according to the start date and the end date 
from the earliest to the latest. It is expected that, for each patient, there should be no gaps and 
overlaps among dosing intervals, with the exception that, the end date of a dosing interval can 
be the same as the start date of its next dosing interval, when the patient may take the previous 
dispensing level in the morning and start a different dispensing level in the evening.
In the presence of gaps or overlaps, data conventional imputation algorithm will be applied to 
the start date and end date. Detailed algorithm will be provided in the study programming 
datasets specifications (PDS).
For patients who permanently discontinue from the study treatment, there should be a dosing 
interval with its start date equal to the date of the permanent discontinuation of the study drug, 
its end date equal to the study completion/discontinuation date, and its dispensing level equal 
to “No treatment”.
For each dosing interval, the dispensing level of the study drug will be recorded together with 
the start date and end date. The dose level and the daily dose (mg/day) are defined based on the 
dispensing level according to Table 2-5.
Table 2-5
Dose levels and daily doses of the study drug
Dispensing
Level
Dose
Level
Dose
Daily Dose
LCZ696
Valsartan
Enalapril
LCZ696
Valsartan
Enalapril
No treatment
0
No Dose
No Dose
No Dose
0 mg/day
0 mg/day
0 mg/day
Dose level 1
1
50 mg bid.
40 mg bid.
2.5 mg bid.
100 mg/day
80 mg/day
5 mg/day
Dose level 2
2
100 mg bid.
80 mg bid.
5.0 mg bid.
200 mg/day 160 mg/day 10 mg/day
Dose level 3
3
200 mg bid. 160 mg bid. 10.0 mg bid. 400 mg/day 320 mg/day 20 mg/day
Dispensing level, dose level and daily dose at each visit
For a given visit, the visit associated dosing interval is defined as the dosing interval with its 
start date prior to or equal to the date of visit AND its end date later than or equal to the date of 
visit; the dispensing level, dose level and daily dose (mg/day) at the visit are defined as the 
dispensing level, dose level and daily dose (mg/day) for the visit associated dosing interval. In 
the case that, the visit date is equal to the end date of an earlier dosing interval as well as the 
start date of a later dosing interval, the later dosing interval will be taken as the visit associated 
dosing interval.
The dispensing level will be summarized by treatment group and visit, for overall and for each 
stratum (ACEi, ARB, No RASi), using the number and percentage of patients on each level; 
the dose level will be summarized by treatment group and visit, for overall and for each stratum 


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(ACEi, ARB, No RASi), using number of observations, mean, standard deviation, median, 
minimum, Q1, Q3, and maximum; the daily dose (mg/day) will be summarized by treatment 
group and visit, for each stratum (ACEi, ARB, No RASi), but not for overall, using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum. The 
summary will include all scheduled visits in the randomized treatment epoch.
The SAF will be used for the above analyses.
Duration of treatment
The duration (day) of treatment is defined as the date of the last dose of the study drug minus 
the date of the first dose of the study drug plus one day, regardless of temporary treatment 
interruption.
The duration (week) of treatment will be converted from the duration (day) of treatment using 
a factor of 7 day/week, and will be summarized by treatment group, for overall and for each 
stratum (ACEi, ARB, No RASi), using number of observations, mean, standard deviation, 
median, minimum, Q1, Q3, and maximum.
The duration (week) of treatment will be categorized into the following categories.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 16 weeks

≥16 weeks
The categorized duration of treatment will be summarized by treatment group, for overall and 
for each stratum (ACEi, ARB, No RASi), using the number and percentage of patients within 
each category.
Besides, the overall patient-weeks on-treatment will be provided by treatment group, for overall 
and for each stratum (ACEi, ARB, No RASi), where the overall patient-weeks on-treatment is 
defined as the sum of duration (week) of treatment among all patients within the corresponding 
treatment group and stratum.
The SAF will be used for the above analyses.
Duration on each dose level
For a given dose level, the duration (day) on this dose level is defined as the number of days on 
this dose level during the period from the date of the first dose of the study drug to the date of 
the last dose of the study drug. In the case that, the end date of an earlier dosing interval is the 
same as the start date of a later dosing interval, the day will be counted as 0.5 day on both the 
earlier dose level and the later dose level. In the case that, the date of permanent discontinuation 
of the study drug is the same as the date of the last dose the study drug, the day will be counted 
as 0.5 day on the dose level of the last dose but not counted on dose level 0.
The duration (week) on each dose level will be converted from the duration (day) on this dose 
level using a factor of 7 day/week, and will be summarized by treatment group, for overall and 
for each stratum (ACEi, ARB, No RASi).
The SAF will be used for the above analyses.


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Duration of study drug exposure
The duration (day) of study drug exposure is defined as the sum of the duration (day) on dose 
level 1 to 3.
The duration (week) of study drug exposure will be converted from the duration (day) of study 
drug exposure using a factor of 7 day/week, and will be summarized by treatment group, for 
overall and for each stratum (ACEi, ARB, No RASi), using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum.
The duration (week) of study drug exposure will be categorized into the following categories.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 16 weeks

≥16 weeks
The categorized duration of study drug exposure will be summarized by treatment group, for 
overall and for each stratum (ACEi, ARB, No RASi), using the number and percentage of 
patients within each category.
The SAF will be used for the above analyses.
Percentage of study drug exposure
For each patient, the percentage of study drug exposure is defined as the percentage of the 
duration (day) of study drug exposure out of the duration (day) of treatment.
The percentage of study drug exposure will be summarized by treatment group, for overall and 
for each stratum (ACEi, ARB, No RASi), using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum.
The SAF will be used for the above analyses.
Study treatment permanent discontinuation at each visit
For a given visit, a patient is considerred as permanently discontinued from the study treatment 
at this visit, if the patient permanently discontinued from the study treatment prior to or on the 
date of this visit.
For overall and for each stratum (ACEi, ARB, No RASi), the number and percentage of patients
who permanently discontinued from the study treatment will be provided for each scheduled 
visit in the randomized treatment epoch.
Mean daily dose and mean dose level
For each patient, the mean dose level is defined as the weighted mean of the dose level among 
dose level 0 to 3 using the duration (day) on each dose level as the weight, i.e.,
∑
 × Duration (day) on Dose Level 
3
=0
∑
Duration (day) on Dose Level 
3
=0
.


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The mean dose level will be summarized by treatment group, for overall and for each stratum 
(ACEi, ARB, No RASi), using number of observations, mean, standard deviation, median, 
minimum, Q1, Q3, and maximum.
For each patient and each dosing interval, the daily dose is defined based on the dose level and 
the active study medication for the actual arm according to Table 1-1 and Table 2-5. If there is 
no active study medication for the actual arm (i.e., the IMT arm in the No RASi stratum), the 
daily dose is defined as 0 mg/day.
For each patient, the mean daily dose (mg/day) is defined as the weighted mean of the daily 
dose (mg/day) among dose level 0 to 3 using the duration (day) on each dose level as the weight, 
i.e.
The mean daily dose (mg/day) will be summarized by treatment group, for each stratum (ACEi, 
ARB, No RASi), but not for overall, using number of observations, mean, standard deviation, 
median, minimum, Q1, Q3, and maximum.
The SAF will be used for the above analyses.
Duration of study exposure
The duration (day) of study exposure is defined as the date of last visit minus the date of 
randomization plus one day.
The duration (week) of study exposure will be derived from the duration (day) of study exposure 
using a factor of 7 day/week, and will be summarized by treatment group, for overall and for 
each stratum (ACEi, ARB, No RASi), using number of observations, mean, standard deviation, 
median, minimum, Q1, Q3, and maximum.
The duration (week) of study exposure will be categorized into the following categories.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 16 weeks

≥16 weeks
The categorized duration of study exposure will be summarized by treatment group, for overall 
and for each stratum (ACEi, ARB, No RASi), using the number and percentage of patients 
within each category.
The SAF will be used for the above analyses.
Last recorded dose level
The last recorded dose level is defined as the dose level for the last dosing interval.
The last recorded dose level will be summarized by treatment group, for overall and for each 
stratum (ACEi, ARB, No RASi), using the number and percentage of patients on each dose 
level.
The SAF will be used for the above analyses.
∑
Daily Dose (mg/day) for Dose Level  × Duration (day) on Dose Level 
3
=0
∑
Duration (day) on Dose Level 
3
=0
.


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Dose down-titration
A down-titration dosing interval is defined as a dosing interval whose dose level is changed to 
a lower dose level from its previous dosing interval.
The dose down-titration will be summarized by treatment group, for overall and for each 
stratum (ACEi, ARB, No RASi), using the number and percentage of patients with at least one 
down-titration dosing interval.
The SAF will be used for the above analyses.
Time to first down-titration of the study drug
The time (day) to first down-titration is defined as the start date of first down-titration dosing 
interval minus the date of first dose plus one day. If no down-titration occurred for the patient, 
the time (day) to first down-titration will be censored on the date of death (if the patient died), 
or the date of last visit (if the patient did not die) for the patient.
For overall and for each stratum (ACEi, ARB, No RASi), the time (day) to first down-titration, 
will be summarized by treatment group, using Kaplan-Meier curves.
The SAF will be used for the above analyses.
Dose interruption
A dose-interruption dosing interval is defined as a dosing interval whose dose level is 0.
The number and percentage of patients with at least one dose-interruption dosing interval will 
be provided by treatment group, for overall and for each stratum (ACEi, ARB, No RASi).
The duration of dose interruption is defined as the sum of (the end date minus the start date plus 
one day) among all dose-interruption dosing intervals.
The number and percentage of patients whose duration of dose interruption is larger than 14 
days will be provided by treatment group, for overall and for each stratum (ACEi, ARB, No 
RASi).
The SAF will be used for the above analyses.
Compliance
As presented in Table 1-1, in this study, the study medication includes LCZ696 Active/Placebo
(for all patients), Enalapril Active/Placebo (only for patients in the ACEi stratum) and Valsartan
Active/Placebo (only for patients in the ARB stratum).
For each applicable study medication, the compliance will be recorded on the CRF page: “Study 
Treatment Compliance per Visit”, whereby, for each post-baseline scheduled visit (Week 2, 
Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24), the compliance from the closest 
previous attended scheduled visit to the current visit should be recorded.
Specifically, for patients in the ACEi stratum, the compliance for LCZ696 Active/Placebo and 
Enalapril Active/Placebo will be recorded; for patients in the ARB stratum, the compliance for 
LCZ696 Active/Placebo and Valsartan Active/Placebo will be recorded; for patients in the No 
RASi stratum, the compliance for LCZ696 Active/Placebo will be recorded.


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For each patient and each post-baseline scheduled visit, the on treatment duration (day) from 
the closest previous attended scheduled visit to the current visit is defined as the number of days 
on any positive dose level during the period from the date of the closest previous attended 
scheduled visit (inclusive for the first post-baseline scheduled visit, but exclusive for all 
afterwards) to the date of the current visit (inclusive).
For each patient and each applicable study medication (Table 1-1) , the overall compliance for 
the study medication is defined as the weighted mean of the compliance using the on treatment 
duration (day) as the weight, i.e.
where period k is the period from the date of the closest attended scheduled visit prior to Visit 
k (inclusive for the first post-baseline scheduled visit, but exclusive for all afterwards) to the 
date of Visit k (inclusive), and the sum is over all attended post-baseline scheduled visit.
For each stratum (ACEi, ARB, No RASi) and each applicable study medication (Table 1-1), 
the overall compliance (%) will be summarized separately by treatment group, using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum.
2.4.2
Prior and concomitant therapies
Prior and concomitant medications will be recorded on the CRF page: “Prior and Concomitant 
Medications”. Procedures and significant non-drug therapies (prior and concomitant) will be 
recorded on the CRF page “Surgical and Medical Procedures”.
The missing or partially missing start/end date for prior/concomitant therapies will be imputed 
based on the Novartis ADaM Governance Board (AGB) global standards.
Prior and concomitant medications/non-drug therapies will be identified based on recorded or 
imputed start dates and end dates.
Prior medications are defined as any recorded medication with its start date (recorded or 
imputed) prior to the date of the first dose of the study drug.
Concomitant medications are defined as any recorded medication with its end date (recorded or 
imputed) later than or equal to the date of the first dose of the study drug AND its start date 
(recorded or imputed) prior to or equal to the end date of the study.
Prior non-drug therapies are defined as any procedure/significant non-drug therapy with its start 
date (recorded or imputed) prior to the date of the first dose of the study drug.
Concomitant non-drug therapies are defined as any recorded procedure/significant non-drug 
therapy with its end date (recorded or imputed) later than or equal to the date of the first dose 
of the study drug AND its start date (recorded or imputed) prior to or equal to the end date of 
the study.
For overall and for each stratum (ACEi, ARB, No RASi), prior and concomitant medications 
will be summarized separately by treatment group, anatomical therapeutic classification (ATC) 
and PT; prior and concomitant non-drug therapies will be summarized separately by treatment 
group, SOC, PT.
∑On Treatment Duration (day) in Period  × Compliance(%) in Period 

∑On Treatment Duration (day) in Period 

,


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In addition, for each of the following classes, prior medications and concomitant medications 
will be summarized by treatment group, for overall and each stratum (ACEi, ARB, No RASi).

Open label ACEi

Open label ARB

Open label ACEi or ARB

Open label dual RAS blockade

Open label sacubitril/valsartan

Renin inhibitors

Beta blockers

Diuretics

Aldoesterone antagonists

Loop diuretics

Thiazide diuretics

Other diuretics

Calcium antagonists

Nitrates

Other vasodilators

Cardiac glycosides (digoxin/digitalis glycoside)

Antiarrhythmic agents

Aspirin

Other antiplatelet agents

Other antithrombotic agents

Vitamin-K antagonist

NOAKs

Statins

Other lipid lowering agents

Insulins

GLP-1 agonists

Oral anti diabetics

SGLT-2 inhibitors
The SAF will be used for the above analyses.
2.4.3
Comorbidity management
The lipid management will be recorded on the CRF page: “Management of Comorbidities –
Lipids Management”, and will be summarized by treatment group and visit, for overall and for 
each stratum (ACEi, ARB, No RASi), using the number and percentage of patients having low-
density lipoprotein (LDL) ≥100 mg/dL and (coronary artery disease [CAD] or diabetes), the 
number and percentage of patients with lipid lowering medications initiated/adjusted, and the 


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number and percentage of patients with lipid lowering medications not initiated/adjusted for
each reason.
The diabetes management will be recorded on the CRF page: “Management of Comorbidities 
– Diabetes Management”, and will be summarized by treatment group and visit, for overall and 
for each stratum (ACEi, ARB, No RASi), using the number and percentage of patients with 
HbA1c > 7.5%, the number and percentage of patients with diabetic medications 
initiated/adjusted, and the number and percentage of patients with diabetic medications not 
initiated/adjusted for each reason.
The atrial fibrillation and atrial flutter management, including rate control and anticoagulation 
or antiplatelet therapy, will be recorded on the CRF page: “Management of Comorbidities –
Atrial Fibrillation and Atrial Flutter”, and will be summarized by treatment group and visit, for 
overall and for each stratum (ACEi, ARB, No RASi), using the number and percentage of 
patients with heart rate ≥100 beats per minute (bpm), the number and percentage of patients
with rate control medications initiated/adjusted, the number and percentage of patients
receiving anticoagulation or antiplatelet therapy, the number and percentage of patients with 
rate control medications not initiated/adjusted for each reason, and the number and percentage 
of patients not receiving anticoagulation or antiplatelet therapy for each reason.
The blood pressure management will be recorded on the CRF page: “Management of 
Comorbidities – Blood Pressure Management”, and will be summarized by treatment group and 
visit, for overall and for each stratum (ACEi, ARB, No RASi), using the number and percentage 
of patients with either SBP > 140 mmHg or DBP > 90 mmHg, the number and percentage of 
patients with blood pressure medications initiated/adjusted, and the number and percentage of 
patients with blood pressure medications not initiated/adjusted for each reason.
The SAF will be used for the above analyses.
2.5
Analysis of the primary objective
2.5.1
Primary endpoints
The primary efficacy variables are the change from baseline in log(NT-proBNP) at Week 12, 
and the change from baseline in 6MWD at Week 24.
Plasma NT-proBNP will be collected using central lab.
All post-screening NT-proBNP from central lab will remain blinded until data base lock. Only 
the NT-proBNP at screening will be reported to the investigator and the Novartis clinical study 
team.
For the NT-proBNP, if the test value is below the lowest limit of quantitation (LLOQ), the test 
value will be imputed by 0.5 × LLOQ; if the test value is above the upper limit of quantitation 
(ULOQ), the test value will be imputed by 1.5 × ULOQ.
For the NT-proBNP, unreliable test values will be set to missing.
The 6MWD will be recorded on the CRF page: “6 Minute Walk Test and Borg Scale”.
Specifically, for the 6MWD, the baseline assessment is defined as the scheduled assessment at 
randomization (nominal visit).


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For patients who have died, the 6MWD after the death will be defined as zero.
For patients who permanently discontinue from study treatment, assessment values collected 
after permanent discontinuation will generally be included in the analysis.
2.5.2
Statistical hypothesis, model, and method of analysis
Since the testing procedure involves both the primary and secondary endpoints, we describe it 
for them together. The analysis methods for the secondary endpoints are described in Section 
2.6.
Testing strategy
The following primary null hypotheses will be included in the testing strategy.

H1: LCZ696 is no better than IMT in change from baseline in log(NT-proBNP) at Week 
12 in the overall study population

H2: LCZ696 is no better than IMT in change from baseline in 6MWD at Week 24 in 
patients with baseline six-minute walk distance (B6MWD) ranging from 100 meters to 
450 meters.
The following secondary null hypotheses will be included in the testing strategy.

H3: LCZ696 is no better than IMT in change from baseline in KCCQ CSS at Week 24 in 
the overall study population.

H4: LCZ696 is no better than IMT in NYHA change from baseline at Week 24 in the 
overall study population.
Each null hypothesis is tested against the one-sided alternative that LCZ696 is better than IMT
in the corresponding variable.
In order to control the family-wise type-I error rate at the one-sided 0.025 significance level, a 
sequentially rejective multiple testing procedure based on the graphical presentation (Bretz et 
al 2009) will be employed, whereby H1 and H2 will be tested first at initially assigned level of 
one-sided (9/10) × α = 0.0225 and one-sided (1/10) × α = 0.0025, accordingly. If H1 and/or H2
are rejected, the alpha for the rejected null hypotheses will be propagated to H3, such that, H3
will be tested at the updated alpha level (one-sided 0.025 if both H1 and H2 are rejected; one-
sided 0.0225 if H1 is rejected but H2 is not rejected; one-sided 0.0025 if H2 is rejected but H1 is 
not rejected); if H3 is rejected, the alpha will be propagated to H2 or H4 based on the initial step 
rejection status.

With H1 rejected but H2 not rejected at the initial step, if H3 is rejected at one-sided 
0.0225, the alpha will be propagated to H2, such that, H2 will be tested again at one-sided 
0.025; if H2 is rejected at one-sided 0.025, the alpha will be further propagated to H4. 
Otherwise, the testing procedure will stop.

With H2 rejected but H1 not rejected at the initial step, if H3 is rejected at one-sided 
0.0025, the alpha will be propagated to H4, such that, H4 will be tested at one-sided 
0.0025. Otherwise, the testing procedure will stop.

With both H1 and H2 rejected at the initial step, if H3 is rejected at one-sided 0.025, the 
alpha will be propagated to H4, such that, H4 will be tested at full alpha (one-sided 0.025). 
Otherwise, the testing procedure will stop.


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Figure 2-1 provides graphical illustration of the sequentially rejective testing procedure.
Figure 2-1
Graphical illustration of the sequentially rejective testing procedure
Based on the above testing procedure, if applicable, H1, H2 and H3 will be tested based on the 
corresponding mixed models for repeated measures (descriptions below and Section 2.6.1.1), 
H4 will be tested based on the longitudinal proportional cumulative odds model (Section 2.6.2)
NT-proBNP analyses
The changes from baseline in log(NT-proBNP) will be analyzed using a mixed model for 
repeated measures (MMRM), in which, the response variable will be the changes from baseline 
in log(NT proBNP); stratum (ACEi, ARB, No RASi), region, treatment (LCZ696, IMT), visit 
and treatment-by-visit interaction will be included as fixed-effect factors; baseline log(NT-
proBNP) (BLNTBNP), stratum-by-BLNTBNP and visit-by-BLNTBNP interactions will be 
included as covariates; the within-patient covariance will be modeled using an unstructured 
covariance matrix (a common matrix for the two treatment groups). The analysis will include 
all post-baseline scheduled visits up to Week 12 (Week 4, Week 12) and will be performed 


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based on the likelihood method with an assumption of missing at random (MAR) for missing 
data (Siddiqui et al 2009, National Research Council 2010).
Based on the MMRM model, the primary null hypothesis, H1, will be tested based on the testing 
strategy, the estimates and the corresponding two-sided 95% confidence intervals will be 
provided for the adjusted geometric means for the ratio to baseline in NT-proBNP at Week 12 
in both treatment groups (LCZ696 and IMT), and for the ratio of the adjusted geometric means 
(LCZ696/IMT). The corresponding one-sided p-values will also be provided based on the 
MMRM model.
The FAS will be used for the above primary analyses.
As a supportive analysis, the same approach will also be performed on the PPS.
6MWD analyses
The changes from baseline in 6MWD will be analyzed using a MMRM model, in which, the 
response variable will be the changes from baseline in 6MWD; stratum (ACEi, ARB, No RASi),
region, treatment (LCZ696, IMT), visit and treatment-by-visit interaction will be included as 
fixed-effect factors; B6MWD, BSBP, stratum-by-B6MWD, stratum-by-BSBP and visit-by-
B6MWD interactions will be included as covariates; the within-patient covariance will be 
modeled using an unstructured covariance matrix (a common matrix for the two treatment 
groups). The analysis will include all patients with B6MWD ranging from 100 meters to 450 
meters, and all post-baseline scheduled visits up to Week 24 (Week 16 and Week 24), and will 
be performed based on the likelihood method with an assumption of MAR for missing data 
(other than due to death).
Based on the MMRM model, the primary null hypothesis, H2, will be tested based on the testing 
strategy, the estimates and the two-sided 95% confidence intervals will be provided for the 
adjusted means for the change from baseline in 6MWD at each post-baseline scheduled visit
(Week 16 and Week 24) in both treatment groups (LCZ696 and IMT), and for the adjusted 
mean difference (LCZ696 minus IMT) at each post-baseline scheduled visit (Week 16 and 
Week 24). The corresponding one-sided p-values will also be provided based on the MMRM
model.
All patients in the FAS with B6MWD ranging from 100 meters to 450 meters will be used for 
the above primary analysis.
As a supportive analysis, the same approach will also be performed on the FAS with all patients 
included, regardless of B6MWD values, and on the PPS.
In addition, the improvement and the deterioration in 6MWD will be analyzed separately using 
longitudinal binary logistic regression models, in which, the response variables will be, the 
6MWD improvement (event defined by at least 30 meters improvement in 6MWD) and the 
6MWD deterioration (event defined by at least 30 meters deterioration in 6MWD), accordingly; 
stratum (ACEi, ARB, No RASi), region, treatment (LCZ696, IMT), visit and treatment-by-visit 
interaction will be included as fixed-effect factors; B6MWD, BSBP, stratum-by-B6MWD, 
stratum-by-BSBP and visit-by-B6MWD interactions will be included as covariates; patient-
specific intercepts will be included as random effects. The analysis will include all post-baseline 


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scheduled visits up to Week 24 (Week 16 and Week 24) and will be performed based on the 
likelihood method with an assumption of MAR for missing data (other than due to death).
Based on the longitudinal binary logistic regression models, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted odds ratios (LCZ696/IMT) at each post-
baseline scheduled visit (Week 16 and Week 24). The corresponding one-sided p-values will 
also be provided based on the longitudinal binary logistic model.
Besides, the 6MWD will be summarized by treatment group and visit, for overall and for each 
stratum (ACEi, ARB, No RASi), using number of observations, mean, standard deviation, 
median, minimum, Q1, Q3, and maximum.
As additional supportive analyses, the Mantel-Haenszel estimates and the corresponding 95% 
confidence intervals will be provided by visit, for the relative risks and the risk differences, for 
6MWD improvement and 6MWD deterioration, accordingly.
In addition to the 6MWD, the pre-test and post-test heart rate (HR), SBP, DBP, Borg scale for 
dyspnea and Borg scale for fatigue, will also be recorded on the CRF page: “6 Minute Walk 
Test and Borg Scale” and will be summarized by treatment group and visit, for overall and for 
each stratum (ACEi, ARB, No RASi), using number of observations, mean, standard deviation, 
median, minimum, Q1, Q3, and maximum.
The FAS will be used for the above analyses.
2.5.3
Handling of missing values/censoring/discontinuations
Missing data will be handled with the likelihood method with the assumption that they are MAR 
in the primary analysis.
2.5.4
Supportive and sensitivity analyses
In order to explore the robustness of the MAR assumption on the primary analysis, a sensitivity 
analysis will be carried out which assesses the situation where the data are missing not at 
random (MNAR); In particular, the sensitivity analysis will assume that LCZ696 patients who 
discontinue from the study treatment due to adverse events, death or lack of efficacy will not 
have adhered to therapy if they had stayed in the study.
Patients who discontinue from the study treatment due to adverse events, death or lack of 
efficacy are defined as those who discontinued from the study treatment during the randomized 
treatment epoch, and had the primary reason for discontinuation of study treatment (CRF page: 
“End of Study Treatment”) specified as “Adverse event”, “Death” or “Lack of efficacy”.
A controlled multiple imputation approach based on pattern mixture models will be applied
(Carpenter and Kenward 2013), whereby all missing data of patients in the LCZ696 group who 
permanently discontinue study treatment due to: adverse events, death or lack of efficacy, will 
be assumed to behave like patients in the IMT group after permanent discontinuation and will 
be imputed based on the data from patients in the IMT group according to the stratum (ACEi, 
ARB, No RASi).

For changes from baseline in log(NT-proBNP), for each post-baseline scheduled visit up 
to Week 12 (Week 4, Week 12), the imputation model will be a linear regression model 
specified using fully conditional specifications, in which, the response variable will be the 


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change from baseline in log(NT-proBNP) at the visit; region will be included as a fixed-
effect factor; BLNTBNP, change from baseline in log(NT-proBNP) at the closest previous 
post-baseline scheduled visit (not applicable for Week 4, Week 4 for Week 12) will be 
included as covariates. For each stratum (ACEi, ARB, No RASi), the imputation model 
will be fitted separately based on the data from all patients in the IMT group within the 
stratum.

For changes from baseline in 6MWD, for each post-baseline scheduled visit up to Week 
24 (Week 16 and Week 24), the imputation model will be a linear regression model 
specified using fully conditional specifications, in which, the response variable will be the 
change from baseline in 6MWD at the visit; region will be included as a fixed-effect 
factor; B6MWD, BSBP, change from baseline in 6MWD at the closest previous post-
baseline scheduled visit (not applicable for Week 16, Week 16 for Week 24) will be 
included as covariates. For each stratum (ACEi, ARB, No RASi), the imputation model 
will be fitted separately based on the data from patients with B6MWD ranging from 100 
meters to 450 meters in the IMT group within the stratum.
All other missing data will be considered as MAR within each arm and will be imputed using a 
multiple imputation approach (Carpenter and Kenward 2013) based on observed data within 
each arm according to the stratum. Of note, patients who permanently discontinue study 
treatment, are not considered discontinued from the study. It is planned to continue to collect 
and use data at scheduled visits even after permanent discontinuation of study treatment.

For changes from baseline in log(NT-proBNP), for each post-baseline scheduled visit up 
to Week 12 (Week 4, Week 12), the imputation model will be a linear regression model 
specified using fully conditional specifications, in which, the response variable will be the 
change from baseline in log(NT-proBNP) at the visit; region will be included as a fixed-
effect factor; BLNTBNP, change from baseline in log(NT-proBNP) at the closest previous 
post-baseline scheduled visit (not applicable for Week 4, Week 4 for Week 12) will be 
included as covariates. For each stratum (ACEi, ARB, No RASi) and each arm, the 
imputation model will be fitted separately based on the data from all patients in the arm 
within the stratum.

For changes from baseline in 6MWD, for each post-baseline scheduled visit up to Week 
24 (Week 16 and Week 24), the imputation model will be a linear regression model 
specified using fully conditional specifications, in which, the response variable will be the 
change from baseline in 6MWD at the visit; region will be included as a fixed-effect 
factor; B6MWD, BSBP, change from baseline in 6MWD at the closest previous post-
baseline scheduled visit (not applicable for Week 16, Week 16 for Week 24) will be 
included as covariates. For each stratum (ACEi, ARB, No RASi) and each arm, the 
imputation model will be fitted separately based on the data from patients with B6MWD 
ranging from 100 meters to 450 meters in the arm within the stratum.
Furthermore, the missing data patterns in the change from baseline in the log(NT-proBNP) and 
the change from baseline in 6MWD will be explored via by-treatment-group box plots for 
patients who permanently discontinue from study treatment due to adverse events, death or lack 
of efficacy, for patients who permanently discontinue from study treatment due to any other 
reasons, for patients who did not permanently discontinue from study treatment, and for patients 


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who take open label LCZ696 after permanent discontinuation from study treatment. Similar box 
plots will also be provided for on-treatment assessments.
As additional supportive analyses, the primary analyses for the primary endpoints (change from 
baseline in log[NT-proBNP] at Week 12, and change from baseline in 6MWD at Week 24) 
described in Section 2.5.2 will be performed for the following data as applicable.

Data where the 6MWD after the death were set to missing for patients who died.

Data where the last observation carry forward (LOCF) approach was performed for 
missing data.

Data where the responses after the first dose of open-label RASi or open-label LCZ696 
after permanent discontinuation of the study treatment will be set to missing and 
considered MAR. (This is called on-treatment analysis.)
The FAS will be used for the above analyses.
As an additional supportive analysis, the change from baseline in 6MWD will be analyzed using 
a partial linear MMRM model, in which, the response variable will be the changes from baseline
in 6MWD; stratum (ACEi, ARB, No RASi), region, treatment (LCZ696, IMT), visit and 
treatment-by-visit interaction will be included as fixed-effect factors; B6MWD and BSBP will 
be included as non-parametric fixed-effect covariates, denoted as g(B6MWD) and h(BSBP), 
stratum-by-g(B6MWD) interaction, stratum-by-h(BSBP) interaction, visit-by-g(B6MWD) 
interaction and treatment-by-g(B6MWD) interaction will also be included as covariates. The 
non-parametric effects will be approximated using natural cubic splines, in which the quintiles 
are used as knots. Based on the model, the estimated adjusted mean difference for change from 
baseline in 6MWD at Week 24 will be plotted against theB6MWD.
The FAS will be used for the above analyses.
2.5.5
Subgroup analyses
For each primary endpoint (Section 2.5.1), subgroup analyses will be performed utilizing the 
corresponding primary analysis model (Section 2.5.2), after adding the fixed-effect factors of 
subgroup variable and subgroup-variable-by-treatment interaction into the original model. The 
following subgroup variables (Section 2.2.1, Table 2-3) will be used for the subgroup analyses 
for both primary endpoints.

Region

Stratum (ACEi, ARB, No RASi)

Age group (< 65 years, ≥ 65 years)

Age group (< 75 years, ≥ 75 years)

Sex

Baseline NYHA class group

Diabetes (history or HbA1c ≥ 6.5%)

LVEF group (<= 60%, > 60%)

Prior heart failure hospitalization


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For changes from baseline in log(NT-proBNP), based on the subgroup analysis models, the 
estimates and the two-sided 95% confidence intervals will be provided for adjusted geometric 
means for ratio to baseline in NT-proBNP at Week 12 in both treatment groups (LCZ696 and 
IMT) within each subgroup, and for the ratio of the adjusted geometric means (LCZ696/IMT)
at Week 12 within each subgroup; the p-value for the subgroup-variable-by-interaction will be 
provided for each subgroup variable.
For changes from baseline in 6MWD, based on the subgroup analysis models, the estimates and 
the two-sided 95% confidence intervals will be provided for the adjusted means for the change 
from baseline in 6MWD at Week 24 in both treatment groups (LCZ696 and IMT) within each 
subgroup, and for the adjusted mean difference (LCZ696 minus IMT) at Week 24 within each 
subgroup; the p-value for the subgroup-variable-by-interaction will be provided for each
subgroup variable.
In addition, for each primary endpoint (Section 2.5.1), multivariate subgroup analyses will be 
performed utilizing the corresponding primary analysis model (Section 2.5.2), after adding the 
fixed-effect factors of all the follwoing subgroup variables and subgroup-variable-by-treatment 
interactions into the original model. The p value for the global interaction test (null hypothesis: 
all interaction terms are equal to zero) will be presented, together with the p value for each 
interaction.

Region

Stratum (ACEi, ARB, No RASi)

Age group (< 75 years, ≥ 75 years)

Sex

Baseline NYHA class group

Diabetes (history or HbA1c ≥ 6.5%)

LVEF group (<= 60%, > 60%)

Prior heart failure hospitalization
The FAS will be used for the above subgroup analyses.
2.6
Analysis of secondary efficacy objective(s)
All secondary efficacy variables will be analyzed using the FAS, unless otherwise specified.
2.6.1
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ consists of 23 individual items comprising 10 summary scores.
For each individual item, the item response will be mapped into numeric response score, using 
the mapping criteria defined in Table 2-6.
Table 2-6
KCCQ item response scoring
Item ID
Item Response
Response
Score
1(a)-1(f)
EXTREMELY LIMITED
0.00
QUITE A BIT LIMITED
0.25


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Item ID
Item Response
Response
Score
MODERATELY LIMITED
0.50
SLIGHTLY LIMITED
0.75
NOT AT ALL LIMITED
1.00
LIMITED FOR OTHER REASONS OR DID NOT DO THE ACTIVITY
Missing
2
MUCH WORSE
0.00
SLIGHTLY WORSE
0.25
NOT CHANGED
0.50
SLIGHTLY BETTER
0.75
MUCH BETTER
1.00
I’VE HAD NO SYMPTOMS OVER THE LAST 2 WEEKS
0.50
3
EVERY MORNING
0.00
3 OR MORE TIMES A WEEK, BUT NOT EVERY DAY
0.25
1-2 TIMES A WEEK
0.50
LESS THAN ONCE A WEEK
0.75
NEVER OVER THE PAST 2 WEEKS
1.00
4, 6 and 8
EXTREMELY BOTHERSOME
0.00
QUITE A BIT BOTHERSOME
0.25
MODERATELY BOTHERSOME
0.50
SLIGHTLY BOTHERSOME
0.75
NOT AT ALL BOTHERSOME
1.00
I’VE HAD NO SWELLING
1.00
I’VE HAD NO FATIGUE
1.00
I’VE HAD NO SHORTNESS OF BREATH
1.00
5 and 7
ALL OF THE TIME
0.00
SEVERAL TIMES PER DAY
1/6
AT LEAST ONCE A DAY
1/3
3 OR MORE TIMES A WEEK, BUT NOT EVERY DAY
0.50
1-2 TIMES A WEEK
2/3
LESS THAN ONCE A WEEK
5/6
NEVER OVER THE PAST 2 WEEKS
1.00
9
EVERY NIGHT
0.00
3 OR MORE TIMES A WEEK, BUT NOT EVERY DAY
0.25
1-2 TIMES A WEEK
0.50
LESS THAN ONCE A WEEK
0.75
NEVER OVER THE PAST 2 WEEKS
1.00
10
NOT AT ALL SURE
0.00
NOT VERY SURE
0.25
SOMEWHAT SURE
0.50
MOSTLY SURE
0.75
COMPLETELY SURE
1.00
11
DO NOT UNDERSTAND AT ALL
0.00


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Item ID
Item Response
Response
Score
DO NOT UNDERSTAND VERY WELL
0.25
SOMEWHAT UNDERSTAND
0.50
MOSTLY UNDERSTAND
0.75
COMPLETELY UNDERSTAND
1.00
12
IT HAS EXTREMELY LIMITED MY ENJOYMENT OF LIFE
0.00
IT HAS LIMITED MY ENJOYMENT OF LIFE QUITE A BIT
0.25
IT HAS MODERATELY LIMITED MY ENJOYMENT OF LIFE
0.50
IT HAS SLIGHTLY LIMITED MY ENJOYMENT OF LIFE
0.75
IT HAS NOT LIMITED MY ENJOYMENT OF LIFE AT ALL
1.00
13
NOT AT ALL SATISFIED
0.00
MOSTLY DISSATISFIED
0.25
SOMEWHAT SATISFIED
0.50
MOSTLY SATISFIED
0.75
COMPLETELY SATISFIED
1.00
14
I FELT THAT WAY ALL OF THE TIME
0.00
I FELT THAT WAY MOST OF THE TIME
0.25
I OCCASIONALLY FELT THAT WAY
0.50
I RARELY FELT THAT WAY
0.75
I NEVER FELT THAT WAY
1.00
15(a)-15(d)
SEVERELY LIMITED
0.00
LIMITED QUITE A BIT
0.25
MODERATELY LIMITED
0.50
SLIGHTLY LIMITED
0.75
DID NOT LIMIT AT ALL
1.00
DOES NOT APPLY OR DID NOT DO FOR OTHER REASONS
Missing
KCCQ physical limitation score
The KCCQ physical limitation score will be defined as
100 × the mean of the non-missing response scores among items {1(a)-1(f)},
if there are at least three non-missing response scores among items {1(a)-1(f)}; the score will 
be left as missing if there are not enough non-missing response scores among these items.
KCCQ symptom stability score
The KCCQ symptom stability score will be defined as
100 × the response score for item 2,
if the response score for item 2 is non-missing; the score will be left as missing if the response 
score is missing.
KCCQ symptom frequency score
The KCCQ symptom frequency score will be defined as
100 × the mean of the non-missing response scores among items {3, 5 , 7, 9},


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if there are at least two non-missing response scores among items {3, 5 , 7, 9}; the score will 
be left as missing if there are not enough non-missing response scores among these items.
KCCQ symptom burden score
The KCCQ symptom burden score will be defined as
100 × the mean of the non-missing response scores among items {4, 6, 8},
if there are at least one non-missing response scores among items {4, 6, 8}; the score will be 
left as missing if the response scores are missing for all items among items {4, 6, 8}
KCCQ self-efficacy score
The KCCQ self-efficacy score will be defined as
100 × the mean of the non-missing response scores among items {10, 11},
if there are at least one non-missing response scores among items {10, 11}; the score will be 
left as missing if the response scores are missing for both item 10 and item 11.
KCCQ quality of life score
The KCCQ quality of life score will be defined as
100 × the mean of the non-missing response scores among items {12, 13, 14},
if there are at least one non-missing response scores among items {12, 13, 14}; the score will 
be left as missing if the response scores are missing for all items among items {12, 13, 14}.
KCCQ social limitation score
The KCCQ social limitation score will be defined as
100 × the mean of the non-missing response scores among items {15(a)-15(d)},
if there are at least two non-missing response scores among items {15(a)-15(d)}; the score will
be left as missing if there are not enough non-missing response scores among these items.
Table 2-7
KCCQ summary scores
Summary Score
Relevant Items
Minimum Number of 
Non-Missing Response Scores
KCCQ physical limitation score
1(a)-1(f)
3
KCCQ symptom stability score
2
1
KCCQ symptom frequency score
3, 5, 7, 9
2
KCCQ symptom burden score
4, 6, 8
1
KCCQ self-efficacy score
10, 11
1
KCCQ quality of life score
12, 13, 14
1
KCCQ social limitation score
15(a)-15(d)
2
In summary, the above seven KCCQ summary scores will be defined as 100 times the mean of 
the non-missing response scores for the relevant items, if there are enough items with non-
missing response scores among the relevant items. The relevant items and the minimum number 
of non-missing response scores are given in Table 2-7.


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KCCQ total symptom score
The KCCQ total symptom score will be defined as the mean of the non-missing scores among 
the KCCQ symptom frequency score and the KCCQ symptom burden score. The KCCQ total 
symptom score will be left as missing, if the KCCQ symptom frequency score and the KCCQ 
symptom burden score are both missing.
KCCQ clinical summary score (CSS)
The KCCQ CSS will be defined as the mean of the non-missing scores among the following.

KCCQ physical limitation score

KCCQ total symptom score
If the above scores are both missing, the KCCQ CSS will be left as missing.
KCCQ overall summary score (OSS)
The KCCQ OSS will be defined as the mean of the non-missing scores among the following.

KCCQ physical limitation score

KCCQ total symptom score

KCCQ quality of life score

KCCQ social limitation score
If the above scores are all missing, the KCCQ OSS will be left as missing.
2.6.1.1
KCCQ clinical summary score (CSS) change from baseline
For patients who have died, the KCCQ CSS after the death will be imputed as zero.
For patients who permanently discontinue study treatment, values collected after permanent 
discontinuation will generally be included in the analysis.
The changes from baseline in KCCQ CSS will be analyzed using a MMRM model, in which, 
the response variable will be the changes from baseline in KCCQ CSS; stratum (ACEi, ARB, 
No RASi), region, treatment (LCZ696, IMT), visit and treatment-by-visit interaction will be 
included as fixed-effect factors; baseline KCCQ CSS (BCSS), BSBP, stratum-by-BCSS, 
stratum-by-BSBP, and visit-by-BCSS interactions will be included as covariates; the within-
patient covariance will be modeled using an unstructured covariance matrix (a common matrix 
for the two treatment groups). If the model fitting procedure does not converge, the AR(1) 
covariance structure will be used. The analysis will include all post-baseline scheduled visits 
up to Week 24 (Week 4, Week 12, Week 16 and Week 24) and will be performed based on the 
likelihood method with an assumption of MAR for missing data (other than due to death).
Based on the MMRM model, the secondary null hypothesis, H3, will be tested (if applicable) 
based on the testing strategy, the estimates and the two-sided 95% confidence intervals will be
provided for the adjusted mean changes from baseline in KCCQ CSS at each post-baseline 
scheduled visit (Week 4, Week 12, Week 16 and Week 24) in both treatment groups (LCZ696 
and IMT), and for the adjusted mean difference (LCZ696 minus IMT) at each post-baseline 
scheduled visit (Week 4, Week 12, Week 16 and Week 24). The corresponding one-sided p-
values will also be provided based on the MMRM model.


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In addition, the improvement and the deterioration in KCCQ CSS will be analyzed separately,
to further illustrate the clinical relevance of the observed differences in terms of proportion of 
responders, using longitudinal binary logistic regression models, in which, the response 
variables will be, the KCCQ CSS improvement (event defined by at least 5-points improvement 
in KCCQ CSS) and the KCCQ CSS deterioration (event defined by at least 5-points 
deterioration in KCCQ CSS), accordingly; stratum (ACEi, ARB, No RASi), region, treatment 
(LCZ696, IMT), visit and treatment-by-visit interaction will be included as fixed-effect factors; 
BCSS, BSBP, stratum-by-BCSS, stratum-by-BSBP and visit-by-BCSS interactions will be 
included as covariates; patient-specific intercepts will be included as random effects. The 
analysis will include all post-baseline scheduled visits up to Week 24 (Week 4, Week 12, Week 
16 and Week 24) and will be performed based on the likelihood method with an assumption of 
MAR for missing data (other than due to death). No multiplicity adjustment will be done for 
these supportive responder analyses (i.e., the tests for the responder analyses will be performed 
at nominal level of one-sided 0.025).
Based on the longitudinal binary logistic regression models, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted odds ratios (LCZ696 / IMT) at each post-
baseline scheduled visit (Week 4, Week 12, Week 16 and Week 24). The corresponding one-
sided p-values will also be provided based on the longitudinal binary logistic model.
Besides, the KCCQ CSS and the change from baseline in KCCQ CSS will be summarized by 
treatment group and visit, for overall and for each stratum (ACEi, ARB, No RASi), using 
number of observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum; 
the improvement and the deterioration in KCCQ CSS of at least 5-points will be summarized 
by treatment group and visit, for overall and for each stratum (ACEi, ARB, No RASi), using 
the numbers and percentages of patients whose KCCQ CSS improved at least 5 points, whose
KCCQ CSS deteriorated at least 5 points, whose KCCQ CSS changed less than 5 points, and 
whose KCCQ CSS is missing.
As additional supportive analyses, the Mantel-Haenszel estimates and the corresponding 95% 
confidence intervals will be provided by visit, for the relative risks and the risk differences, for 
KCCQ CSS improvement and KCCQ CSS deterioration, accordingly.
The FAS will be used for the above analyses.
2.6.1.2
KCCQ overall summary score (OSS) change from baseline
As additional exploratory analyses, the same analyses as KCCQ CSS will also be performed 
for KCCQ OSS, except that the BCSS in the analysis models will be replaced by baseline 
KCCQ OSS (BOSS), stratum-by-BCSS and visit-by-BCSS interactions in the analysis models
will be replaced by stratum-by-BOSS and visit-by-BOSS interactions.
The FAS will be used for the above analyses.
2.6.2
NYHA class change
The heart failure symptoms and the NYHA class will be recorded on the CRF page: “Signs and 
Symptoms of Heart Failure including New York Heart Association Classification”.
Table 2-8 defines the NYHA class change at each post-baseline visit.


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Table 2-8
NYHA Class Change
NYHA Class Change
Post-Baseline Visit
Class I
Class II
Class III
Class IV
Death
Baseline
Class I
unchanged
worsened
worsened
worsened
worsened
Class II
improved
unchanged
worsened
worsened
worsened
Class III
improved
improved
unchanged
worsened
worsened
Class IV
improved
improved
improved
unchanged
worsened
For patients who died, the NYHA class will be set to a firth category (death), and the NYHA 
class change after the death will be categorized into “worsened”. For patients who permanently 
discontinue study treatment, values collected after permanent discontinuation will generally be 
included in the analysis.
The NYHA class change will be analyzed using a longitudinal proportional cumulative odds 
model, in which, the response variable will be the NYHA class change (order defined by 
“improved” < “unchanged” < “worsened”); stratum (ACEi, ARB, No RASi), region, treatment 
(LCZ696, IMT), visit, treatment-by-visit interaction, baseline NYHA class, stratum-by-
baseline and visit-by-baseline interactions will be included as fixed-effect factors; BSBP and 
stratum-by-BSBP interaction will be included as covariates; patient-specific intercepts will be 
included as random effects. The analysis will include all post-baseline scheduled visits up to 
Week 24 (Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24) and will be 
performed based on the likelihood method with an assumption of MAR for missing data (other 
than due to death).
Based on the longitudinal proportional cumulative odds model, the secondary null hypothesis, 
H4, will be tested based on the testing strategy (if applicable), the estimate and the two-sided
95% confidence interval will be provided for the adjusted odds ratio (LCZ696 / IMT) at each 
post-baseline scheduled visit (Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and 
Week 24). The corresponding one-sided p-values will also be provided based on the model.
In addition, the improvement and the deterioration in NYHA class will be analyzed separately 
using longitudinal binary logistic regression models, in which, the response variables will be,
accordingly, the NYHA class improvement (event defined by NYHA class change of level 
“improved”) and the NYHA class deterioration (event defined by NYHA class change of level 
“worsened”); stratum (ACEi, ARB, No RASi), region, treatment (LCZ696, IMT), visit, 
treatment-by-visit interaction, baseline NYHA class, stratum-by-baseline and visit-by-baseline 
interactions will be included as fixed-effect factors; BSBP and stratum-by-BSBP interaction 
will be included as covariates; patient-specific intercepts will be included as random effects. 
The analysis will include all post-baseline scheduled visits up to Week 24 (Week 2, Week 4, 
Week 8, Week 12, Week 16, Week 20 and Week 24) and will be performed based on the 
likelihood method with an assumption of MAR for missing data (other than due to death).
Based on the longitudinal binary logistic regression models, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted odds ratios (LCZ696 / IMT) at each post-
baseline scheduled visit (Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 
24). The one-sided p-values will also be provided based on the longitudinal binary logistic 
model.


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Besides, the NYHA class and the NYHA class change will be summarized by treatment group 
and visit, for overall and for each stratum (ACEi, ARB, No RASi), using the numbers and 
percentages of patients within each category.
The heart failure symptoms will be summarized by treatment group and visit, for overall and 
for each stratum (ACEi, ARB, No RASi), using the numbers and percentages of patients with 
each heart failure symptom.
As additional supportive analyses, the Mantel-Haenszel estimates and the corresponding 95% 
confidence intervals will be provided by visit, for the relative risks and the risk differences, for 
NYHA improvement and NYHA deterioration, accordingly.
The FAS will be used for the above analyses.
2.6.3
Short Form Health Survey (SF-36)
The SF-36 consists of 36 individual items comprising eight scales: physical functioning, role-
physical, bodily pain, general health, vitality, social functioning, role-emotional and mental 
health. For each of the eight scales, a raw score ranging from 0 to 100, and a normalized score 
(normed to the US population) will be calculated. Based on the normalized scores, two overall 
summary scores: physical component summary (PCS) score and mental component summary 
(MCS) score will be calculated. The raw scores, the normalized scores and the overall summary
scores will be provided by Optum.
The raw scores, the normalized scores and the overall summary scores will be summarized by 
treatment group and visit, accordingly, for overall and for each stratum (ACEi, ARB, No RASi),
using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum.
2.6.3.1
SF-36 physical component summary (PCS) score
For patients who have died, the SF-36 PCS score after the death will be imputed as zero. For 
patients who permanently discontinue from study treatment, values collected after permanent 
discontinuation will generally be included in the analysis.
The changes from baseline in SF-36 PCS score will be analyzed using a MMRM model, in 
which, the response variable will be the changes from baseline in SF-36 PCS score; stratum 
(ACEi, ARB, No RASi), region, treatment (LCZ696, IMT), visit and treatment-by-visit 
interaction will be included as fixed-effect factors; baseline SF-36 PCS score (BPSS), BSBP, 
stratum-by-BPSS, stratum-by-BSBP and visit-by-BPSS interactions will be included as 
covariates; the within-patient covariance will be modeled using an unstructured covariance 
matrix (a common matrix for the two treatment groups). The analysis will include all post-
baseline scheduled visits up to Week 24 (Week 16 and Week 24) and will be performed based 
on the likelihood method with an assumption of MAR for missing data (other than due to death).
Based on the MMRM model, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted mean SF-36 PCS scores and the adjusted mean changes from baseline 
in the SF-36 PCS score at each post-baseline scheduled visit (Week 16 and Week 24) in both 
treatment groups (LCZ696 and IMT), and for the adjusted mean difference (LCZ696 minus 


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IMT) at each post-baseline scheduled visit (Week 16 and Week 24). The one-sided p-values 
will also be provided based on the MMRM model.
In addition, the improvement and the deterioration in SF-36 PCS score will be analyzed 
separately using longitudinal binary logistic regression models, in which, the response variables 
will be, the SF-36 PCS score improvement (event defined by at least 3.4 points improvement 
in SF-36 PCS score) and the SF-36 PCS deterioration (event defined by at least 3.4 points 
deterioration in SF-36 PCS score), accordingly; stratum (ACEi, ARB, No RASi), region, 
treatment (LCZ696, IMT), visit and treatment-by-visit interaction will be included as fixed-
effect factors; BPSS, BSBP, stratum-by-BPSS, stratum-by-BSBP and visit-by-BPSS
interactions will be included as covariates; patient-specific intercepts will be included as 
random effects. The analysis will include all post-baseline scheduled visits up to Week 24 
(Week 16 and Week 24) and will be performed based on the likelihood method with an 
assumption of MAR for missing data (other than due to death).
Based on the longitudinal binary logistic regression models, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted odds ratios (LCZ696 / IMT) at each post-
baseline scheduled visit (Week 16 and Week 24). The corresponding one-sided p-values will 
also be provided based on the longitudinal binary logistic model.
As additional supportive analyses, the Mantel-Haenszel estimates and the corresponding 95% 
confidence intervals will be provided by visit, for the relative risks and the risk differences, for 
SF-36 PCS score improvement and SF-36 PCS score deterioration, accordingly.
The FAS will be used for the above analyses.
2.6.3.2
SF-36 mental component summary score
The same analyses as SF-36 PCS score will also be performed for SF-36 MCS score, except 
that the BPSS in the models will be replaced by baseline SF-36 MCS score (BMSS), stratum-
by-BPSS and visit-by-BPSS interactions in the analysis models will be replaced by stratum-by-
BMSS and visit-by-BMSS interactions, and that the cut-off of 3.4 points for the improvement 
and the deterioration will be replaced by 4.6 points.
The FAS will be used for the above analyses.
2.6.4
Handling of missing values/censoring/discontinuations
In the analyses described in the above sections (Section 2.6.1 to 2.6.3), death is considered the 
worst possible outcome and hence scheduled visits after death will be imputed to be the worst 
score accordingly. Other missing data is assumed to be MAR.
As in Section 2.5.3, patients who discontinue from the study treatment due to adverse events, 
death or lack of efficacy are defined as patients who discontinued from the study treatment 
during the randomized treatment epoch, and had the primary reason for discontinuation of study 
treatment (CRF page: “End of Study Treatment”) specified as “Adverse event”, “Death” or 
“Lack of efficacy”.
As sensitivity analyses, the controlled multiple imputation approach based on pattern mixture 
models will be applied (Carpenter and Kenward 2013), whereby all missing data of patients in 
the LCZ696 group who permanently discontinue study treatment due to: adverse events, death 


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or lack of efficacy, will be assumed to behave like patients in the IMT group after permanent 
discontinuation and will be imputed based on the data from patients in the IMT group according 
to the stratum (ACEi, ARB, No RASi).

For changes from baseline in KCCQ CSS, for each post-baseline scheduled visit up to 
Week 24 (Week 4, Week 12, Week 16 and Week 24), the imputation model will be a 
linear regression model specified using fully conditional specifications, in which, the 
response variable will be the change from baseline in KCCQ CSS at the visit; region will 
be included as a fixed-effect factor; BCSS, BSBP, change from baseline in KCCQ CSS at 
the closest previous post-baseline scheduled visit (not applicable for Week 4, Week 4 for 
Week 12, Week12 for Week 16, Week 16 for Week 24) will be included as covariates. For 
each stratum (ACEi, ARB, No RASi), the imputation model will be fitted separately based 
on the data from patients in the IMT group within the stratum.

For changes from baseline in KCCQ OSS, for each post-baseline scheduled visit up to 
Week 24 (Week 4, Week 12, Week 16 and Week 24), the imputation model will be a 
linear regression model specified using fully conditional specifications, in which, the 
response variable will be the change from baseline in KCCQ OSS at the visit; region will 
be included as a fixed-effect factor; BOSS, BSBP, change from baseline in KCCQ OSS at 
the closest previous post-baseline scheduled visit (not applicable for Week 4, Week 4 for 
Week 12, Week12 for Week 16, Week 16 for Week 24) will be included as covariates. For 
each stratum (ACEi, ARB, No RASi), the imputation model will be fitted separately based 
on the data from patients in the IMT group within the stratum.

For NYHA class change, for each post-baseline scheduled visit up to Week 24 (Week 2, 
Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24), the imputation model will 
be a proportional cumulative odds model specified using fully conditional specifications, 
in which, the response variable will be the NYHA class change (order defined by 
“improved” < “unchanged” < “worsened”) at the visit; region, baseline NYHA class,
NYHA class change at the closest previous post-baseline scheduled visit (not applicable 
for Week 2, Week 2 for Week 4, Week 4 for Week 8, Week 8 for Week 12, Week 12 for 
Week 16, Week 16 for Week 20 and Week 20 for Week 24) will be included as fixed-
effect factors; BSBP will be included as a covariate. For each stratum (ACEi, ARB, No 
RASi), the imputation model will be fitted separately based on the data from patients in 
the IMT group within the stratum.

For changes from baseline in SF-36 PCS score, for each post-baseline scheduled visit up 
to Week 24 (Week 16 and Week 24), the imputation model will be a linear regression 
model specified using fully conditional specifications, in which, the response variable will 
be the change from baseline in SF-36 PCS score at the visit; region will be included as a 
fixed-effect factor; BPSS, BSBP, change from baseline in SF-36 PCS score at the closest 
previous post-baseline scheduled visit (not applicable for Week 16, Week 16 for Week 24) 
will be included as covariates. For each stratum (ACEi, ARB, No RASi), the imputation 
model will be fitted separately based on the data from patients in the IMT group within the 
stratum.

For changes from baseline in SF-36 MCS score, for each post-baseline scheduled visit up 
to Week 24 (Week 16 and Week 24), the imputation model will be a linear regression 
model specified using fully conditional specifications, in which, the response variable will 


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be the change from baseline in SF-36 MCS score at the visit; region will be included as a 
fixed-effect factor; BMSS, BSBP, change from baseline in SF-36 MCS score at the closest 
previous post-baseline scheduled visit (not applicable for Week 16, Week 16 for Week 24) 
will be included as covariates. For each stratum (ACEi, ARB, No RASi), the imputation 
model will be fitted separately based on the data from patients in the IMT group within the 
stratum.
All other missing data will be considered as MAR within each arm and will be imputed using a 
multiple imputation approach (Carpenter and Kenward 2013) based on observed data within 
each arm according to the stratum. Of note, patients who permanently discontinue study 
treatment, are not considered discontinued from the study. It is planned to continue to collect 
and use data at scheduled visits even after permanent discontinuation of study treatment.

For changes from baseline in KCCQ CSS, for each post-baseline scheduled visit up to 
Week 24 (Week 4, Week 12, Week 16 and Week 24), the imputation model will be a 
linear regression model specified using fully conditional specifications, in which, the 
response variable will be the change from baseline in KCCQ CSS at the visit; region will 
be included as a fixed-effect factor; BCSS, BSBP, change from baseline in KCCQ CSS at 
the closest previous post-baseline scheduled visit (not applicable for Week 4, Week 4 for 
Week 12, Week12 for Week 16, Week 16 for Week 24) will be included as covariates. For 
each stratum (ACEi, ARB, No RASi) and each arm, the imputation model will be fitted 
separately based on the data from patients in the arm within the stratum.

For changes from baseline in KCCQ OSS, for each post-baseline scheduled visit up to 
Week 24 (Week 4, Week 12, Week 16 and Week 24), the imputation model will be a 
linear regression model specified using fully conditional specifications, in which, the 
response variable will be the change from baseline in KCCQ OSS at the visit; region will 
be included as a fixed-effect factor; BOSS, BSBP, change from baseline in KCCQ OSS at 
the closest previous post-baseline scheduled visit (not applicable for Week 4, Week 4 for 
Week 12, Week12 for Week 16, Week 16 for Week 24) will be included as covariates. For 
each stratum (ACEi, ARB, No RASi) and each arm, the imputation model will be fitted 
separately based on the data from patients in the arm within the stratum.

For NYHA class change, for each post-baseline scheduled visit up to Week 24 (Week 2, 
Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24), the imputation model will 
be a proportional cumulative odds model specified using fully conditional specifications, 
in which, the response variable will be the NYHA class change (order defined by 
“improved” < “unchanged” < “worsened”) at the visit; region, baseline NYHA class,
NYHA class change at the closest previous post-baseline scheduled visit (not applicable 
for Week 2, Week 2 for Week 4, Week 4 for Week 8, Week 8 for Week 12, Week 12 for 
Week 16, Week 16 for Week 20 and Week 20 for Week 24) will be included as fixed-
effect factors; BSBP will be included as a covariate. For each stratum (ACEi, ARB, No 
RASi) and each arm, the imputation model will be fitted separately based on the data from 
patients in the arm within the stratum.

For changes from baseline in SF-36 PCS score, for each post-baseline scheduled visit up 
to Week 24 (Week 16 and Week 24), the imputation model will be a linear regression 
model specified using fully conditional specifications, in which, the response variable will 
be the change from baseline in SF-36 PCS score at the visit; region will be included as a 


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fixed-effect factor; BPSS, BSBP, change from baseline in SF-36 PCS score at the closest 
previous post-baseline scheduled visit (not applicable for Week 16, Week 16 for Week 24) 
will be included as covariates. For each stratum (ACEi, ARB, No RASi) and each arm, the 
imputation model will be fitted separately based on the data from patients in the arm 
within the stratum.

For changes from baseline in SF-36 MCS score, for each post-baseline scheduled visit up 
to Week 24 (Week 16 and Week 24), the imputation model will be a linear regression 
model specified using fully conditional specifications, in which, the response variable will 
be the change from baseline in SF-36 MCS score at the visit; region will be included as a 
fixed-effect factor; BMSS, BSBP, change from baseline in SF-36 MCS score at the closest 
previous post-baseline scheduled visit (not applicable for Week 16, Week 16 for Week 24) 
will be included as covariates. For each stratum (ACEi, ARB, No RASi) and each arm, the 
imputation model will be fitted separately based on the data from patients in the arm 
within the stratum.
Furthermore, the missing data patterns in the secondary endpoint variables will be explored via 
by-treatment-group box plots or bar plots as appropriate for patients who permanently 
discontinue from study treatment due to adverse events or lack of efficacy, for patients who 
permanently discontinue study treatment due to any other reasons, for patients who did not 
permanently discontinue study treatment and for patients who take open label LCZ696 after 
permanent discontinuation from study treatment. Similar box plots or bar plots will also be 
provided for on-treatment assessments.
As additional supportive analyses, the main analyses for the secondary endpoints described in 
the above sections (Section 2.6.10 to 2.6.3), will be performed for the following data.

Data where the responses after the death were set to missing for patients who died.

Data where the LOCF approach was performed for missing data .

Data where the responses after the first dose of open-label RASi or open-label LCZ696 
after permanent discontinuation of study treatment will be set to missing and considered 
MAR. (This is called on-treatment analysis.)
2.6.5
Subgroup analyses
For each secondary endpoint, subgroup analyses will be performed utilizing the corresponding 
secondary analysis model (Section 2.6.1 to Section 2.6.3), after adding the fixed-effect factors 
of subgroup variable and subgroup-variable-by-treatment interaction into the original model. 
The following subgroup variables (Section 2.2.1, Table 2-3) will be used for the subgroup 
analyses for all secondary endpoints.

Region

Stratum (ACEi, ARB, No RASi)

Age group (< 65 years, ≥ 65 years)

Age group (< 75 years, ≥ 75 years)

Sex

Baseline NYHA class group


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
Diabetes (history or HbA1c ≥ 6.5%)

LVEF group (<= 60%, > 60%)

Prior heart failure hospitalization
For changes from baseline in KCCQ CSS, KCCQ OSS, SF-36 PCS score and SF-36 MCS score, 
based on the corresponding subgroup analysis model, the estimates and the two-sided 95% 
confidence intervals will be provided for the adjusted means for the change from baseline at 
Week 24 in both treatment groups (LCZ696 and IMT) within each subgroup, and for the 
adjusted mean difference (LCZ696 minus IMT) at Week 24 within each subgroup; the p-value
for the subgroup-variable-by-interaction will be provided for each subgroup variable.
For NYHA class change, based on the corresponding subgroup analysis model, the estimates 
and the two-sided 95% confidence intervals will be provided for the adjusted odds ratios 
(LCZ696 / IMT) at Week 24 within each subgroup; the p-value for the subgroup-variable-by-
interaction will be provided for each subgroup variable.
The FAS will be used for the above subgroup analyses.
2.7
Analysis of the exploratory objectives
2.7.1
NT-proBNP up to Week 24
Plasma NT-proBNP will be collected using central lab.
All post-screening NT-proBNP from central lab will remain blinded until data base lock. Only 
the NT-proBNP at screening will be reported to the investigator and the Novartis clinical study 
team.
For the NT-proBNP, if the test value is below the LLOQ, the test value will be imputed by 0.5 
× LLOQ; if the test value is above the ULOQ, the test value will be imputed by 1.5 × ULOQ.
For the NT-proBNP, unreliable test values will be set to missing.
For patients who permanently discontinue study treatment, values collected after permanent 
discontinuation will generally be included in the analysis.
The changes from baseline in log(NT-proBNP) will be analyzed using a MMRM model, in 
which, the response variable will be the changes from baseline in log(NT-proBNP); stratum 
(ACEi, ARB, No RASi), region, treatment (LCZ696, IMT), visit and treatment-by-visit 
interaction will be included as fixed-effect factors; BLNTBNP, stratum-by-BLNTBNP and 
visit-by-BLNTBNP interactions will be included as covariates; the within-patient covariance 
will be modeled using an unstructured covariance matrix (a common matrix for the two 
treatment groups). If the model fitting procedure does not converge, the AR(1) covariance 
structure will be used. The analysis will include all post-baseline scheduled visits up to Week 
24 (Week 4, Week 12 and Week 24) and will be performed based on the likelihood method with 
an assumption of MAR for missing data.
Based on the MMRM model, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted geometric means for the ratio to baseline in NT-proBNP at each post-
baseline scheduled visit (Week 4, Week 12 and Week 24) in both treatment groups (LCZ696 
and IMT), and for the ratio of the adjusted geometric means (LCZ696/IMT) at each post-


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baseline scheduled visit (Week 4, Week 12 and Week 24). The corresponding one-sided p-
values will also be provided based on the MMRM model.
As an additional supportive analysis, the changes from baseline in log(NT-proBNP) will be 
analyzed using a MMRM model, in which, the response variable will be the changes from 
baseline in log(NT-proBNP); stratum (ACEi, ARB, No RASi), region, visit, treatment (LCZ696, 
IMT) and treatment-by-visit interaction will be included as fixed-effect factors; BLNTBNP, 
BSBP, stratum-by-BLNTBNP, stratum-by-BSBP and visit-by-BLNTBNP interactions will be 
included as covariates; the within-patient covariance will be modeled using an unstructured 
covariance matrix (a common matrix for the two treatment groups). If the model fitting 
procedure does not converge, the AR(1) covariance structure will be used. The analysis will 
include all post-baseline scheduled visits up to Week 24 (Week 4, Week 12 and Week 24) and 
will be performed based on the likelihood method with an assumption of MAR for missing data.
Based on the supportive MMRM model, the estimates and the two-sided 95% confidence 
intervals will be provided for the adjusted geometric means for the ratio to baseline in NT-
proBNP at each post-baseline scheduled visit (Week 4, Week 12 and Week 24) in both treatment 
groups (LCZ696 and IMT), and for the ratio of the adjusted geometric means (LCZ696/IMT)
at each post-baseline scheduled visit (Week 4, Week 12 and Week 24). The corresponding one-
sided p-values will also be provided based on the MMRM model.
Besides, the NT-proBNP test values and NT-proBNP ratio to baseline will be summarized by 
treatment group and visit, for overall and for each stratum (ACEi, ARB, No RASi), using 
number of observations, mean, standard deviation, geometric mean, 95% confidence interval 
for geometric mean, median, minimum, Q1, Q3, maximum, number of observations below the 
LLOQ and number of observations above the ULOQ.
The FAS will be used for the above analyses.
2.7.2
Estimated glomerular filtration rate (eGFR)
The eGFR will be evaluated by the central laboratory, but local laboratory assessments will be 
performed in addition to the required central laboratory.
Only the central laboratory assessments will be used in the following analyses.
For the rate change in eGFR, the eGFR slope will be estimated from a mixed model, in which, 
the response variable will be the eGFR; stratum (ACEi, ARB, No RASi), region, and treatment 
(LCZ696, IMT) will be included as fixed-effect factors; time (in month) and treatment-by-time 
interaction will be included as covariates; a patient level random intercept and a patient level 
random slope (time) will be included as random effects with a unstructured covariance matrix 
(a common matrix for the two treatment groups). Here, the time (in month) will be computed 
as (date of assessment minus date of randomization plus one day)/(30.4375 day/month). The 
analysis will include all assessments from central laboratory at all visits up to Week 24 
(Baseline to Week 24, scheduled or unscheduled) and will be performed based on the likelihood 
method with an assumption of MAR for missing data.
Based on the mixed model, the estimates and the two-sided 95% confidence intervals will be 
provided for the adjusted mean slope in each of the two treatment groups (LCZ696 and IMT), 
and for the adjusted mean difference (LCZ696 minus IMT).


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Besides, the eGFR test values and the change from baseline in eGFR will be summarized by 
treatment group and visit, separately, for overall and for each stratum (ACEi, ARB, No RASi), 
using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum. The summary will include all scheduled assessments.
The FAS will be used for the above analyses.
2.8
Safety analyses
The SAF will be used for all safety analyses.
2.8.1
Adverse events (AEs)
All AEs will be recorded on the CRF page “Adverse Events” and be identified using Medical 
Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for reporting the 
study will be described in a footnote.
An AE with its severity increased should be considered and recorded as a new AE.
The missing or partially missing start/end date for AEs will be imputed based on the Novartis 
AGB global standards.
Treatment emergent adverse events (TEAEs) are defined as any recorded AE with its start date 
(recorded or imputed) later than or equal to the date of the first dose of the study drug.
Study drug related AEs are defined as any recorded AE with “Reasonable possibility that AE 
is related to study treatment” answered as “YES”.
AEs leading to permanent discontinuation of study treatment are defined as any recorded AE 
with “Action taken with study treatment” answered as “DRUG WITHDRAWN”.
AEs leading to dose adjustment or temporarily interruption of study treatment are defined as 
any recorded AE with “Action taken with study treatment” answered as “DOSE REDUCED”, 
“DOSE INCREASED” or “DRUG INTERRUPTED”.
Most common TEAEs are defined as any recorded TEAE corresponding to a PT with at least 
2% of patients in either treatment group (LCZ696 or IMT) having at least one TEAE of this PT.
SAEs are defined as any recorded AE with “Does AE meet the definition of an SAE” answered 
as “Yes”.
The following rules are applicable to the summaries.

If a patient reported more than one AE with the same PT, the patient will be counted only 
once with the greatest severity at the PT level

If a patient reported more than one AE within the same SOC, the patient will be counted 
only once with the greatest severity at the SOC level, where applicable.
The following summaries will be performed.

TEAEs will be summarized by treatment group, SOC and PT, and summarized by 
treatment group, SOC, PT and maximum severity, for overall and for each stratum (ACEi, 
ARB, No RASi).


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
Study drug related TEAEs will be summarized by treatment group, SOC and PT, and 
summarized by treatment group, SOC, PT and maximum severity, for overall and for each 
stratum (ACEi, ARB, No RASi).

TEAEs leading to permanent discontinuation of study treatment will be summarized by 
treatment group, SOC and PT, for overall and for each stratum (ACEi, ARB, No RASi).

TEAEs leading to dose adjustment or temporarily interruption of study treatment will be 
summarized by treatment group, SOC and PT, for overall and for each stratum (ACEi, 
ARB, No RASi).

Most common TEAEs will be summarized by treatment group, SOC and PT, for overall 
and for each stratum (ACEi, ARB, No RASi).

Study drug related most common TEAEs will be summarized by treatment group, SOC 
and PT, for overall and for each stratum (ACEi, ARB, No RASi).

Treatment emergent SAEs (TESAEs) will be summarized by treatment group, SOC and 
PT for overall and for each stratum (ACEi, ARB, No RASi).

Most common TESAEs will be summarized by treatment group, SOC and PT, for overall 
and for each stratum (ACEi, ARB, No RASi).

Study drug related TESAEs will be summarized by treatment group, SOC and PT, for 
overall and for each stratum (ACEi, ARB, No RASi).
The SAF will be used for the above analyses.
Table 2-9 shows the safety topics of interest for LCZ696 and the specifically specified analyses 
for each safety topic. In addition, the following standard analyses will be applied to all safety 
topics.

Numbers and percentages of patients with any TEAE within the safety topic name (or PT 
within safety topic name) will be provided by treatment group, safety topic name, PT and 
maximum severity, for overall and for each stratum (ACEi, ARB, No RASi).

Exposure adjusted incidence rates per 100 patient-years for TEAEs within the risk name 
will be provided by treatment group and safety topic name, for overall and for each 
stratum (ACEi, ARB, No RASi).

Listing of patients numbers per safety topic.
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for the safety 
topics in Table 2-9 are store in the LCZ696 Case Retrieval Strategy (2019).
Table 2-9
Safety Topics of Interest
Safety Topic of Interest
Analysis
Anaphylaxis
Standard analyses;
Angioedema
Standard analyses;
Change in bone growth
Standard analyses;
Cognitive impairment (Broad SMQ)
Standard analyses;
Cognitive impairment (Narrow SMQ)
Standard analyses;
Embryo-fetal toxicity
Standard analyses;


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Safety Topic of Interest
Analysis
Hepatotoxicity
1. Standard analyses;
2. Summary of the shift from baseline to minimum and 
maximum post-baseline category (Section 2.8.3.1) in 
alkaline phosphatase (ALP), alanine aminotransferase
(ALT), aspartate aminotransferase (AST) and total 
bilirubin (TBL)
3. Numbers and percentages of patients with each of the 
following events will be provided by treatment group, for 
overall and for each stratum (ACEi, ARB, No RASi);
a. (ALT > 3 × ULN) or (AST > 3 × ULN)
b. (ALT > 5 × ULN) or (AST > 5 × ULN)
c. (ALT > 8 × ULN) or (AST > 8 × ULN)
d. (ALT > 10 × ULN) or (AST > 10 × ULN)
e. (ALT > 20 × ULN) or (AST > 20 × ULN)
f.
[(ALT > 3 × ULN) or (AST > 3 × ULN)] and (TBL > 1.5 
× ULN)
g. [(ALT > 3 × ULN) or (AST > 3 × ULN)] and (TBL > 2 × 
ULN)
h. [(ALT > 5 × ULN) or (AST > 5 × ULN)] and (TBL > 2 × 
ULN)
i.
[(ALT > 8 × ULN) or (AST > 8 × ULN)] and (TBL > 2 × 
ULN)
j.
[(ALT > 10 × ULN) or (AST > 10 × ULN)] and (TBL > 2 
× ULN)
k. [(ALT > 20 × ULN) or (AST > 20 × ULN)] and (TBL > 2 
× ULN)
l.
(ALP > 2 × ULN)
m. (ALP > 3 × ULN)
n. (ALP > 5 × ULN)
o. (TBL > 1.5 × ULN)
p. (TBL > 2 × ULN)
q. (TBL > 3 × ULN)
r.
(ALP > 3 × ULN) and (TBL > 2 × ULN)
s. (ALP > 5 × ULN) and (TBL > 2 × ULN)
t.
[(ALT > 3 × ULN) or (AST > 3 × ULN)] and [nausea or 
vomiting or fatigue or general malaise or abdominal 
pain or (rash and eosinophilia)]
u. [(ALT > 3 × ULN) or (AST > 3 × ULN)] and (TBL > 2 × 
ULN) and (ALP ≤ 2 × ULN)
v. ([(ALT > 3 × ULN) or (AST > 3 × ULN)] and [(TBL > 2 
× ULN) and (ALP ≤ 2 × ULN)]) or reported Hy’s Law 
case
w. (TBL > 3 × ULN) and [(AST ≤ 3 × ULN) or (ALT ≤ 3 × 
ULN)] and (ALP ≤ 1.5 × ULN)
x. (ALP > 3 × ULN) and AST, ALT, TBL are within 
normal range
Hyperkalemia
1. Standard analyses;


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Safety Topic of Interest
Analysis
2. Numbers and percentages of patients with treatment 
emergent hyperkalemia leading to study treatment 
interruption will be provided by treatment group, for 
overall and for each stratum (ACEi, ARB, No RASi);
3. Numbers and percentages of patients with treatment 
emergent hyperkalemia leading to study treatment 
permanent discontinuation will be provided by treatment 
group, for overall and for each stratum (ACEi, ARB, No 
RASi);
4. Numbers and percentages of patients with any post-
baseline serum potassium ≥5.5 mEq/L, >6.0 mEq/L 
and >6.5 mEq/L will be provided by treatment group, for 
overall and for each stratum (ACEi, ARB, No RASi);
Hypersensitivity (Broad SMQ)
Standard analyses;
Hypersensitivity (Narrow SMQ)
Standard analyses;
Hypotension
1. Standard analyses;
2. Blood pressures and change from baseline in blood 
pressures will be summarized by treatment group and 
visit, for overall and for each stratum (ACEi, ARB, No 
RASi), using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum;
3. Numbers and percentages of patients with the following 
events will be provided by treatment group, for overall and 
for each stratum (ACEi, ARB, No RASi);
a. Post-baseline SBP < 100 mmHg;
b. At least 30 mmHg drop in SBP (post-baseline 
assessments comparing to baseline);
c. Simultaneous post-baseline SBP < 100 mmHg and at 
least 30 mmHg drop in SBP (post-baseline 
assessments comparing to baseline);
Malignancy
Standard analyses;
Neonatal toxicity through breast milk
Standard analyses;
Renal impairment (Broad SMQ)
1. Standard analyses;
2. For serum creatinine and eGFR, the test values and 
changes from baseline will be summarized by treatment 
group and visit, for overall and for each stratum (ACEi, 
ARB, No RASi), using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and 
maximum;
3. Numbers and percentages of patients with each of the 
following events will be provided by treatment group, for 
overall and for each stratum (ACEi, ARB, No RASi);
a. eGFR decline by >25%, >40%, >50%, and >30 
mL/min/1.73 m2 (post-baseline assessments 
comparing to baseline);
b. Serum creatinine increase by >50% and >0.5 mg/dL 
(post-baseline assessments comparing to baseline);
c. Post-baseline serum creatinine >2.0 mg/dL, >2.5 
mg/dL, >3.0 mg/dL;


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Safety Topic of Interest
Analysis
4. Standard analyses within the subgroups: patients with 
baseline eGFR < 60 mL/min/1.73 m2 and >= 60 
mL/min/1.73 m2;
Renal impairment (Narrow SMQ)
Standard analyses;
Rhabdomyolysis and Myoglobinuria
Standard analyses;
Statin drug drug interaction
Standard analyses;
The following subgroup analyses will be based on selected subgroup variables (Section 2.2.1).

Treatment emergent SAEs will be summarized within each subgroup, by treatment group, 
SOC and PT.

Numbers and percentages of patients with any TEAE within the safety topic name (or 
SOC/PT within safety topic name) for identified and potential safety topics will be 
provided within each subgroup, by treatment group, safety topic name, SOC, PT and 
maximum severity.
The SAF will be used for the subgroup analyses.
2.8.2
Death
Death and primary cause of death will be reported by the investigator.
The investigator reported death and primary cause of death will be recorded on the CRF page: 
“Death”.
The investigator reported death and primary cause of death will be summarized by treatment 
group, for overall and for each stratum (ACEi, ARB, No RASi), using the number and 
percentage of patients who died, as well as the numbers and percentages of patients whose 
primary cause of death is in each category and each sub-category.
The SAF will be used for the above analyses.
2.8.3
Laboratory data
2.8.3.1
General laboratory data
Complete laboratory evaluations (hematology, biochemistry, and urine) outlined in Table 2-10
will be performed at screening, randomization, Week 12 and Week 24.
Abbreviated laboratory evaluations will be performed at Week 2, Week 4, Week 8, Week 16, 
and Week 20. Abbreviated laboratory includes: creatinine, potassium, eGFR, and blood urea 
nitrogen (BUN).
A central laboratory will be used for analysis of all specimens collected.
In addition to the required central laboratory assessments, a local laboratory may be used for 
the assessment of creatinine, potassium and eGFR during the up titration period. The results 
from the local laboratory during the up titration period will be allowed to be used for decision 
making regarding the eligibility of the patient to continue on in the study and will be recorded 
on the appropriate eCRF.


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In addition, local laboratory assessments may be performed on an as-needed basis to monitor 
tolerability to study drug at unscheduled visits during the randomized treatment period and will 
be recorded in the appropriate eCRF.
Table 2-10
Complete laboratory evaluations
Hematology
Biochemistry
Urine measurements
Hematocrit
Alanine aminotransferase (ALT)
Urinalysis
Hemoglobin
Albumin (Alb)
Platelet count
Alkaline phosphatase (ALP)
Red blood cell count (RBC)
Aspartate aminotransferase (AST)
White blood cell count (WBC)
Blood urea nitrogen (BUN)*
WBC differential
Calcium
Red blood cell distribution
width (RDW)
Chloride
Mean corpuscular volume (MCV)
Creatinine*
Mean corpuscular hemoglobin
concentration (MCHC)
eGFR*
Glucose
Hemoglobin A1C
Lipid profile (total cholesterol, 
LDL, HDL, and triglycerides)
Phosphate
Potassium*
Serum pregnancy test
Sodium
Total bilirubin (TBL)
Fractionated bilirubin 
(if total bilirubin > 2 x upper limit of 
normal range [ULN])
Total protein
Uric acid
*Laboratory assessments for the abbreviated laboratory evaluation at visits where the complete 
laboratory evaluation is not performed
Both complete laboratory evaluations and abbreviated laboratory evaluations will be included 
in the summaries for laboratory data. In general, local lab and central lab data will be analyzed 
separately.
For the laboratory assessments, if the test value is below the LLOQ, the test value will be 
imputed by 0.5 × LLOQ; if the test value is above the ULOQ, the test value will be imputed by 
1.5 × ULOQ.
For each laboratory parameter, the baseline assessment is defined as the last non-missing central 
laboratory assessment (scheduled or unscheduled) prior to or on the first dose date of the study 
drug.


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Test values and change from baseline in test values based on the central laboratory assessment
will be summarized, separately, for overall and for each stratum (ACEi, ARB, No RASi), by 
laboratory parameter, treatment group and visit, using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum.
For each laboratory parameter and each specific assessment, the test value will be categorized 
into normal, low, or high, according to the corresponding normal range.
For each laboratory parameter and each specific post-baseline visit, the shift from baseline to 
the visit is defined as the shift from the baseline category to the categorized post-baseline test 
value (low to low, low to normal, low to high, normal to low, normal to normal, normal to high, 
high to low, high to normal, high to high).
The shift from baseline will be summarized by laboratory parameter, treatment group and visit, 
for overall and for each stratum (ACEi, ARB, No RASi), using the numbers and percentages of 
patients within each shift category. By-visit summaries will be conducted for central laboratory 
assessments and local laboratory assessments, separately. The baseline in summaries for local 
laboratory assessments will be taken from the central laboratory assessments. 
For each laboratory parameter and each visit, the visit based minimum and maximum category
are defined based on categorized test values at this visit according to Table 2-11. All central or 
local assessments will be included in the calculation.
The shift from baseline to visit based minimum and maximum category will be summarized 
separately, by laboratory parameter, treatment group and visit, for overall and for each stratum 
(ACEi, ARB, No RASi), using the numbers and percentages of patients within each category.
For each individual laboratory parameter, the minimum and maximum post-baseline category 
are defined based on categorized post-baseline test values according to Table 2-11. All central 
or local, scheduled or unscheduled assessments will be included in the calculation.
Table 2-11
Minimum and maximum post-baseline category
Range of Categorized
Post-Baseline Test Values
Minimum post-baseline
category
Maximum post-baseline
category
Low, Normal, High, Missing
Low
High
Low, Normal, High
Low
High
Low, Normal, Missing
Low
Normal
Low, Normal
Low
Normal
Low, High, Missing
Low
High
Low, High
Low
High
Low, Missing
Low
Low
Low
Low
Low
Normal, High, Missing
Normal
High
Normal, High
Normal
High
Normal, Missing
Normal
Normal
Normal
Normal
Normal
High, Missing
High
High
High
High
High


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Range of Categorized
Post-Baseline Test Values
Minimum post-baseline
category
Maximum post-baseline
category
Missing
Missing
Missing
The shift from baseline to minimum and maximum post-baseline category will be summarized 
separately, by laboratory parameter and treatment group, for overall and for each stratum (ACEi, 
ARB, No RASi), using the numbers and percentages of patients within each category.
Table 2-12 provides criteria for clinically notable laboratory abnormality.
Table 2-12
Clinical notable criteria for laboratory values
Parameter
Criteria
Hematology
Hematocrit
> 50% increase, > 20% decrease
Hemoglobin
> 50% increase, > 20% decrease
Platelet count
> 75% increase, > 50% decrease
RBC count
> 50% increase, > 20% decrease
WBC count
> 50% increase, > 50% decrease
Blood Chemistry
Alkaline phosphatase
> 100% increase
ALT (SGPT)
> 150% increase
AST (SGOT)
> 150% increase
BUN
> 50% increase
Calcium
> 10% increase, > 10% decrease
Chloride
> 10% increase, > 10% decrease
Creatinine
> 50% increase
Potassium
> 20% increase, > 20% decrease
Total bilirubin
> 100% increase
Uric acid
> 50% increase
In the above table, increase and decrease are defined as compared to the baseline value.
The clinically notable laboratory abnormality based on the local laboratory assessments and the 
central laboratory assessments will be summarized separately, by criteria and treatment group, 
for overall and for each stratum (ACEi, ARB, No RASi), using the numbers and percentages of 
patients satisfying such criteria.
The SAF will be used for the above analyses.
2.8.3.2
Special laboratory data
Liver function related laboratory data based on the local laboratory and the central laboratory 
assessments will be summarized separately, using the hepatotoxicity analyses in Table 2-9.
Renal function related laboratory data based on the local laboratory and the central laboratory 
assessments will be summarized separately, using the renal impairment analyses in Table 2-9.
The SAF will be used for the above analyses.


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2.8.4
Other safety data
2.8.4.1
Electrocardiogram (ECG)
The ECG parameters (heart rate, RR interval, PR interval, QRS duration, QT interval, QTcF 
interval) will be recorded on the CRF page: “12 Lead ECG Evaluation - Local Analysis”.
The test value and the change from baseline in ECG parameters, will be summarized by ECG 
parameter, treatment group and visit, for overall and for each stratum (ACEi, ARB, No RASi), 
using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum.
In addition, any of the following clinically significant abnormalities, will also be recorded on 
the same CRF page: “12 Lead ECG Evaluation - Local Analysis”.

atrial fibrillation

atrial flutter

LBB block

RBB block

pathological Q waves

left ventricular hypertrophy

paced rhythm
The clinically significant abnormalities will be summarized by treatment group and visit, for 
overall and for each stratum (ACEi, ARB, No RASi), using the numbers and percentages of 
patients with each abnormality and with each newly onset abnormality, where the newly onset 
abnormality is defined as an abnormality not present at baseline but present at the visit
The SAF will be used for the above analyses.
2.8.4.2
Vital signs
The test values and the changes from baseline in vital signs (sitting pulse, sitting SBP, sitting 
DBP, weight, waist circumference and hip circumference) will be summarized by parameter, 
treatment group and visit, for overall and for each stratum (ACEi, ARB, No RASi), using 
number of observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum. 
By-visit summary will only include scheduled assessments.
Table 2-13 provides criteria for clinically notable vital sign.
The clinically notable vital signs will be summarized by criteria and treatment group, for overall 
and for each stratum (ACEi, ARB, No RASi), using the numbers and percentages of patients 
with at least one post-baseline assessment satisfying such criteria.
Table 2-13
Criteria for clinically notable vital signs
Vital Sign (unit)
Clinically notable criteria
Weight (kg)

decrease > 7% from baseline

increase > 7% from baseline
Sitting pulse (bpm)

< 50 bpm and decrease from baseline of > 15 bpm


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Vital Sign (unit)
Clinically notable criteria

> 120 bpm and increase from baseline of >15 bpm
Sitting SBP (mmHg)

< 90 mmHg and decrease from baseline of > 20 mmHg

> 180 mmHg and increase from baseline of > 20 mmHg
Sitting DBP (mmHg)

< 50 mmHg and decrease from baseline of > 15 mmHg

> 105 mmHg and increase from baseline of > 15 mmHg
The SAF will be used for the above analyses.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
See Section 2.6.1 and Section 2.6.3.
2.12
Biomarkers
Plasma NT-proBNP will be analyzed according to Section 2.5 and Section 2.7.1.
2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
No formal interim efficacy analysis is planned.
An established program level DMC independent of Novartis that reviews safety data from 
LCZ696 studies will be used for this study. The DMC will review SAEs in an unblinded manner 
on a regular basis and determine if it is safe to continue the study. Any major recommendation 
from the DMC will be communicated to the Executive Committee and must be reviewed and 
ratified by the Executive Committee in consultation with Novartis prior to its enactment.


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3
Sample size calculation
The sample size (2500 randomized patients) has been chosen in order to provide adequate power 
to evaluate both primary and secondary endpoints.
With an alpha of one-sided 0.0225, the power for the NT-proBNP will range from 92% to more 
than 99%, to detect a relative reduction ranging from 11% to 24% in change from baseline to 
Week 12 in NT-proBNP, assuming a standard deviation of 0.81 for change from baseline in the 
log-transformed NT-proBNP (based on PARAMOUNT-HF data of patients with baseline 
KCCQ CSS < 75) and an overall drop-out rate of 10%.
With an alpha of one-sided 0.0025, the power for the 6MWD will range from 90% to 99%, to 
detect a mean difference ranging from 22 meters to 30 meters in change from baseline to Week 
24 in 6MWD, assuming a standard deviation of 120 meters (Ingle et al 2005), an overall drop-
out rate of 10%, and an overall proportion of 88% for patients with B6MWD ranging from 100 
meters to 450 meters.
With an alpha of one-sided 0.0225, the power for the KCCQ CSS will range from 87% to 99%, 
to detect a mean difference ranging from 2 points to 3 points in change from baseline to Week 
24 in KCCQ CSS, assuming a standard deviation of 15.52 points for change from baseline in 
the KCCQ CSS (based on PARAMOUNT-HF data of patients with baseline KCCQ CSS < 75) 
and an overall drop-out rate of 5%.
All alpha levels in the following sample size calculations will be one-sided 0.025.
This sample size of 2500 randomized patients aims to provide a power of approximately 90%, 
with the one-sided alpha level of 0.025, to demonstrate a 5% responder advantage in at least 5-
point deterioration for patients who are treated with LCZ696 over IMT when assuming the 
proportion of patients with at least 5-point deterioration from baseline to Week 24 in the IMT 
group is 20% (based on PARAMOUNT-HF data of patients with baseline KCCQ CSS < 75) 
and an overall 5% dropouts.
With the same assumption of the dropout rate, this sample size will also provide a power of 69% 
to detect a 5% responder advantage in at least 5-points improvement in the KCCQ clinical 
summary score for patients who are treated with LCZ696 over IMT when assuming the 
proportion of patients with at least 5-points improvement from baseline to Week 24 in the IMT 
group is 55% (based on PARAMOUNT-HF data of patients with baseline KCCQ CSS < 75).
The sensitivity of power for at least 5-points deterioration in the KCCQ clinical summary score 
to changes in assumptions is outlined in Table 3-1.
Table 3-1
Sensitivity of power for at least 5-points deterioration in KCCQ CSS to 
changes in assumptions for N = 2500
Assumed probability of 
at least 5-points deterioration
Power for at least 5-points deterioration
(one-sided alpha = 0.025)
IMT
LCZ696
Difference
(LCZ696 - IMT)
With 5%
drop-out 
rate
With 10%
drop-out 
rate
With 15%
drop-out 
rate
With 20%
drop-out 
rate
20%
15%
-5%
90%
88%
86%
84%
35%
30%
-5%
74%
72%
69%
67%


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The sensitivity of power for at least 5-points improvement in the KCCQ CSS to changes is 
outlined in Table 3-2.
Table 3-2
Sensitivity of power for at least 5-points improvement in KCCQ CSS to 
changes in assumptions for N = 2500
Assumed probability of 
at least 5-points improvement
Power for at least 5-points improvement
(one-sided alpha = 0.025)
IMT
LCZ696
Difference
(LCZ696 - IMT)
With 5%
drop-out rate
With 10%
drop-out rate
With 15%
drop-out rate
With 20%
drop-out rate
55%
60%
5%
69%
67%
65%
62%
41%
46%
5%
69%
67%
64%
62%
The assumed dropout rates (Table 3-1 and Table 3-2) are for the purpose of power sensitivity 
analysis. During the conduct of the study, all efforts will be made to reduce missing data.
For other secondary endpoints, this sample size will provide adequate powers for reasonable 
effect size assumptions: power of 90% for NYHA class change, assuming 14% of the patients 
in the comparator and 19% of the patients in the LCZ696 group are improved in NYHA class 
change, 6% of the patients in the comparator and 5% of the patients in the LCZ696 group are 
worsened in NYHA class change (based on Week 24 PARAMOUNT-HF data of patients with 
baseline KCCQ CSS < 75); and power of approximately 90% to detect a between treatment 
group mean difference of 1.4 points or more in change from baseline in SF-36 physical 
component summary score, assuming a standard deviation of 10-points (Edelmann et al 2013).
East 6.3 was used for the sample size calculations.
4
Change to protocol specified analyses
No change from protocol.
5
Appendix
5.1
Imputation rules
The missing or partially missing start/end date for AEs and prior/concomitant therapies will be 
imputed based on the Novartis AGB global standards. Details will be provided in the study PDS.
5.2
Rule of exclusion criteria of analysis sets
The protocol deviation criteria are listed in the sheet “Protocol Deviations” in the data review 
plan. The protocol deviation criteria leading to exclusion from the analysis sets are provided in
Table 5-1, which may be updated prospectively and will be finalized before database lock.
Table 5-1
Protocol deviation criteria leading to exclusion from the analysis sets
Protocol Deviation
Excluding from Analysis Set
ID
Description
SCR
RAN
FAS
PPS
SAF
INCL01A
No study informed consent obtained
X
X
X
X
X


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Protocol Deviation
Excluding from Analysis Set
INCL03A
Patient's qualifying LVEF <= 40% or the qualifying 
echo does not support LVEF >40%
X
INCL04
Heart failure symptoms not requiring diuretic 
treatment for at least 30 days prior to Visit 1
X
INCL05
NYHA Class I at Visit 1 or no heart failure symptoms 
at Visit 1
X
INCL08A
NT-proBNP at Visit 1 <= 220 pg/mL and no atrial 
fibrillation/atrial flutter (AF) on the Visit 1 ECG
X
INCL08B
NT-proBNP at Visit 1 <= 600 pg/mL and atrial 
fibrillation/atrial flutter (AF) on the Visit 1 ECG
X
INCL09
KCCQ clinical summary score >= 75 at Visit 1
X
EXCL08
Walking distance primarily limited by non-cardiac 
comorbid conditions
X
TRT03
Patient was randomized in error and no double-blind 
study medication was taken
X
X
X
TRT05
Patient was randomized within the wrong stratum 
and no double-blind study medication was taken
X
X
X
OTH01
Major GCP violation at site
X
X
OTH02
Blind was broken accidently at the site
X
Table 5-2 presents patient classification criteria including protocol deviation criteria and non-
protocol-deviation criteria leading to exclusion from analysis sets.
Table 5-2
Patient classification
Analysis
Set
Protocol Deviation ID leading
to exclusion of patients
Non-protocol deviation criteria leading
to exclusion from analysis sets
SCR
INCL01A
Not applicable
RAN
INCL01A

Patient without a randomization number
FAS
INCL01A, TRT03, TRT05, OTH01

Patient without a randomization number
PPS
INCL01A, INCL03A, INCL04, 
INCL05, INCL08A, INCL08B,
INCL09, EXCL08, TRT03, TRT05, 
OTH01, OTH02

Patient without a randomization number

Patient randomized but not receiving any
study drug
SAF
INCL01A, TRT03, TRT05

Patient without a randomization number

Patient randomized but not receiving any
study drug
6
Reference
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28(4): 586-604.
Carpenter JR. and Kenward, MG (2013) Multiple imputation and its application, New York: 
John Wiley &Sons.
Ingle, L, Rhidian J, Shelton AS. Rigby, et al (2005) The reproducibility and sensitivity of the 
6-min walk test in elderly patients with chronic heart failure. Eur Heart J; 26(17): 1742-1751.


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Edelmann F, Wachter R, Schmidt AG, et al (2013) Effect of spironolactone on diastolic function 
and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-
DHF randomized controlled trial. JAMA; 309(8):781-91.
National Research Council (2010): The Prevention and Treatment of Missing Data in Clinical 
Trials. Panel on Handling Missing Data in Clinical Trials. Committee on National Statistics, 
Division of Behavioral and Social Sciences and Education. The National Academies Press, 
Washington, DC.
Novartis ADaM Governance Board (AGB) global standard
Siddiqui O, Hung HM, O'Neill R (2009). MMRM vs. LOCF: a comprehensive comparison 
based on simulation study and 25 NDA datasets. J Biopharm Stat;19(2):227-46.
The Kansas City Cardiomyopathy Questionnaire Scoring Instructions
Ware, J. E., Kosinski, M., Bjorner, J. B., Turner-Bowker, D. M., Gandek, B., & Maruish, M. E. 
(2008): User's manual for the SF-36v2 Health Survey. Quality Metric.