Clinical trial NCT01920711
Conditions: Heart Failure With Preserved Ejection Fraction
Keywords: Heart failure preserved ejection fraction diastolic heart failure
Sponsor: Novartis Pharmaceuticals
Start date: 2014-07-18; Completion date: 2019-06-07
Enrollment: 4822 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the effect of LCZ696 compared to valsartan in the reduction of cardiovascular death and heart failure(HF) hospitalizations in patients with HF with preserved ejection fraction.

Detailed description:
This was a multicenter, randomized, double-blind, parallel group, active-controlled, study to evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction. Specifically, the study evaluated the effect of sacubitril/valsartan compared to the active comparator valsartan in the reduction of the rate of CV death and total HF hospitalizations in patients with HFpEF. The trial consisted of two periods: (1) a single-blind treatment run-in epoch that lasted from 3 to 8 weeks, in which patients received valsartan 80 mg bid, followed by sacubitril/valsartan 100 mg bid and (2) a double-blind randomized treatment epoch (sacubitril/valsartan 200 mg bid or valsartan 160 mg bid). In this study, investigators were responsible for assessing and submitting all events which could potentially fulfill the criteria for the primary, secondary, or other clinical endpoints to a Clinical Endpoint Committee (CEC). Investigator reported events were assessed by the CEC for adjudication.

For angioedema or angioedema-like events, investigators completed an Adjudication Questionnaire for an Angioedema-like Event form. All angioedema reports were forwarded to an Angioedema Adjudication Committee (AAC) by Novartis for assessment.

Arms: arm 1: Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of LCZ696 during the double blind period is 200 mg b.i.d. arm 2: Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of Valsartan during the double blind period is 160 mg b.i.d.
Interventions: intervention 1: LCZ696 intervention 2: Valsartan
Intervention descriptions: intervention 1: LCZ696 50mg, 100mg and 200 mg dosage strengths will be available for dose adjustments. intervention 2: Valsartan 40mg, 80mg and 160mg dosage strengths will be available for dose adjustments.

Protocol documents:
Prot_000.pdf: 
Clinical Development 
LCZ696 
Clinical Trial Protocol CLCZ696D2301 / NCT01920711
A multicenter, randomized, double-blind, parallel group, 
active-controlled study to evaluate the efficacy and safety 
of LCZ696 compared to valsartan, on morbidity and 
mortality in heart failure patients (NYHA Class II-IV) with 
preserved ejection fraction  
Authors: 
 
Principal or Coordinating 
Investigator 
and 
 for the 
CLCZ696D2301 Steering Committee 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2013-001747-31 
Version number: 
v04 Clean 
Development phase: 
III 
Release date: 
09-Dec-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Protocol synopsis ............................................................................................................... 12 
Amendment 4 ........................................................................................................................... 17 
Amendment rationale ........................................................................................................ 17 
1 
Introduction ....................................................................................................................... 19 
1.1 
Background ............................................................................................................ 19 
1.2 
Purpose .................................................................................................................. 22 
2 
Study objectives ................................................................................................................. 22 
2.1 
Primary objective ................................................................................................... 22 
2.2 
Secondary objectives ............................................................................................. 22 
2.3 
Exploratory objectives ........................................................................................... 23 
3 
Investigational plan ........................................................................................................... 24 
3.1 
Study design........................................................................................................... 24 
3.2 
Rationale of study design ....................................................................................... 29 
3.2.1 
Target study population and rationale ................................................... 29 
3.2.2 
Rationale for primary endpoint ............................................................. 29 
3.2.3 
Rationale for secondary endpoints ........................................................ 30 
3.2.4 
Rationale for treatment run-in epoch .................................................... 31 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 31 
3.4 
Rationale for choice of comparator ....................................................................... 31 
3.5 
Purpose and timing of interim analyses ................................................................. 32 
3.6 
Risks and benefits .................................................................................................. 32 
4 
Population .......................................................................................................................... 32 
4.1 
Inclusion criteria .................................................................................................... 32 
4.2 
Exclusion criteria ................................................................................................... 33 
5 
Treatment ........................................................................................................................... 36 
5.1 
Protocol requested treatment ................................................................................. 36 
5.1.1 
Investigational treatment ....................................................................... 36 
5.1.2 
Additional study treatment .................................................................... 37 
5.2 
Treatment arms ...................................................................................................... 37 
5.3 
Treatment assignment, randomization ................................................................... 37 


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5.4 
Treatment blinding ................................................................................................. 37 
5.5 
Treating the patient ................................................................................................ 38 
5.5.1 
Patient numbering ................................................................................. 38 
5.5.2 
Dispensing the investigational treatment .............................................. 38 
5.5.3 
Handling of study treatment .................................................................. 39 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 39 
5.5.5 
Permitted dose adjustments and interruptions of treatment .................. 40 
5.5.6 
Rescue medication ................................................................................ 42 
5.5.7 
Concomitant treatment .......................................................................... 42 
5.5.8 
Prohibited Treatment ............................................................................. 43 
5.5.9 
Discontinuation of study treatment ....................................................... 43 
5.5.10 
Withdrawal of consent .......................................................................... 44 
5.5.11 
Lost to follow-up ................................................................................... 45 
5.5.12 
Emergency breaking of treatment assignment ...................................... 45 
5.5.13 
Study completion and post-study treatment .......................................... 45 
5.5.14 
Early study termination ......................................................................... 46 
6 
Visit schedule and assessments ......................................................................................... 46 
Additional Procedures to be implemented in Japan only .................................................. 46 
Additional procedures to be implemented in India only ................................................... 47 
6.1 
Information to be collected on screening and run-in failures ................................ 53 
6.2 
Patient demographics/other baseline characteristics ............................................. 53 
6.3 
Treatment exposure and compliance ..................................................................... 53 
6.4 
Efficacy .................................................................................................................. 54 
6.4.1 
Appropriateness of efficacy assessments .............................................. 54 
6.5 
Safety ..................................................................................................................... 54 
6.5.1 
Physical examination ............................................................................ 54 
6.5.2 
Vital signs.............................................................................................. 55 
6.5.3 
Height and weight ................................................................................. 55 
6.5.4 
Laboratory evaluations .......................................................................... 55 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 57 
6.5.6 
Pregnancy and assessments of fertility ................................................. 57 
6.5.7 
Angioedema .......................................................................................... 57 
6.5.8 
Appropriateness of safety measurements .............................................. 58 
6.6 
Other assessments .................................................................................................. 58 
6.6.1 
Resource utilization ............................................................................... 58 
6.6.2 
Health-related Quality of Life ............................................................... 58 


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6.6.3 
NT-proBNP ........................................................................................... 59 
6.6.4 
Echocardiography ................................................................................. 59 
6.6.5 
Atrial fibrillation ................................................................................... 59 
6.6.6 
Cognitive function assessment .............................................................. 60 
6.6.7 
Biomarker substudy .............................................................................. 61 
6.6.8 
Pharmacokinetics substudy ................................................................... 61 
6.6.9 
Pharmacogenetics/Pharmacogenomics ................................................. 62 
7 
Safety monitoring .............................................................................................................. 63 
7.1 
Adverse events ....................................................................................................... 63 
7.2 
Serious adverse event reporting ............................................................................. 65 
7.3 
Protocol specific unblinding rules for SUSARs that are also efficacy 
endpoints ................................................................................................................ 66 
7.3.1 
Primary and secondary endpoints ......................................................... 66 
7.3.2 
Adverse events that are commonly seen in the study population ......... 66 
7.3.3 
Exploratory endpoints and other SAEs that meet the definition of 
SUSARs ................................................................................................ 67 
7.4 
Liver safety monitoring ......................................................................................... 67 
7.5 
Pregnancy reporting ............................................................................................... 68 
8 
Data review and database management ............................................................................. 68 
8.1 
Site monitoring ...................................................................................................... 68 
8.2 
Data collection ....................................................................................................... 69 
8.3 
Database management and quality control ............................................................ 69 
8.4 
Data Monitoring Committee .................................................................................. 70 
8.5 
Adjudication Committees ...................................................................................... 70 
8.6 
Source documentation verification ........................................................................ 71 
9 
Data analysis ...................................................................................................................... 71 
9.1 
Analysis sets .......................................................................................................... 71 
9.2 
Patient demographics and other baseline characteristics ....................................... 72 
9.3 
Treatments ............................................................................................................. 72 
9.4 
Analysis of the primary and secondary variable(s) ............................................... 73 
9.4.1 
Variable(s) ............................................................................................. 73 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 73 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 79 
9.5 
Analysis of exploratory variables .......................................................................... 79 
9.5.1 
Exploratory variables ............................................................................ 79 
9.5.2 
Analysis methods .................................................................................. 80 
9.5.3 
Safety variables ..................................................................................... 84 


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9.5.4 
Resource utilization ............................................................................... 85 
9.5.5 
Health-related Quality of Life ............................................................... 85 
9.5.6 
Pharmacokinetics .................................................................................. 85 
9.5.7 
Pharmacogenetics .................................................................................. 85 
9.5.8 
Pharmacogenomics ............................................................................... 85 
9.5.9 
Biomarkers ............................................................................................ 86 
9.6 
Interim analyses ..................................................................................................... 86 
9.7 
Sample size calculation .......................................................................................... 86 
9.7.1 
Sample size for the primary analysis .................................................... 86 
9.7.2 
Sample size re-estimation ..................................................................... 87 
9.7.3 
Powers for the secondary analyses ........................................................ 88 
10 Ethical considerations ........................................................................................................ 89 
10.1 
Regulatory and ethical compliance ........................................................................ 89 
10.2 
Informed consent procedures ................................................................................. 89 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 90 
10.4 
Publication of study protocol and results............................................................... 90 
11 Protocol adherence ............................................................................................................ 91 
11.1 
Protocol amendments ............................................................................................. 91 
12 References ......................................................................................................................... 91 
13 Appendix 1: Clinically notable laboratory values ............................................................. 97 
14 Appendix 2: Liver event definitions and follow-up requirements .................................... 97 
15 Appendix 3: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.3 mmol/L [mEq/L]) .................................................................................... 100 
16 Appendix 4: Guidelines for the management of blood pressure ..................................... 101 
17 Appendix 5: Guidelines for the management of renal dysfunction ................................. 102 
18 Appendix 6: Blood log for PK sample collection ........................................................... 103 
 
 
 
 
 
 
 


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List of tables 
Table 3-1 
Minimum pre-study total daily doses of commonly used ACEIs 
and ARBs allowing patients to begin the treatment run-in epoch at 
Visit 102 ................................................................................................ 26 
Table 3-2 
Safety monitoring criteria that must be met at Visit 1 (screening), 
Visit 103 and Visit 199/201 .................................................................. 28 
Table 3-3 
Study drug dose levels during randomized treatment epoch ................ 28 
Table 5-1 
Study drug dispensed for the treatment run-in epoch by study visit ..... 39 
Table 5-2 
Study drug dispensed during the randomized treatment epoch by 
study visit .............................................................................................. 40 
Table 5-3 
Prohibited treatment .............................................................................. 43 
Table 6-1 
Assessment schedule ............................................................................. 48 
Table 6-2 
Routine laboratory examinations .......................................................... 56 
Table 7-1 
Adverse events commonly seen in study population ............................ 67 
Table 9-1 
Sample size and power estimations through simulations ...................... 87 
Table 9-2 
PARAMOUNT NYHA incidence rates ................................................ 88 
Table 9-3 
Powers for NYHA class comparisons ................................................... 88 
Table 14-1 
Liver event definitions .......................................................................... 97 
Table 14-2 
Liver event follow up requirements ...................................................... 98 
List of figures 
Figure 3-1 
Study design .......................................................................................... 24 
Figure 3-2 
Abbreviated inclusion criteria ............................................................... 25 
Figure 3-3 
Treatment run-in epoch overview ......................................................... 26 
Figure 9-1 
Illustration of weights for alpha relocation in the sequentially 
rejective multiple test procedure for the secondary hypotheses ............ 78 
 


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List of abbreviations 
AAC  
Angioedema Adjudication Committee 
ACE  
angiotensin converting enzyme 
ACEI  
angiotensin converting enzyme inhibitor 
AE  
 
adverse event 
AESI  
adverse event of special interest 
AF  
 
atrial fibrillation and atrial flutter 
ALB  
albumin 
ALP 
 
alkaline phosphatase 
ALT 
 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANP  
atrial natriuretic peptide 
APP 
 
aminopeptidase P 
ARB  
angiotensin receptor blocker 
ARNI  
angiotensin receptor neprilysin inhibitor 
AST 
 
aspartate aminotransferase 
AT1 
 
angiotensin type 1 
AUC  
area under the curve 
b.i.d.  
twice a day 
BMI 
 
body mass index 
BNP  
B-type natriuretic peptide  
BP  
 
blood pressure 
bpm 
 
beats per  minute 
BUN  
blood urea nitrogen 
CABG  
coronary artery bypass graft 
CCB  
calcium channel blocker 
CEC  
Clinical Endpoint Committee 
cGMP  
cyclic guanosine monophosphate 
CHF  
chronic heart failure 
CNP  
C-type natriuretic peptide 
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 
CV  
 
cardiovascular 
DBP  
diastolic blood pressure 


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DM  
 
diabetes mellitus 
DMC  
Data Monitoring Committee 
EC  
 
Ethics Committee 
ECG  
Electrocardiogram 
echo 
 
echocardiogram 
EDC  
Electronic Data Capture 
EF  
 
ejection fraction 
eGFR  
estimated glomerular filtration rate 
EOS 
 
end of study 
ER  
 
emergency room 
ESRD  
end stage renal disease 
FAS 
 
full analysis set 
FDA  
Food and Drug Administration 
FMV  
first morning void 
hCG 
 
human chorionic gonadotropin 
HF  
 
heart failure 
HFpEF 
heart failure with preserved ejection fraction 
HFrEF  
heart failure with reduced ejection fraction 
Hgb 
 
hemoglobin  
hsTnT  
high-sensitivity troponin T  
HTN  
hypertension 
IA  
 
interim analysis 
IB  
 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICU 
 
intensive care unit 
IEC  
 
Independent Ethics Committee 
IN  
 
Investigator Notification 
i.v. (IV) 
intravenous 
IRB 
 
Institutional Review Board 
IRT  
 
Interactive Response Technology 
IUD 
 
intrauterine device 
IUS  
 
intrauterine system 
IV            
intravenous 
IVRS  
Interactive Voice Response System 
KCCQ  
Kansas City Cardiomyopathy Questionnaire 
LA  
 
left atrial 
LAE 
 
left atrial enlargement 
LFT 
 
liver function test 
LV  
 
left ventricular 


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LVEDP 
left ventricular end diastolic pressure 
LVEF  
left ventricular ejection fraction 
LVH  
left ventricular hypertrophy 
MAR  
missing at random 
MCH  
mean corpuscular hemoglobin 
MCV  
mean corpuscular volume 
MDRD            Modification in Diet in Renal Disease 
MI  
 
myocardial infarction 
MMSE  
Mini-Mental State Examination 
MRA  
mineralocorticoid antagonist 
NEP 
 
neprilysin 
NEPi  
neprilysin inhibitor 
NOAF  
new onset atrial fibrillation  
NODM 
new onset diabetes mellitus 
NP  
 
natriuretic peptide 
NSAID 
non-steroidal anti-inflammatory drug 
NTG  
nitroglycerin 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA            New York Heart Association 
o.d.  
 
once a day 
PCI  
 
percutaneous coronary intervention 
PDE-5  
phosphodiesterase-5 
PK  
 
pharmacokinetics 
PT  
 
preferred term 
p.o.  
 
oral 
PP  
 
per protocol 
QoL 
 
quality of life 
RAS  
renin angiotensin system 
RBC  
red blood cell 
RDW             red blood cell distribution width 
RR  
 
rate ratio 
RU  
 
resource utilization 
SAE 
 
serious adverse event 
SAF 
 
safety 
SBP 
 
systolic blood pressure 
SGOT  
serum glutamic oxaloacetic transaminase 
SGPT  
serum glutamic pyruvic transaminase 
SUSAR 
suspected unexpected serious adverse reactions 
TBL 
 
total bilirubin 
T1/2 
 
half life 


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UACR  
urine albumin creatinine ratio 
ULN  
upper limit of normal 
US  
 
United States 
WBC  
white blood cell 
γGT 
 
gamma-glutamyltransferase 


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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
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 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Epoch  
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended. 
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.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage 
Medication number 
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations or 
objectives. For example, a single dose design, a multiple dose design that 
are combined into one protocol, or the same design with different patient 
populations in each part. 
Period 
A subdivision of a cross-over study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up) 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding to 
a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later 
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), 
treatment drug run-ins or background therapy  
Study/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature patient withdrawal 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points 
 


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Protocol synopsis 
 
Protocol number 
CLCZ696D2301 
Title 
A multicenter, randomized, double-blind, parallel group, active-controlled 
study to evaluate the efficacy and safety of LCZ696 compared to 
valsartan, on morbidity and mortality in heart failure patients (NYHA Class 
II-IV) with preserved ejection fraction 
Brief title 
 
Study of efficacy and safety of LCZ696 in heart failure (HF) patients (New 
York Heart Association [NYHA] Class II-IV) with preserved ejection fraction 
(EF) 
Sponsor and Clinical 
Phase 
Novartis, Phase 3  
Investigation type 
Drug 
Study type 
Interventional 
Purpose  
The purpose of this study is to evaluate the effect of LCZ696 compared to 
valsartan in the reduction of cardiovascular (CV) death and HF 
hospitalizations in patients with HF with preserved EF (HFpEF). 
Primary Objective  
The primary objective of this study is to compare LCZ696 to valsartan in 
reducing the rate of the composite endpoint of CV death and total (first and 
recurrent) HF hospitalizations in HF patients (NYHA Class II - IV) with 
preserved EF (left ventricular EF [LVEF] ≥45%). 
Secondary Objectives 
 
• 
To compare LCZ696 to valsartan on changes in the clinical summary 
score for HF symptoms and physical limitations as assessed by 
Kansas City Cardiomyopathy Questionnaire [KCCQ]) at 8 months. 
• 
To compare LCZ696 to valsartan in improving NYHA functional 
classification at 8 months.  
• 
To compare  LCZ696 to valsartan in delaying the time to first 
occurrence of a composite renal endpoint, defined as:  
o 
renal death, or 
o 
reaching end stage renal disease (ESRD), or 
o 
≥ 50% decline in estimated glomerular filtration rate (eGFR) 
relative to baseline 
• 
To compare LCZ696 to valsartan in delaying the time to all-cause 
mortality. 
Note: randomized treatment epoch baseline is used in the secondary 
objectives efficacy analysis 
Study design 
This study is a multi-center, randomized, double-blind, parallel group, 
active comparator, morbidity and mortality trial designed to evaluate the 
efficacy and safety of LCZ696 compared to valsartan in HFpEF patients 
(NYHA class II-IV).  
Population 
Approximately  4,600 male and female patients ≥ 50 years of age with a 
prior history of HF and current symptoms of HF (NYHA class II-IV), a LVEF 
≥45%, and documented structural heart disease will be randomized. 
Inclusion criteria 
1. Written informed consent must be obtained before any assessment is 
performed. 


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2. ≥ 50 years of age, male or female 
3. LVEF ≥45% by echocardiogram (echo) during the screening epoch, or 
within 6 months prior to Visit 1(any local LVEF measurement made 
using echo only) 
4. Symptom(s) of HF requiring treatment with diuretic(s)  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 evidenced by  at least one of the following  
echo findings (any local measurement made during the screening 
epoch or within the 6 months prior to Visit 1): 
a. left atrial (LA) 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 (LVH) defined by septal thickness or 
posterior wall thickness ≥1.1 cm  
7. Patients with at least one of the following: 
a. a HF hospitalization (defined as HF as the major reason for 
hospitalization) within 9 months prior to Visit 1 and NT-
proBNP >200 pg/ml for patients not in atrial fibrillation/flutter (AF) 
or >600 pg/ml for patients in AF on Visit 1 ECG, OR 
b. NT-proBNP >300 pg/ml for patients not in AF or >900 pg/ml for 
patients in AF on the Visit 1 ECG. 
Key Exclusion criteria 
1. Any prior echocardiographic measurement of LVEF <40%. 
2. Acute coronary syndrome (including MI), cardiac surgery, other major 
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 (e.g., MI, coronary artery bypass graft [CABG]), 
unless an echo measurement was performed after the event 
confirming the LVEF to be ≥45%. 
4. Current acute decompensated HF requiring augmented therapy with 
diuretics, vasodilators and/or inotropic drugs. 
5. Patients who require treatment with 2 or more of the following: an 
angiotensin converting enzyme inhibitor (ACEI), an angiotensin 
receptor blocker (ARB) or a renin inhibitor. 
6. History of hypersensitivity to any of the study drugs or to drugs of 
similar chemical classes. 
7. Patients with a known history of angioedema. 
8. Probable alternative diagnoses that in the opinion of the investigator 
could account for patient’s HF symptoms (i.e., dyspnea, fatigue) such 
as significant pulmonary disease (including primary pulmonary 
hypertension), anemia or obesity. Specifically, patients with the below 
are excluded: 
a. severe chronic obstructive pulmonary disease (COPD) (i.e., 
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, or  
c. 
body mass index (BMI) > 40 kg/m2 
9. Patients with any of the following: 


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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, 
mineralocorticoid antagonist (MRA), ACEI, or ARB, beta blocker 
and calcium channel blocker (CCB), or   
c. SBP <110 mmHg at Visit 1, or 
d. SBP < 100 mmHg or symptomatic hypotension as determined by 
the investigator at Visit 103 or Visit 199/201. 
10. Patients with history of any dilated cardiomyopathy, including 
peripartum cardiomyopathy, chemotherapy induced cardiomyopathy, 
or viral myocarditis. 
11. Evidence of right sided HF in the absence of left-sided structural heart 
disease. 
12. Known pericardial constriction, genetic hypertrophic cardiomyopathy, 
or infiltrative cardiomyopathy. 
13. Clinically significant congenital heart disease that could be the cause 
of the patient’s symptoms and signs of heart failure. 
14. Presence of hemodynamically significant valvular heart disease in the 
opinion of the investigator.  
15. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty 
within the 3 months prior to Visit 1.   
16. Coronary or carotid artery disease or valvular heart disease likely to 
require surgical or percutaneous intervention during the trial. 
17. Life-threatening or uncontrolled dysrhythmia, including symptomatic or 
sustained ventricular tachycardia and atrial fibrillation or flutter with a 
resting ventricular rate >110 beats per minute (bpm). 
18. Patients with a cardiac resynchronization therapy (CRT) device. 
19. Patients with prior major organ transplant or intent to transplant (i.e. on 
transplant list). 
20. 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. 
21. Evidence of hepatic disease as determined by any one of the 
following: SGOT (AST) or SGPT (ALT) values exceeding 3x ULN, 
bilirubin >1.5 mg/dl at Visit 1. 
22. Patients with one of the following:    
a. eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet 
in Renal Disease (MDRD) formula at Visit 1, or 
b. eGFR <25 mL/min/1.73m2 at Visit 103 or Visit 199/201, or 
c. eGFR reduction ≥35% (compared to Visit 1) at Visit 103 or Visit 
199/201. 
23. Patients with one of the following: 
a. serum potassium >5.2 mmol/L (mEq/L) at Visit 1, or 
b. serum potassium >5.4 mmol/L (mEq/L) at Visit 103 or Visit 
199/201. 
24. Pregnant or nursing (lactating) women. 
25. Women of child-bearing potential unless they are using highly effective 
methods of contraception.  


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Investigational and 
reference therapy 
LCZ696 
50 mg (dose level 1), 100 mg (dose level 2), 200 mg (dose level 3) 
Valsartan 
40 mg (dose level 1), 80 mg (dose level 2), 160 mg (dose level 3) 
Efficacy assessments 
• 
CV death 
• 
Total HF hospitalizations  
• 
KCCQ clinical summary score for HF symptoms and physical 
limitations scores at 8 months  
• 
NYHA functional classification at 8 months 
• 
 Composite renal endpoint  
• 
All-cause mortality 
Safety assessments 
• 
AEs and SAEs 
• 
Sitting systolic BP, sitting diastolic BP, and heart rate  
• 
Laboratory values (including monitoring for hyperkalemia, renal 
dysfunction) 
• 
ECG changes 
• 
Angioedema surveillance 
Other assessments 
• 
Total non-fatal MIs  
• 
Total non-fatal strokes 
• 
Resource utilization 
• 
Health-related Quality of Life 
o 
KCCQ overall summary score and subdomain scores; KCCQ 
clinical summary score relative to the beginning of  run-in epoch 
(in the subset of patients in whom KCCQ assessment was 
collected at that point) and relative to randomization  
o 
Clinical composite assessment 
o 
EuroQol (EQ-5D) 
• 
New onset of atrial fibrillation (NOAF)  
• 
Echocardiography parameters  
• 
Pharmacokinetics 
• 
Pharmacogenetics/Pharmacogenomics 
• 
Biomarkers 
• 
Mini-Mental State Examination score 
Data analysis 
The primary efficacy variable is the cumulative number of primary 
composite endpoint events for a given patient, over time during the double 
blind period of the study.  
The secondary efficacy variables are: 
• 
Change in KCCQ clinical summary score from baseline to Month 8  
• 
Change in NYHA class from baseline to Month 8  
• 
Time to composite renal endpoint 
• 
Time to all-cause mortality 
Note: randomized treatment epoch baseline is used in the secondary 
efficacy analysis  
The primary efficacy analysis will be using a proportional conditional rates 
model based on cumulative, recurrent events approach analyzing CV 


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death and HF hospitalizations. The primary hypothesis will be tested at a 
one-sided significance level of  0.024 adjusted for interim analysis (IA).  
One efficacy interim analysis is planned when approximately two-thirds of 
the target number of adjudicated primary events is obtained.  
Key words 
heart failure with preserved ejection fraction, cardiovascular death, heart 
failure hospitalization, atrial fibrillation, echocardiography, NYHA, Clinical 
Composite Assessment, Kansas City Cardiomyopathy Questionnaire, EQ-
5D 


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Amendment 4 
Amendment rationale  
Recruitment in Study CLCZ696D2301, also known as PARAGON-HF, began on 15-Jul-
2014. As of 07-Dec-2015, 1,514 patients have been randomized into the study. 
This is the fourth amendment to the current protocol. The purpose of the current amendment 
is to include changes required by the Japanese Health Authority (PMDA) and the Indian 
Health Authority. The following changes have been made and will only be applicable to Japan 
and India, as indicated: 
Japan: 
1. All patients must enter the treatment run-in epoch at Visit 101.  
2. Patients who have not received an ACEI or an ARB during the 30 days prior to the 
screening visit will be required to attend an additional clinic visit (Visit 101J) 
approximately one week after Visit 101 and will have the same procedures as Visit 102. 
Visit 102 will occur approximately one week after Visit 101J in these patients.  
3. Central safety laboratory assessments will be required at Visit 101J and Visit 102. 
4. All patients will be required to attend three additional clinic visits at approximately 1 
week (Visit 201J1), 8 weeks (Visit 202J8), and 12 weeks (Visit 202J12) following 
randomization.  
5. Visits 206, 208, 210, 212, 214, 216, 218 and 220 will be conducted as clinic visits, not 
phone visits, with the same procedures as Visit 202. Study medication dispensing, drug 
accountability and serum/urine pregnancy tests are not required at any of the additional 
double-blind treatment epoch visits implemented for Japan. 
India: 
1. All patients will be required to attend an additional clinic visit (Visit 201I1) approximately 
1 week following randomization (i.e. start of double-blind study medication dose level 3) 
where a potassium assessment will be performed.  
2. For inclusion in the study, the ejection fraction must be measured using 2D volumetric 
methods.  
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. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein are also reflected in the Informed Consent. 
Summary of previous amendments 
The first amendment of protocol CLCZ696D2301 (v01 of the protocol) was dated 10-Jun-
2014. The main purpose of this amendment was to increase the contraception period for 
women of child-bearing potential after being taken off study medication from 4 days to 7 days 


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in the exclusion criteria. Also, information on the results of the TOPCAT and PARADIGM-
HF studies were included.  
The second amendment of protocol CLCZ696D2301 (v02 of the protocol) was dated 06-May-
2015. The main purposes of this amendment were (1) to promote two exploratory endpoints 
(KCCQ clinical summary score at 8 months and the composite renal endpoint) to key 
secondary endpoints; (2) to demote the extended composite endpoint (i.e., the composite of 
cardiovascular [CV] death, total HF hospitalizations, total non-fatal strokes, and total non-
fatal myocardial infarctions [MIs]) and the new onset atrial fibrillation (NOAF) endpoint to 
exploratory endpoint status; (3) to eliminate the ambulatory cardiac monitoring substudy and 
the associated exploratory objectives; (4) to include cognitive function assessments using the 
Mini-Mental State Examination (MMSE) instrument at baseline and annually thereafter; (5) to 
modify several entry criteria; (6) to move the interim efficacy analysis to occur after 
approximately two-thirds of the target number of primary composite events (i.e., ~1148 
primary composite events) rather than half as previously defined; and (7) to eliminate the 
futility analysis. 
The third amendment of protocol CLCZ696D2301 (v03 of the protocol) was dated 04-Dec-
2015. The main purpose of this amendment was (1) to add the KCCQ assessment at V101/102 
(whichever occurs first); (2) to include a mechanism for central source data verification of 
medical history; (3) to adjust the sample size from 4300 to 4600; (4) to modify the stopping 
rules for interim analysis; and (5) clarify responsibilities of the investigator with regards to 
emergency unblinding.  
 
 


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1 
Introduction 
1.1 
Background   
Heart failure with preserved ejection fraction (HFpEF) 
Cardiovascular (CV) disease is the leading cause of death in the western world. Heart failure 
(HF) incidence approaches 10 per 1000 population after 65 years of age in the United States 
(US) (Roger et al 2012) with HF prevalence between 2 and 3% in Europe and between 10 and 
20% in European elderly (McMurray et al 2012). It affects nearly 6.6 million people over the 
age of 18 in the US with an additional 3 million new cases expected by 2030; a 25% increase 
from 2010 (Roger et al 2012).  
In recent years, HF has been shown to occur with normal systolic function. HF with normal or 
“near-normal” ejection fraction (EF) has been designated HF with preserved ejection fraction 
(HFpEF).  Studies have typically defined preserved EF with a cut-off of 40-50%, with 45% 
being the most common EF cut-off utilized in clinical trials. HFpEF accounts for 
approximately half of HF cases, and is associated with substantial morbidity and mortality 
(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 (Lenzen et al 2004, MAGGIC 
2012). 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 (Tartière-Kesri et al 2012, Tan et al 2009). 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). 
HF hospitalization is the single most common cause of admission in patients with HFpEF, 
representing an important marker of disease progression and, thus, an important indicator of 
poor subsequent outcomes, including death. Hospitalization for HF also adversely affects 
quality of life (QoL) and, in addition, because these events are frequently recurrent, HF 
hospitalization places a huge economic burden on health-care systems. This problem is a 
growing one in patients with HFpEF, as HF hospitalization is becoming relatively more 
common in patients with HFpEF compared to those with HFrEF (Lewis et al 2007, Hoekstra 
et al 2011). Recurrent HF hospitalizations are frequent in HFpEF with rates similar to HFrEF 
(Lenzen et al 2004, Fonarow et al 2007, Ahmed et al 2008, Solomon et al 2007, Steinberg et 
al 2012).  
Unlike HFrEF, no pharmacologic therapies have shown benefit in HFpEF. Current guidelines 
focus on treating co-morbid conditions, such as diabetes mellitus (DM), HTN, renal 
insufficiency, AF and coronary artery disease, which are common in HFpEF patients (Hunt et 
al 2005, McMurray et al 2012). Thus, there is no evidence-based therapy specific for HFpEF 
and a substantial need exists for clinical trials investigating therapeutic options for patients 


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with HFpEF.  Three recent outcomes trials (PEP-CHF, perindopril; CHARM-Preserved, 
candesartan; I-PRESERVE, irbesartan) have failed to show a clinical benefit in HFpEF 
(Cleland et al 2006, Yusuf et al 2003, Massie et al 2008, Pitt et al 2014). In TOPCAT 
(Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), a 
recent outcomes study in HFpEF, spironolactone did not significantly reduce the incidence of 
the primary composite outcome of death from CV causes, aborted cardiac arrest, or 
hospitalization for the management of HF (Pitt et al 2014). 
LCZ696 Clinical Profile and Development in HFpEF 
Natriuretic peptides (NPs), acting through the second messenger cyclic guanosine 
monophosphate (cGMP), have potent natriuretic and vasodilator properties, inhibit the activity 
of the renin angiotensin system (RAS), lower sympathetic drive and have antifibrotic and 
antihypertrophic effects (Levin et al 1998, Gardner et al 2007, Pandey 2008). Neprilysin 
degrades biologically active NPs, including atrial natriuretic peptide (ANP), B-type natriuretic 
peptide (BNP) and C-type natriuretic peptide (CNP) but not the biologically inert N-terminal 
pro-brain natriuretic peptide (NT-proBNP) which is not a substrate for this enzyme (Martinez-
Rumayor et al 2008). 
LCZ696 is a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI). Following 
ingestion, LCZ696 provides systemic exposure to AHU377, a neprilysin (neutral 
endopeptidase 24.11, NEP) inhibitor (NEPi) and valsartan, an angiotensin receptor blocker 
(ARB). AHU377 is further metabolized via esterases to the active NEPi, LBQ657. Exposures 
to AHU377, LBQ657, and valsartan increased dose linearly in the 80-600 mg dose range. 
With a 2-fold increase in LCZ696 dose, the exposure of AHU377 and LBQ657 increases by 
1.8- and 1.9-fold, and valsartan exposure increases by 1.46-fold. Minimal accumulation of the 
analytes occurs after multiple dosing. The mean elimination half-life (T1/2) is approximately 
1, 12 and 14 hours for AHU377, LBQ657 and valsartan, respectively. Following multiple 
dose administration of LCZ696, steady-state is achieved within 3-4 days. In patients with 
HFrEF, administration of LCZ696 100 mg and 200 mg doses (CLCZ696A2117) resulted in 
half-life estimates for LBQ657 (active NEPi) and valsartan that were comparable to those in 
healthy subjects. At corresponding doses (LCZ696 100, 200 and 400 mg vs. Diovan® 80, 160 
and 320 mg, respectively), LCZ696 or Diovan® administration results in comparable valsartan 
exposure (AUC) in healthy volunteers and in patients with HFrEF.  
LCZ696, through its dual mode of action, potentiates NPs via NEP inhibition while inhibiting 
the RAS via angiotensin type 1 (AT1) receptor blockade; mechanisms which are considered to 
act in a complementary and at least additive manner. Prior research had suggested that the 
potential clinical benefits from NEP inhibition can only be leveraged if the RAS system is 
inhibited concomitantly (Campbell 2003, Mangiafico et al 2012). Enhancement of the NP 
system through NEP inhibition alone has not been successful in trials, likely due to its effects 
of increasing angiotensin II levels, which, would be expected to counteract the beneficial 
vasodilatory, antifibrotic, and antihypertrophic effects of NPs. By contrast, when the RAS 
system is inhibited concurrently, there is a potential synergy of enhanced beneficial and 
inhibited negative effects. 
Previous attempts to simultaneously augment the NP system while blocking the RAS, using 
ACE-NEP (“vasopeptidase”) inhibitors, were complicated by safety issues. Omapatrilat, 


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which was the most extensively evaluated vasopeptidase inhibitor, simultaneously inhibited 
NEP and angiotensin converting enzyme (ACE) but was associated with an increased 
incidence of angioedema. (Kostis et al 2004). It was hypothesized that omapatrilat’s 
concomitant inhibition of three pathways (ACE, aminopeptidase P [APP], and NEP) involved 
in bradykinin breakdown (the putative mediator of ACE inhibitor [ACEI]-induced 
angioedema) was the most likely explanation for this finding (Fryer et al 2008). Different 
from omapatrilat, the risk of angioedema associated with LCZ696 is considered low, as 
LCZ696 inhibits NEP and is a poor inhibitor of ACE and APP, the two major enzymes 
responsible for bradykinin breakdown. To date, the angioedema rate with LCZ696 has been 
low and similar to comparator agents. 
It is anticipated that LCZ696, an inhibitor of NEP and a blocker of the AT1 receptor, may 
deliver clinical benefits to patients with CV disease, including HF and HTN, in which 
vasoconstriction, volume expansion, and target organ damage (i.e., fibrosis, hypertrophy, 
myocardial/vascular stiffness) play a key role in pathophysiology.  
In a dose-ranging study (n=1328), a total of 497 hypertensive patients received LCZ696 (100 
mg, 200 mg and 400 mg). This study showed that LCZ696 (400 mg/d and 200 mg/d) lowered 
blood pressure (BP) to a greater extent than corresponding doses of valsartan 320 mg/d and 
160 mg/d. Discontinuation rate due to adverse events (AEs) was similar to placebo. No dose 
related trends were observed for any specific AEs. The most frequent AE was headache, 
which was more frequent in the placebo group compared to any other group. 
There is an ongoing Phase III outcomes study (PARADIGM-HF, CLCZ696B2314, n=8442) 
in patients with HFrEF comparing LCZ696 and enalapril for the reduction of CV death and 
HF hospitalization. Patient enrollment has completed. The study design incorporates a single-
blind, treatment run-in epoch aimed to ensure as large a proportion as possible of patients 
remain on high dose study drug during the long term follow up. On 28 March 2014, the Data 
Monitoring Committee (DMC) unanimously recommended stopping of the PARADIGM-HF 
study ahead of schedule because patients treated with LCZ696 were less likely than those 
treated with enalapril to die from CV causes or be admitted to the hospital with worsening HF 
(McMurray et al 2014). 
The mechanisms of action of LCZ696 suggests that it may impact the suspected 
pathophysiology of HFpEF, in which it is believed that excessive fibrosis and myocyte 
hypertrophy lead to abnormal left ventricular relaxation filling, impaired diastolic 
distensibility and/or increased vascular stiffness, with consequent elevated cardiac filling 
pressures (Krum and Abraham 2009). Of interest, it was recently reported that patients with 
HFpEF have lower levels of myocardial cGMP concentration (and lower protein kinase G 
activity) compared with patients with HFrEF or patients with aortic stenosis (van Heerebeek 
et al 2012). Enhancing NP action therefore seems a reasonable potential therapeutic option. 
By augmenting the active NPs, NEP 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 (CLCZ696B2214) was a recently completed, Phase II proof of concept 
(therapeutic validation) trial in HFpEF comparing LCZ696 with valsartan. It consisted, of a 


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12 week core study period and a 24 week extension period (Solomon et al 2012). The study 
met its primary endpoint, demonstrating a 23% greater reduction in NT-proBNP (p=0.005) at 
12 weeks for LCZ696 compared with valsartan. At 36 weeks, NT-proBNP remained reduced 
from baseline in the LCZ696 group, but the treatment difference was not statistically 
significant (p=0.20). At 36 weeks, however, there were greater reductions in all 
echocardiographic measures of left atrial size (left atrial volume, p = 0.003; left atrial 
dimension, p = 0.03), along with improvements in New York Heart Association (NYHA) 
classification (p=0.05), in the LCZ696 group compared with the valsartan group. No 
differences were observed for quality of life measures. LCZ696 was well tolerated. Three 
deaths were reported, one occurring in the LCZ696 arm and two occurring in the valsartan 
arm. None were suspected to be related to study drug by the investigator. Serious adverse 
events (SAEs) were reported by 22 (14.8%) and 30 (19.7%) patients in the LCZ696 and 
valsartan groups, respectively. While hyperkalemia >5.5 mmol was more frequent in the 
LCZ696 group than in the valsartan group (16.2% vs. 11.2%, p=0.21), hyperkalemia >6.0 
mmol was reported in 5 vs. 6 patients in the two groups, respectively. 
NT-proBNP is a marker of left ventricular wall stress. Elevated NP levels are associated with 
adverse outcomes and reductions in NT-proBNP levels have been associated with better 
outcomes in patients with HF (Masson et al 2008, Komajda et al 2011). An enlarged left 
atrium is a characteristic finding in HFpEF and is reflective of sustained elevations in left 
ventricular filling pressures; reductions in left atrial size have also been associated with better 
in CV outcomes (Brenyo et al 2011, Gerdts et al 2007, Meris et al 2009).  
While the positive results in PARAMOUNT were based on a biomarker (NT-proBNP) and 
surrogate endpoints (left atrial size) these data provide strong support for a Phase III outcomes 
trial in HFpEF patients.  
Please refer to the LCZ696 Investigator Brochure (IB) for further details on the clinical profile 
of LCZ696.  
1.2 
Purpose  
The purpose of this study is to evaluate the effect of LCZ696 compared to valsartan in the 
reduction of CV death and rate of HF hospitalizations in patients with HFpEF. This study will 
serve as a registration trial for LCZ696 as a treatment for patients with HFpEF. 
2 
Study objectives 
2.1 
Primary objective 
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of 
the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF 
patients (NYHA Class II-IV) with preserved EF (LVEF ≥45%). 
2.2 
Secondary objectives 
• To compare LCZ696 to valsartan on changes in the clinical summary score for HF 
symptoms and physical limitations, as assessed by the Kansas City Cardiomyopathy 
Questionnaire [KCCQ]) at 8 months.  


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• To compare LCZ696 to valsartan in improving NYHA functional classification at 8 
months. 
• To compare  LCZ696 to valsartan in delaying the time to first occurrence of a composite 
renal endpoint, defined as:  
1. renal death, or 
2. reaching end stage renal disease (ESRD), or 
3. ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline 
• To compare LCZ696 to valsartan in delaying the time to all-cause mortality. 
2.3 
Exploratory objectives  
• To compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV 
death, total HF hospitalizations, total non-fatal strokes, and total non-fatal myocardial 
infarctions (MIs). Total is defined as the first and all recurrent events. 
• To compare LCZ696 to valsartan on changes in clinical composite assessment (assessed 
by NYHA, global patient assessment, and major adverse clinical events as defined by CV 
death and hospitalization for HF) at 8 months. 
• To compare LCZ696 to valsartan on patient global assessment at 8 months.  
• To compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV 
death, total non-fatal HF hospitalizations, total non-fatal strokes, and total non-fatal 
myocardial infarctions (MIs). Total is defined as the first and all recurrent events. 
• To compare LCZ696 to valsartan in delaying the time to new onset AF (NOAF). 
• To compare LCZ696 to valsartan on changes in the health related quality of life (assessed 
by overall summary score, clinical summary score and individual scores of the sub-
domains from the KCCQ [relative to treatment run-in epoch baseline scores and relative to 
randomized treatment epoch baseline scores] and total score of the EQ-5D for health 
status).  
• To compare LCZ696 to valsartan in reducing CV deaths and total worsening HF events. A 
subject will be defined as having a CV death or worsening HF event when the subject has: 
1. CV death or 
2. a hospitalization for HF or 
3. received intravenous (IV) decongestive therapy (IV diuretics, IV neseritide or other 
natriuretic peptide, IV inotropes, and IV nitroglycerin [NTG]), and does not result in 
formal inpatient hospital admission, regardless of the setting (i.e. in an emergency 
room (ER) setting, in the physician’s office, an outpatient treatment facility, etc.).  
• To compare LCZ696 to valsartan on hospitalizations (all cause and cause specific). 
• To compare LCZ696 to valsartan on the number of days alive and out of hospital at 12 
months.  
• To compare LCZ696 to valsartan in slowing the rate of decline in eGFR. 
• To compare LCZ696 to valsartan on delaying time to new onset diabetes mellitus 
(NODM).  


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• To compare LCZ696 to valsartan on reducing healthcare resource utilization, e.g., number 
of days/stays in intensive care unit (ICU), number of re-hospitalizations, and number of 
ER visits for HF. 
• To compare LCZ696 to valsartan on 30 day HF hospital readmissions and readmission 
rate after a prior HF hospitalization. 
• To compare LCZ696 to valsartan on the time between HF hospital readmissions. 
• To compare LCZ696 to valsartan on the profile of pre-specified biomarkers (e.g., cardiac, 
vascular, renal, collagen, metabolism, inflammatory, and/or other relevant biomarkers) 
from baseline to predefined time points in a subset of patients. 
• To characterize LCZ696 and valsartan pharmacokinetics (PK) at steady-state using 
population modeling and/or non-compartmental based methods in a subset of patients. 
• To compare LCZ696 to valsartan on the primary composite and secondary endpoints, and 
key exploratory endpoints in ACEI-intolerant patients. 
• To compare LCZ696 to valsartan in evaluating the changes in cognitive function (assessed 
by the Mini-Mental State Examination [MMSE]) at 2 years. 
3 
Investigational plan 
3.1 
Study design 
Figure 3-1 
Study design 
 
 


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This study is a multi-center, randomized, double-blind, parallel group, active comparator, 
morbidity and mortality trial designed to evaluate the efficacy and safety of LCZ696 
compared to valsartan in HF patients (NYHA class II-IV) with preserved EF (Figure 3-1). The 
study population will consist of patients ≥ 50 years of age with a LVEF >45% and evidence of 
structural heart disease (left atrial enlargement [LAE] or left ventricular hypertrophy [LVH]) 
within 6 months prior to enrollment, current symptomatic HF (NYHA class II-IV) and 
symptoms of HF requiring  treatment with diuretic therapy for at least 30 days prior to Visit 1. 
In addition, patients will have at least one of the following: (1) a hospitalization for HF within 
9 months prior to enrollment and NT-proBNP >200 pg/ml for patients not in AF or >600 
pg/ml for patients in AF at Visit 1, OR (2) NT-proBNP >300 pg/ml for patients not in AF 
or >900 pg/ml for patients in AF at Visit 1 (Figure 3-2).  
Figure 3-2 
Abbreviated inclusion criteria 
 
Complete inclusion criteria, including diagnostic criteria, are available in Section 4.1. 
Patients with documented AF on the Visit 1 ECG will be limited to approximately 33% of the 
overall study population.  
Patients should be on an optimal medical regimen of diuretics and background medications to 
effectively treat co-morbidities such as HTN, DM, AF and coronary artery disease.  
Investigators should make every effort to control a patient’s BP in accordance with local 
treatment guidelines and investigator judgment (see Section 5.5.7) 
Screening epoch 
A screening period, or epoch, of approximately 2 weeks will be used to determine if patients 
qualify to enter the treatment run-in epoch. 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 treatment run-in 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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Screening NT-proBNP, potassium, eGFR, and liver function tests will be assessed by sending 
blood samples to the central lab. Since 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, it is 
recommended that at Visit 1 the site schedule the patient’s next visit approximately one week 
after Visit 1. 
A patient who enters screening but is determined not to be eligible to enter the treatment run-
in epoch 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 up to two times. A minimum of 2 weeks 
must elapse between re-screenings. 
Treatment run-in epoch       
The screening epoch will be followed by a single-blind, treatment run-in epoch, or period, 
ranging from 3 to 8 weeks (Figure 3-3). The concomitant use of open label ACEI, ARB or 
renin inhibitor in addition to study drug during the treatment run-in epoch is strictly prohibited. 
Patients will enter the treatment run-in period based on their use of RAS blockade 
medications at the time of enrollment (Figure 3-3 and Table 3-1).   
Figure 3-3 
Treatment run-in epoch overview 
 
Table 3-1 
Minimum pre-study total daily doses of commonly used ACEIs and 
ARBs allowing patients to begin the treatment run-in epoch at Visit 
102    
ACEI 
Dose 
ARB 
Dose 
Benazepril 
20 mg  
Azilsartan 
40 mg 
Captopril 
100 mg  
Candesartan 
16 mg  
Cilazapril 
2.5 mg 
Eprosartan 
400 mg  


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ACEI 
Dose 
ARB 
Dose 
Enalapril 
10 mg  
Irbesartan 
150 mg  
Fosinopril 
20 mg 
Losartan 
50 mg  
Imidapril 
10 mg 
Olmesartan 
10 mg  
Lisinopril 
10 mg  
Telmisartan 
40 mg  
Moxepril 
7.5 mg 
Valsartan 
160 mg  
Perindopril 
4 mg  
 
 
Quinapril 
20 mg  
 
 
Ramipril 
5 mg  
 
 
Trandolapril 
2 mg  
 
 
Zofenopril 
30 mg 
 
 
Patients should enter the treatment run-in epoch at Visit 101 if they have been on an ACEI or 
ARB medication at doses considered to be less than the total daily dose defined in Table 3-1. 
Study drug should not be dispensed unless the patient meets all inclusion criteria and none of 
the exclusion criteria at Visit 1.  These patients will begin treatment with valsartan 40 mg b.i.d. 
for 1 to 2 weeks.  At Visit 102, patients can be up-titrated to valsartan 80 mg b.i.d. for 1 to 2 
weeks.  Patients who meet the safety monitoring criteria (Table 3-2) at Visit 103 will be 
switched to treatment with LCZ696 100 mg b.i.d. for 2 to 4 weeks.    
Patients should enter the treatment run-in epoch at Visit 102 if they have been on an ACEI or 
ARB medication at doses considered to be at least the total daily dose (Table 3-1). At the 
investigator’s discretion, these patients can also enter the treatment run-in epoch at Visit 101. 
Study drug should not be dispensed unless the patient meets all inclusion criteria and none of 
the exclusion criteria at Visit 1.  These patients will begin treatment with valsartan 80 mg b.i.d. 
for 1 to 2 weeks. Patients who meet the safety monitoring criteria (Table 3-2) at Visit 103 can 
begin treatment with LCZ696 100 mg b.i.d. for 2-4 weeks.      
To assess the patient’s eligibility to continue in the study, either local or central laboratory 
should be used for the assessment of potassium and eGFR at Visits 103 and 199 (end of 
treatment run-in visit). If central laboratory is used, since it may take up to 72 hours to obtain 
the results, it is recommended that the site take this into consideration when scheduling 
subsequent study visits, while keeping the patient on the study medication.  If a local 
laboratory is selected, the same samples should also be sent to the central laboratory, while 
the evaluation should be solely based on the local laboratory results.  Patients should NOT 
enter Visits 103 or 199 without evaluating the safety monitoring criteria (Table 3-2).   
Down-titration or interruption of study drug is not allowed during the treatment run-in period. 
Patients who are not able to tolerate study drug at the doses prescribed during the treatment 
run-in epoch will be discontinued. 
Investigators may consider adjusting (dose reduced or discontinued) background medications 
(e.g., diuretic(s), antihypertensive agents nitrates) if the study drug is not tolerated (e.g., 
occurrence of AEs such as hyperkalemia, hypotension, and renal dysfunction) to ensure 
patients meet the safety criteria in Table 3-2 during the treatment run-in epoch.  Patients may 
be seen at any time for unscheduled visits during the treatment run-in epoch for re-evaluation 
of safety criteria parameters. 


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Patients who experience angioedema at any time during the treatment run-in epoch must be 
discontinued from the study. 
Patients who are discontinued from the treatment run-in epoch due to intolerance to the study 
drug dosages during the period, angioedema or for failure to meet the specified safety criteria 
will be considered treatment run-in failures and are not eligible to be re-screened for study 
entry (Section 6.1).  
Table 3-2 
Safety monitoring criteria that must be met at Visit 1 (screening), Visit 
103 and Visit 199/201 
Parameter 
Visit 1 (screening) 
Visits 103 (treatment run-in) and Visit 
199/201 (end of treatment run-
in/randomization) 
Potassium level 
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 1  
Blood pressure 
SBP ≥110 mmHg  
No symptomatic hypotension as 
determined by the investigator and SBP 
≥100 mmHg. 
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 
At the end of the treatment run-in epoch (Visit 199/201), patients who meet the safety criteria 
(Table 3-2) and tolerate LCZ696 100 mg b.i.d. for at least 2 weeks are eligible for 
randomization at Visit 201. For these patients, Visit 199 and 201 should be combined into one 
clinic visit (Visit 199/201), and occur on the same day.  Patients should be instructed not to 
take their morning (AM) dose of treatment run-in study drug on the day they start randomized 
study drug. 
Randomized treatment epoch 
At randomization (Visit 199/201), eligible patients will be randomized to 1 of 2 treatment 
arms, LCZ696 200 mg b.i.d. or valsartan 160 mg b.i.d (Table 3-3).  
Every attempt should be made to maintain patients on the target study drug dose (dose level 3) 
(Table 3-3) throughout the trial. If the patient does not tolerate the target study drug dose level 
the investigator should consider if appropriate, adjusting background medications to rectify 
the situation before considering to down-titrate to the next lower study drug dose level (see 
Section 5.5).  
Table 3-3 
Study drug dose levels during randomized treatment epoch 
Dose level 
LCZ696 Treatment Arm 
Valsartan Treatment Arm 
3 
200 mg b.i.d.  
160 mg b.i.d.  
2 
100 mg b.i.d.  
80 mg b.i.d.  
1 
50 mg b.i.d.  
40 mg b.i.d.  
At each dose level the patient will also take matching placebo for the other treatment arm study drug. 


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Study drug dose level adjustments should be based on overall safety and tolerability with 
special focus on a) hyperkalemia, b) symptomatic hypotension, and c) clinically significant 
decrease in eGFR/increase in serum creatinine. Treatment guidelines for hyperkalemia, 
management of BP, and renal dysfunction are provided in Appendix 3, Appendix 4, and 
Appendix 5, respectively. 
The trial will be event driven with a target total of  1847 primary endpoint events to be 
accrued. It is anticipated that the total trial duration will be approximately 4.75 years, with a 
projected recruitment period of 2.75 years, followed by approximately 2 years of follow-up 
after the last patient is enrolled. 
3.2 
Rationale of study design 
3.2.1 
Target study population and rationale 
The study population will consist of patients ≥50 years of age with a LVEF ≥45% and 
evidence of structural heart disease (LAE or LVH), current symptoms of HF (NYHA class II-
IV) and prior symptoms of HF requiring treatment with diuretic therapy. In addition, patients 
will have at least one of the following: (1) a hospitalization for HF within 9 months prior to 
enrollment and NT-proBNP >200 pg/ml for patients without AF or >600 pg/ml for patients 
with AF on Visit 1 ECG; OR, (2) NT-proBNP >300 pg/ml for patients not in AF or >900 
pg/ml for patients in AF on Visit 1 ECG. These criteria should identify the target HFpEF 
population at risk for major CV events.  
Structural heart disease (LAE and LVH) is a key diagnostic criterion for HFpEF in the most 
recent guidelines (McMurray et al 2012). 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 either LAE or LVH will help ensure a diagnosis of 
HFpEF. The EF lower boundary at 45% was selected to include a wide spectrum of patients 
for whom no proven therapy is currently available. Prior HF hospitalization and elevated NT-
proBNP were the strongest independent predictors of mortality and subsequent HF 
hospitalization in the I-PRESERVE study (Solomon et al 2007, Komajada et al, 2011). 
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 AF 
patients will be limited to approximately one third in the current study (based on the Visit 1 
ECG) so that the proportion of patients with AF in the study will be representative of the 
HFpEF population (Massie et al 2008, Steinberg et al 2012, West et al 2011). 
3.2.2 
Rationale for primary endpoint 
The primary endpoint is the composite of CV death and total HF hospitalizations. There is 
general agreement that the major goal of treating HFpEF is to reduce the major fatal and non-
fatal consequences of this illness; CV death and hospitalization for worsening HF. 
Hospitalization for worsening HF is the single most common cause of hospitalization in these 
patients.  It is an important clinically relevant problem for HF patients and represents a key 
component of the patient’s clinical course. Importantly, HF hospitalization reflects 
progression of the HF syndrome and portends high subsequent risk, both of readmission and 
death (Ahmed et al 2008, Solomon et al 2007).  


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Traditionally, outcomes studies have assessed composite endpoints using a time-to-first-
event-analysis. Limitations of this approach have been increasingly recognized (Cohn et al 
2009, Neaton et al 2005, Pocock et al 2012). Time-to-first event only focuses on the first 
occurring event and does not consider subsequent events, leading to a substantial loss of 
information. This is particularly relevant to HFpEF, which is characterized by a high 
frequency of recurrent HF hospitalizations. A review of recent HF studies found that 
approximately 40% of all CV deaths and HF hospitalizations are “ignored” in a time-to-first 
event analysis (Anker and McMurray 2012). A total events approach as applied to a 
progressive disorder such as HF has the benefit of more accurately capturing the patient’s 
clinical course and better reflects the true burden of the illness on the patient and the 
healthcare system. This understanding of HF and its treatment has led to the choice of a 
disease-specific composite outcome of CV death and total HF hospitalization as the primary 
endpoint in this study.  
3.2.3 
Rationale for secondary endpoints 
There are four secondary endpoints: (1)  KCCQ clinical summary score, (2) change in NYHA 
functional classification, (3) the time to first occurrence of a composite renal endpoint, 
defined as renal death, reaching ESRD, or ≥ 50% decline in eGFR relative to baseline 
(whichever occurs first), and (4) all-cause mortality. These endpoints are clinically relevant 
and particularly appropriate as secondary endpoints in this population.  
The KCCQ is a validated instrument for assessing quality of life and health status on HF 
patients. The clinical summary score, which is derived from the physical limitations and HF 
symptoms domains of the KCCQ is a valid measure for assessing the patient’s health aspects 
that may be influenced by CV medications. Given the symptomatic burden of HF and its 
associated physical limitations, this endpoint is of particular relevance to patients and is an 
important goal of HF treatment. The KCCQ clinical summary score has been used frequently 
as an endpoint in other trials, and is appropriate for use in the current trial. 
NYHA classification is an accepted measure of functional status and will provide important 
information on disease progression. NYHA classification will be analyzed at month 8 to 
minimize the number of missing data points.  
The composite renal endpoint of renal death, reaching ESRD, or ≥ 50% decline in eGFR 
relative to baseline is frequently used in clinical trial of medications that may influence renal 
function, such as the medications used in the current trial. This endpoint is of significance 
because renal dysfunction is common in HF patients, is associated with poorer clinical 
outcomes, and complicates clinical management. Also, outcome modifying agents, such as 
ACEIs and ARBs, are often sub-optimally prescribed due to concerns of further worsening 
renal dysfunction. Thus, prevention of renal dysfunction is of considerable clinical importance 
and deserves further investigation in the HFpEF population. 
All-cause mortality is a standard endpoint that is routinely assessed in morbidity and mortality 
trials, such as the current one. 


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3.2.4 
Rationale for treatment run-in epoch  
The single-blind treatment run-in epoch most closely mimics clinical practice (where patients 
are only continued on treatments if they are tolerated). The goal of the single-blind treatment 
run-in epoch is to (1) optimize safety in an older vulnerable population (exclude patients 
developing renal dysfunction, hypotension and hyperkalemia), (2) maximize adherence, both 
to the treatment and the protocol, and consequently, (3) minimize the loss to follow-up. As a 
result, the trial should provide the most robust test of its hypothesis.  
The current abbreviated treatment run-in design will assess the safety and tolerability of 
patients to drug dose level 2.  Drug dose level 3 is not included in the run-in design, because 
(a) BP effect is largely attained by LCZ696 100 mg b.i.d. with small incremental BP effect at 
200 mg b.i.d., and (b) the great majority of patients who tolerated LCZ696 100 mg b.i.d. were 
able to tolerate 200 mg b.i.d. in the run-in period of the PARADIGM-HF trial. 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
An LCZ696 dose of 200 mg twice daily was chosen as the target dose because it delivers  
similar valsartan exposure (assessed by AUC) as Diovan® (valsartan) 160 mg twice daily, 
which is the evidence based dose of valsartan and the one thought to be equivalent to the dose 
of ACE inhibitors. Biomarker analysis and modeling indicate that this dose of LCZ696 
delivers approximately 90% of its maximal NEP inhibition. 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, particularly in elderly patients. 
3.4 
Rationale for choice of comparator 
The active comparator valsartan (a RAS blocker) is not being used to treat HFpEF, as no 
therapy to date has convincingly been shown to reduce morbidity and mortality (Cleland et al 
2006, Yusuf et al 2003, Massie et al 2008).  Valsartan is being given to treat the comorbidities 
that are prevalent in HFpEF, such as HTN, DM, and coronary artery disease where there is an 
indication for RAS blocking therapy (McMurray et al 2012). For the same reason, background 
ACEIs or ARBs were permitted in other outcomes studies in HFpEF for treating co-
morbidities, including the most recently completed TOPCAT study where a RAS blocker was 
used in 85% of patients at baseline (Desai et al 2011).  
Valsartan was chosen as the RAS blocker comparator because it is a commonly prescribed 
ARB, and the target dose of LCZ696 delivers systemic exposure similar to the target dose of 
valsartan. Furthermore, a placebo comparator is not considered appropriate in this long term 
trial, as the comorbidities commonly present in HFpEF patients require RAS inhibition (i.e., 
ACEI or ARB). RAS inhibition should not be used concomitantly with LCZ696 due to the 
potential increased risk of angioedema (ACEI), and because LCZ696 already provides AT1 
blockade (ARB).   


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3.5 
Purpose and timing of interim analyses 
One interim analysis (IA) is planned to assess efficacy. The cut-off time for the IA is planned 
to be when approximately two-thirds of the target number of primary events adjudicated (i.e. 
approximately a total of 1231 events of either HF hospitalizations or CV deaths).  
3.6 
Risks and benefits  
Patients will be instructed not to take any RAS blockade medications (ACEI or ARB) on the 
day they start treatment run-in study drug to avoid excess RAS blockade. The risk of 
discontinuation of concomitant ACEIs or ARBs will be minimal as it will be reflective of the 
typical dosing schedule of most ACEIs and ARBs. All patients will be allowed to continue 
receiving the rest of their background CV medications. The risk to patients in this trial will be 
minimized by compliance with the eligibility criteria and close clinical monitoring. 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 off 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 ≥50 years of age and therefore the risk of pregnancy during the trial is 
minimal. 
Since this is a long-term outcome study, 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 male and female patients age 50 years or older with 
current symptomatic HF (NYHA class II-IV) and symptoms of HF requiring  treatment with 
diuretic therapy for HF for  at least 30 days prior to Visit 1, an LVEF ≥45% and documented 
structural heart disease. It is aimed to randomize approximately 4,600 patients in 
approximately 800 centers worldwide. With an expected screening and run-in failure rate of 
approximately 50%, it is estimated that approximately 9,200 patients will have to be screened. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2.  ≥ 50 years of age, male or female. 
3. LVEF >45% by echo during the screening epoch, or within 6 months prior to Visit 1 (any 
local LVEF measurement made using echo only). 
4. Symptom(s) of HF requiring treatment with diuretic(s) 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 evidenced by at least one of the following echo findings (any local 
measurement made during the screening epoch or within the 6 months prior to Visit 1): 


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a. left atrial (LA) 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 (LVH) defined by septal thickness or posterior wall 
thickness ≥1.1 cm 
7. Patients with at least one of the following: 
a. a HF hospitalization (defined as HF as the major reason for hospitalization) within 9 
months prior to Visit 1 and NT-proBNP >200 pg/ml for patients not in AF or >600 
pg/ml for patients in AF on Visit 1 ECG, OR  
b. NT-proBNP >300 pg/ml for patients not in AF or >900 pg/ml for patients in AF on 
the Visit 1 ECG. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria during the screening period, unless otherwise 
specified, 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 %. 
2. Acute coronary syndrome (including MI), cardiac surgery, other major 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 
(e.g., MI, coronary artery bypass graft [CABG]), unless an echo measurement was 
performed after the event confirming the LVEF to be ≥45%. 
4. Current acute decompensated HF requiring augmented therapy with diuretics, vasodilators 
and/or inotropic drugs. 
5. Patients who require treatment with 2 or more of the following: an ACEI, an ARB or a 
renin inhibitor. 
6. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes. 
7. Patients with a known history of angioedema. 
8. Probable alternative diagnoses that in the opinion of the investigator could account for the 
patient’s HF symptoms (i.e., dyspnea, fatigue) such as significant pulmonary disease 
(including primary pulmonary HTN), anemia or obesity.  Specifically, patients with the 
following are excluded: 
a. severe pulmonary disease including chronic obstructive pulmonary disease (COPD) 
(i.e., 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, or  
c. body mass index (BMI) >40 kg/m2 
9. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer. 
10. Patients with any of the following: 


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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, mineralocorticoid (MRA), ACEI, ARB, beta blocker and 
calcium channel blocker (CCB), or 
c. SBP <110 mmHg at Visit 1, or  
d. SBP <100 mmHg or symptomatic hypotension as determined by the investigator at 
Visit 103 or Visit 199/201 
11. Patients 
with 
history 
of 
any 
dilated 
cardiomyopathy, 
including 
peripartum 
cardiomyopathy, chemotherapy induced cardiomyopathy, or viral myocarditis. 
12. Evidence of right sided HF in the absence of left-sided structural heart disease. 
13. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative 
cardiomyopathy. 
14. Clinically significant congenital heart disease that could be the cause of the patient’s 
symptoms and signs of HF. 
15. Presence of hemodynamically significant valvular heart disease in the opinion of the 
investigator.  
16. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3 
months prior to Visit 1.   
17. Coronary or carotid artery disease or valvular heart disease likely to require surgical or 
percutaneous intervention during the trial. 
18. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained 
ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate >110 
beats per minute (bpm).  
19. Patients with  a cardiac resynchronization therapy (CRT) device. 
20. Patients with prior major organ transplant or intent to transplant (i.e. on transplant list). 
21. 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. 
22. 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 
23. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or 
SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin >1.5 mg/dl 
at Visit 1. 
24. Patients with one of the following: 
a. eGFR <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease  
(MDRD) formula at Visit 1, or  
b. eGFR <25 mL/min/1.73m2 at Visit 103 or Visit 199/201, or 
c. eGFR reduction >35% (compared to Visit 1) at Visit 103 or Visit 199/201 


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25. Presence of known functionally significant bilateral renal artery stenosis 
26. Patients with either of the following: 
a. serum potassium >5.2 mmol/L (mEq/L) at Visit 1  
b. serum potassium >5.4 mmol/L (mEq/L) at Visit 103 or Visit 199/201 
27. History or presence of any other disease with a life expectancy of <3 years 
28. History of non-compliance to medical regimens and patients who are considered 
potentially unreliable 
29. History or evidence of drug or alcohol abuse within the last 12 months 
30. Persons directly involved in the execution of this protocol 
31. 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 5 
years, regardless of whether there is evidence of local recurrence or metastases. 
32. 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. 
33. 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 off study drug. Highly effective contraception methods 
include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to Visit 1). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject 
• Combination of any two of the following (a+b or a+c, or b+c), according to country 
approvals and availability: 
a. use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception. 
b. placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
• 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
• 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 


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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 
Protocol requested treatment 
5.1.1 
Investigational treatment 
The sponsor will provide the following study drugs: 
Treatment run-in period 
All eligible patients will enter a treatment run-in epoch where they will receive valsartan 
followed by LCZ696. 
The following study drugs will be provided: 
• Valsartan 40 mg and 80 mg   
• Placebo to match valsartan 80 mg 
• LCZ696 100 mg  
• Placebo to match LCZ696 50 mg and 100 mg tablets  
The use of an ACEI, ARB or renin inhibitor in addition to study drug during the treatment 
run-in epoch is strictly prohibited. 
Randomized treatment period 
All eligible patients will be randomized to either LCZ696 200 mg b.i.d. (dose level 3) or 
valsartan 160 mg b.i.d. (dose level 3). In addition, patients will continue to take optimal 
background therapy to treat co-morbid conditions, as considered appropriate by the 
investigator and in accordance with standard therapy guidelines, with the exception of an 
ACEI or ARB as this will be replaced by study drug. The use of an open label ACEI or an 
ARB in addition to randomized study drug is strictly prohibited. 
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 
• Valsartan 40 mg, 80 mg and 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 requirements of the country. They will include storage conditions for the drug and the 
medication number, but no information about the patient. 


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5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
Patients will be assigned to one of the following two treatment arms in a ratio of 1:1 at Visit 
199/201. 
• LCZ696 200 mg b.i.d. 
• Valsartan 160 mg b.i.d. 
5.3 
Treatment assignment, randomization  
At Visit 199/201, all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the patient fulfills all the inclusion 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 IIS 
Randomization Group. 
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:  
• 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:  
1. The independent and unblinded statistician, programmer and data personnel who are 
involved in preparing safety and efficacy interim analysis reports for the Data 
Monitoring Committee (DMC).  These personnel will not be involved in any other 
trial conduct related activities.  
2. The DMC members, due to their review of pooled data from other LCZ696 studies by 
the program level DMC. 


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3. The PK analysts, randomization codes associated with patients from whom 
pharmacokinetics (PK) samples are taken will be disclosed to PK analysts who will 
keep the PK results confidential until database lock.  
• 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 because the identity of the investigational treatment 
cannot be disguised due to their different forms. 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.12), at the time 
of an interim analysis by the DMC and at the conclusion of the study. 
For any patient whose treatment code has been broken the patient must discontinue the study 
treatment. 
5.5 
Treating the patient 
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 study informed consent, 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 should 
select the case report form (CRF) book with a matching Subject Number from the Electronic 
Data Capture (EDC) system to enter data. 
If the patient fails to be treated during the treatment run-in epoch for any reason, the IRT must 
be notified within 2 days of when the investigator or his/her staff are informed that the patient 
was not treated. The reason for not being treated with treatment run-in study drug will be 
entered on the Screening Epoch Study Disposition CRF. Patients that take treatment run-in 
study drug and are not randomized are considered run-in failures. The reason for not being 
treated with randomized study drug will be entered on the appropriate Treatment Run-in 
epoch CRF. 
5.5.2 
Dispensing the investigational treatment  
Each study site will be supplied by Novartis with the investigational treatment in packaging of 
identical appearance. 
The investigational treatment pack 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 and a dose level. 
Investigator staff will identify the investigational treatment package(s) to dispense to the 
patient by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the package to the patient, investigator staff will 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.  


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5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment  
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational 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 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site. 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment  
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 will be required to take a total of two tablets 
(one tablet from the LCZ696/LCZ696 matching placebo pack and one tablet from the 
valsartan/valsartan matching placebo pack) twice a day for the duration of the study. Table 5-
1 summarizes the study drug that will be taken during the run-in epoch and Table 5-2 
summarizes the study drug that will be taken during the randomized treatment epoch.  
Table 5-1 
Study drug dispensed for the treatment run-in epoch by study visit 
Study visit 
Dose level 
LCZ696 
Valsartan 
101a 
1 
50 mg matching placebo b.i.d. 
40 mg b.i.d. 
102 
2 
100 mg matching placebo b.i.d. 
80 mg b.i.d. 
103 
2 
100 mg b.i.d. 
80 mg matching placebo b.i.d. 
a. Investigators may consider initiating treatment on dose level 2 (valsartan 80 mg b.i.d. and 100 mg matching placebo b.i.d.) at 
Visit 102 (see Figure 3-3) in those patients being treated with at least the minimum dose of ACEI or ARB at Visit 1 (see Table 3-
1) 


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Table 5-2 
Study drug dispensed during the randomized treatment epoch by 
study visit 
Study visit 
Dose level 
LCZ696 
Valsartan 
201 
3a 
200 mg or matching placebo b.i.d. 
160 mg or matching placebo b.i.d. 
Available for any 
visit after Visit 201 
2b 
100 mg or matching placebo b.i.d. 
80 mg or matching placebo b.i.d. 
Available for any 
visit after Visit 201 
1c 
50 mg or matching placebo b.i.d. 
40 mg or matching placebo b.i.d. 
a. This dose level must be maintained for as long a duration as possible. If down-titration is necessary due to side effects, the 
patient should be re-challenged as soon as medically possible per the investigator’s judgment. 
b. Only if dose level 3 is not tolerated despite modification of other concomitant medications. 
c. Only if dose levels 2 or 3 are not tolerated despite modification of other concomitant medications. 
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). Patients participating 
in the PK substudy will be required not to take their study drug on the morning of the PK 
substudy visits where blood samples are taken. 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 CRF. All kits of investigational 
treatment assigned by the IRT will be recorded/databased in the IRT. 
The investigator should promote compliance by instructing the patient to take the drug exactly 
as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable for any reason to take the study drug as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of 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 co-morbid conditions 
to rectify the situation, before considering to down titrate to the next lower study drug dose 
level. For hypotension or dizziness, consideration should be given to reduce the dose or to 
stop concomitant antihypertensive agents and non-antihypertensive agents that lower BP, or 
the dose of diuretic can be reduced.   


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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 the study drug dose level according 
to the following instructions: 
During the randomized treatment epoch, down titration of the 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 (Table 5-2). 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 the 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. 
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 (Table 5-2). 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 (Table 5-2) 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 strongly discouraged while patient 
is taking study drug. However, if for any reason a patient off study drug has started open-label 


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treatment with an ACEI it must be discontinued ≥36 hours prior to restarting study drug. For 
patients off study drug treated with an ARB or a renin inhibitor it must be discontinued prior 
to re-initiation of study drug (Table 5-3). 
These changes must be recorded on the Dosage Administration Record CRF. 
In case of pregnancy discovered during the screening or run-in epochs, the patient will be 
withdrawn from the study immediately. In case of pregnancy discovered during the double 
blind epoch, the patient should be instructed to temporarily discontinue study drug 
immediately. Study drug intake should be resumed as soon as possible after the completion of 
the pregnancy and lactation period. Meanwhile, the patient should continue to attend 
scheduled study visits. 
See Section 7.5 for further details on pregnancies and reporting guidelines. 
5.5.6 
Rescue medication  
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in Appendix 3, Appendix 4, and Appendix 5, respectively. Patients may receive 
open-label ACEIs, ARBs or a renin inhibitor during the study ONLY if the study drug has 
been temporarily or permanently discontinued (Table 5-3). 
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies CRF. 
5.5.7 
Concomitant treatment  
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. 
CV medications 
The patient should be on an optimal medical regimen of diuretics and background 
medications to effectively treat comorbidities, such as HTN, DM, AF and coronary artery 
disease. Investigators should take into consideration the patient’s risk factors, such as age and 
comorbidities, and make every effort to control a patient’s BP in accordance with 
international and local treatment guidelines (Mancia et al 2013), as well as other evidence-
based medicine.   
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 
encouraged to assess patients’ potassium levels regularly, especially in those who are 
receiving these medications. 


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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 and intravenous (IV) nitrates 
The concomitant administration of LCZ696 with neseritide and IV nitrates has not been 
studied. In the event a study patient requires the concomitant administration of neseritide 
and/or IV nitrates 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 
(e.g. simvastatin, pravastatin) that are substrates of OATP1B1 and OATP1B3 because of the 
potential to raise plasma statin levels. 
5.5.8 
Prohibited Treatment  
Use of the treatments displayed in Table 5-3 is NOT allowed after the start of study drug due 
to safety reasons, unless the actions specified are taken. 
Table 5-3 
Prohibited treatment 
Medication 
Action to be taken 
Any ACEI 
Discontinue study drug. The open label ACEI 
must be stopped for ≥36 hours prior to re-initiation 
of study drug  
Any ARB 
Discontinue study drug. The open label ARB must 
be stopped prior to re-initiation of study drug 
Any renin inhibitor 
Discontinue study drug. 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. If the addition of an ACEI, ARB or renin inhibitor is 
necessary, then study drug must be temporarily discontinued. If the patient is to be started on 
open-label ACEI, the study drug must be stopped ≥36 hours prior to initiating ACEI. If study 
drug is to start the open-label ACEI must be stopped ≥36 hours prior to re-initiating study 
drug.  ARBs or a renin inhibitor should be stopped prior to resuming study drug. 
5.5.9 
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 
entire study. Patients who have discontinued study drug are expected, and should be 


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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 as specified in Section 5.5.11. The investigator must also contact the IRT to 
register the patient’s  interruption from study treatment and record it on the drug 
administration form CRF. 
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/endpoints pre-specified in the 
protocol have 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. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator  
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 ACEI, ARB or renin inhibitor 
• Pregnancy and post-pregnancy during lactation period (Section 7.5) 
Study drug may be discontinued at the investigator’s discretion if any of the following occurs:  
• Any severe suspected drug-related AE 
• 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.  
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  
However, withdrawal of consent occurs only when a patient does not want to participate in 
the study anymore and does not want any further visits or assessments and does not want any 
further study related contacts and does not allow analysis of already obtained biologic 
material. 
If a patient withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the patient 
are not allowed unless safety findings require communicating or follow-up. 


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5.5.11 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, the patient’s family, friends and family physician as agreed in the informed consent 
and by documenting in the source documents steps taken to contact the patient (e.g., dates of 
telephone calls, registered letters, etc.). A patient should not be considered lost to follow-up 
until his/her scheduled end of study visit would have occurred. 
5.5.12 
Emergency breaking of treatment assignment  
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 
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 un-
blinding 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. 
5.5.13 
Study completion and post-study treatment  
The study will be completed when either: the target total of endpoints are obtained or a 
recommendation is made by the DMC to prematurely stop the study. At the end of the study, 
all patients will return for the final end of study (EOS) visit (Visit 299) and be asked to return 
the remaining study drug. 
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 initiated to allow for study medication to be made available to 
qualified patients, upon formal request, if the study is terminated prematurely due to 
overwhelmingly efficacy of LCZ696 over valsartan by the DMC.  


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5.5.14 
Early study termination  
The study can be terminated at any time for any reason by Novartis. The patient should be 
seen as soon as possible and treated as a prematurely withdrawn patient. The investigator may 
be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing IRBs and/or ECs 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. 
A Visit 199 (end of treatment run-in visit) will be completed for all patients who enter the 
treatment run-in epoch.  For patients who discontinue during the treatment run-in epoch Visit 
199 will be their discontinuation visit.  For patients that are randomized, Visit 199 will be 
their end of treatment run-in disposition visit and will be performed on the same day as Visit 
199/201. Safety monitoring criteria, vital signs and laboratory evaluations for randomization 
(Visit 201) are reflected at Visit 199/201 in Table 6-1.    
Patients will have regular clinic visits performed for the first year (up to and including Week 
48 [Visit 205]).  Thereafter, patients will have clinic visits alternating with telephone contact 
visits every 12 weeks.  
After randomization, study drug discontinuation (permanent or temporary) for any reason 
does not constitute withdrawal from the study and should not lead to the patient being 
withdrawn from the study. Patients who discontinue study drug should be requested to return 
for all of the assessments outlined in Table 6-1 as scheduled. If any patient refuses to return 
for these assessments or is unable to do so, every effort should be made to contact him/her or 
knowledgeable informant by telephone to ask if any of the study endpoint events have 
occurred at the foreseen visit dates for the remaining duration of the study. Documentation of 
attempts to contact the patient should be recorded in the patient’s record. 
Visit 201 will be considered the reference visit for all study visits during the randomized 
treatment epoch. Regardless of the occurrence of any unscheduled visits, scheduled visits 
should be performed within the specified timeframe in relation to Visit 201 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.   
Additional Procedures to be implemented in Japan only 
In Japan, all patients must enter the treatment run-in epoch at Visit 101, i.e. start the valsartan 
run-in on 40 mg b.i.d. For patients who have not received an ACEI or an ARB during the 30 
days prior to the screening visit, an additional clinic visit (Visit 101J), which will be 
conducted approximately one week after Visit 101 and followed by V102 approximately 1 
week later. V101J will have the same procedures as Visit 102 (Table 6-1) with the exception 
that for both V101J and V102 central abbreviated safety laboratory evaluations are mandatory. 
Also, all patients enrolled in Japan will be required to attend three additional clinic visits at 
approximately 1 week (201J1), 8 weeks (202J8) and 12 weeks (V202J12) after randomization 
(V201). In Japan, Visits 206, 208, 210, 212, 214, 216, 218 and 220 will be conducted as clinic 
visits, rather than phone visits. All additional clinical visits in the double-blind period will be 


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conducted with the same procedures as Visit 202 (Table 6-1) with the exception that study 
medication dispensing, drug accountability and serum/urine pregnancy tests are not required.  
Additional procedures to be implemented in India only 
In India, all patients will be required to attend an additional clinic visit (Visit 201I1) 
approximately 1 week following randomization where serum potassium will be assessed. 


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Table 6-1 
Assessment schedule 
Epoch 
 
Screen 
Treatment Run-in 
Randomized Treatment 
Visit 
DS
/S 
1 
101† 
102 
103 
199/ 
201†† 202 
203 
204 
205 
206° 207 
208° 209 
210° 211 
212° 213 
 
214° 
216° 
218° 
220° 
215 
217 
219 
221* 
UNS 
299††† 
EOS 
Day 
 
-70/-49 
-56/  
-35 
-42/  
-28 
-28/   
-14 
1 
28 
112 
224 
336 
420 
504 
588 
672 
756 
840 
924 
1008 
1092 
1260 
1428 
1596 
1176 
1344 
1512 
1680 
 
 
Week(w) 
 
-10/-7 
-8/-5  
 
-6/-4 
-4/-2 
0 
4 
16 
32 
48 
60 
72 
84 
96 
108 
120 
132 
144 
156 
180 
204 
228 
168 
192 
216 
240 
 
 
Obtain informed consent 
S 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety monitoring criteria 
DS 
 
 
(x)15 
x 
x§ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant Medical 
History/Current Medical 
Conditions /Demography 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History Possibly 
Contributing to Liver 
Dysfunction 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HF and Diabetes 
History/Smoking 
History/Alcohol History 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
DS 
x 
x 
x 
x 
x§ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Visit Contact Information 
DS 
 
x 
x 
x 
x§ 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
NYHA Classification (HF 
Signs/Symptoms) 
DS 
x 
 
x 
x 
x§ 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
Physical Exam1 
S 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
Vital signs (BP and   pulse) DS 
x 
x 
x 
x 
   x§  
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 


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Epoch 
 
Screen 
Treatment Run-in 
Randomized Treatment 
Visit 
DS
/S 
1 
101† 
102 
103 
199/ 
201†† 
202 
203 
204 
205 
206° 207 
208° 209 
210° 211 
212° 213 
 
214° 
216° 
218° 
220° 
215 
217 
219 
221* 
UNS 
299††† 
EOS 
Day 
 
-70/-49 
-56/  
-35 
-42/  
-28 
-28/   
-14 
1 
28 
112 
224 
336 
420 
504 
588 
672 
756 
840 
924 
1008 
1092 
1260 
1428 
1596 
1176 
1344 
1512 
1680 
 
 
Week(w) 
 
-10/-7 
-8/-5  
 
-6/-4 
-4/-2 
0 
4 
16 
32 
48 
60 
72 
84 
96 
108 
120 
132 
144 
156 
180 
204 
228 
168 
192 
216 
240 
 
 
Height 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
DS 
x 
 
 
 
x§  
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
Waist/hip 
circumference 
DS 
 
 
 
 
x§  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
ECG2 
DS 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
X2 
(x) 
x 
Echocardiography3 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
QOL Questionnaire 
(KCCQ)4 
DS 
 
x 
 
x 
 
x 
x 
x 
 
 
 
x 
 
 
 
x 
 
X 
 
x 
Patient Global 
Assessment4 
DS 
 
 
 
 
x 
 
x 
x 
x 
 
 
 
x 
 
 
 
x 
 
X 
 
x 
EuroQol (EQ-5D)4 
DS 
 
 
 
 
x 
 
x 
x 
x 
 
 
 
x 
 
 
 
x 
 
X 
 
x 
Mini-Mental State 
Examination (MMSE)16 
DS 
 
 
 
 
x 
 
 
 
 x  
 
 
 
 x 
 
 
 
 x 
 
X 
 
 x 
Complete Laboratory 
Evaluations5 
DS 
x 
 
 
x 
x§  
 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
x13 
 
x 
Abbreviated Laboratory 
Evaluations6 
DS 
 
 
(x) 
 
 
x 
 
x 
 
 
x 
 
 
 
x 
 
 
 
x13 
(x) 
 
Local Laboratory15 
Evaluation 
 
 
 
(x) 
(x) 
(x§)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x) 
 
Urinalysis 
DS 
x 
 
 
 
x  
 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
(x) 
x 


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Epoch 
 
Screen 
Treatment Run-in 
Randomized Treatment 
Visit 
DS
/S 
1 
101† 
102 
103 
199/ 
201†† 
202 
203 
204 
205 
206° 207 
208° 209 
210° 211 
212° 213 
 
214° 
216° 
218° 
220° 
215 
217 
219 
221* 
UNS 
299††† 
EOS 
Day 
 
-70/-49 
-56/  
-35 
-42/  
-28 
-28/   
-14 
1 
28 
112 
224 
336 
420 
504 
588 
672 
756 
840 
924 
1008 
1092 
1260 
1428 
1596 
1176 
1344 
1512 
1680 
 
 
Week(w) 
 
-10/-7 
-8/-5  
 
-6/-4 
-4/-2 
0 
4 
16 
32 
48 
60 
72 
84 
96 
108 
120 
132 
144 
156 
180 
204 
228 
168 
192 
216 
240 
 
 
FSH7 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma NT-proBNP8 
DS 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers/Biobanking9 
DS 
 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
1st morning void (urine)9 
DS 
 
x 
x 
x  
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenomics14 
DS 
 
 
 
x 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetics10 
DS 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
Sampling11 
DS 
 
 
 
 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Serum/Urine Pregnancy 
Test12 
DS 
x 
x 
x 
x 
x§  
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
(x) 
x 
AEs/SAEs 
DS 
 
x 
x 
x 
x§  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Drug Accountability 
DS 
 
 
x 
x 
x§ 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
(x) 
x 
Contact IVRS/IWRS 
S 
x  
x 
x 
x 
x§  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Dispense Study 
Medication 
S 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
(x) 
 
Screening Disposition 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoint Information 
DS 
 
x 
x 
x 
x§  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Run-in Disposition 
DS 
 
 
 
 
x§  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Disposition 
DS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 


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UNS = Unscheduled visit 
EOS = End of Study 
DS = assessment to be recorded in clinical database 
S = assessment to be recorded on source document 
(x) = optional assessment 
† = Visit to be performed only for patients that enter the treatment run-in epoch due to having been on an ACEI or ARB medication at doses lower than the total daily dose listed in Table 3-1 or 
per the investigator’s discretion based on the patient’s clinical status. Patients enrolled in Japan must enter the treatment run-in epoch at Visit 101. Patients who have not been on an ACEI or 
an ARB during the 30 days prior to the screening visit will have an additional clinic visit (V101J), approximately one week after Visit 101 and followed by V102 approximately one week later. 
V101J will have the same procedures similar to V102 (Table 6-1) with the exception that for both V101J and V102 central abbreviated safety laboratory evaluations and safety monitoring 
criteria are mandatory rather than optional.  
†† = Visit 199/201 will be completed for all patients who enter the treatment run-in epoch.  For patients that are randomized, Visit 199/201 should be combined into one clinic visit. For patients 
who discontinue during the treatment run-in epoch, only procedures with “§” will be performed. Patients enrolled in Japan will be required to attend three additional clinic visits at approximately 
1 week (201J1), 8 weeks (202J8), and 12 weeks (V202J12) after randomization (Visit 201); with procedures similar to Visit 202 with the exception of study medication dispensing, drug 
accountability and serum/urine pregnancy tests. Patients enrolled in India will be required to attend an additional clinic visit (V201I1) approximately 1 week following randomization and start of 
the double-blind study medication where serum potassium will be assessed by the central laboratory; a local laboratory assessment can be performed at the investigators discretion.  
††† = Visit 299 (end of randomized treatment visit) will be completed for all patients that enter the randomized treatment epoch 
o Indicates study visits to be conducted as a telephone contact visit, except for patients enrolled in Japan where these visits will be conducted as clinic visits with procedures similar to Visit 202 
with the exception that study medication dispensing, drug accountability and serum/urine pregnancy tests are not required.   
§ At Visit 199/201, only procedures marked with “§” will be performed for patients who discontinue during the run-in epoch. 
1 Complete physical examination required at Visit 1 and 201 and annually thereafter (Visit 205, 209, 213, 217, 221) up until Visit 299 (EOS). Short physical exam required at all interim visits. 
2 ECG is performed at Visits 1, 201, and annually thereafter. 
3 Qualifying LVEF measurements/documentation of structural heart disease will be based on locally obtained echocardiograms (echo) performed ≤ 6 months prior to Visit 1. If an echo 
performed ≤ 6 months prior to Visit 1 is not available, an echo must be performed during the screening epoch.   
4 Patient Global Assessment is not evaluated at Visit 201; patients should be asked to remember how he/she feels at Visit 201, throughout the study the patient will be asked to rate how 
he/she feels compared to at the randomization visit (Visit 201). KCCQ value will be assessed at the beginning of run-in, i.e. Visit 101 or 102 (whichever occurs first), If the study is extended 
beyond Visit 221, KCCQ, Patient Global Assessment, and EuroQOL will be conducted annually.  
5 Complete laboratory evaluations will be collected and sent to the central lab at all specified visits for all patients.  If the study is extended beyond Visit 221 a complete laboratory evaluation 
will be performed annually. Complete blood chemistry laboratory will be evaluated at Visit 103.  
6 Abbreviated laboratory includes: blood urea nitrogen (BUN), creatinine, potassium and eGFR. If the study is extended beyond Visit 221 an abbreviated laboratory evaluation will be performed 
at all interval visits except annual visits.   
7Not required for males or pre-menopausal women. 
8 Visits 1, 101/102 (whichever is first), 103, 199/201, 203 and 205 (central lab) for all patients.  Only the Visit 1 NT-proBNP results will be reported to the investigator and the sponsor.             
9 For patients participating in the biomarker substudy. If patient has biomarker sampled at Visit 101 there is no need for biomarker sample at Visit 102     
10 If the pharmacogenetics substudy sample is not obtained at Visit 103, it can be obtained at any time during the study. 
11 Patients participating in the PK substudy will also participate in the biomarker substudy; however patients may participate in the biomarker substudy without having to participate in the PK 
substudy. PK substudy samples will be collected pre-dose (trough) prior to the start of double-blind study drug (Visit 199/201).  Samples will also be collected pre-dose (trough) prior to 
administration of study drug and at 0.5 to 2 hours and 3 to 5 hours post dose at Visit 203. If the samples are not collected at Visit 203 they will be obtained at Visit 205.  


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12 Serum pregnancy test (not required for post-menopausal women) at Visit 1. Urine pregnancy tests at all other visits (not required for post-menopausal women). A positive urine pregnancy 
test requires immediate interruption of study drug until serum β-hCG is performed and found to be negative. If positive during the screening or treatment run-in period  the patient must be 
discontinued from the trial. After randomization (Visit 201) a positive pregnancy test requires immediate interruption of study drug. 
13 A complete laboratory evaluation will be done at the annual visits (Visits 217 and 221), an abbreviated laboratory will be done at Visit 215, 219.   
14 If  the pharmacogenomics sample is not obtained at Visit 203, it will be obtained at Visit 205. 
15 Serum potassium and eGFR to be performed at Visit 102 only if patient enters the run in epoch at Visit 101.  
16 MMSE is performed at Visit 201 and yearly (Visit 205, 209, 213, 217, 221) thereafter up until Visit 299 (EOS). 
*If the trial is extended, Visit 222, 223 and so forth to be performed as follows: alternating a telephone contact visit (same evaluations as Visit 212) with a clinic visit (same evaluations as Visit 
213) every 12 weeks. 
  


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6.1 
Information to be collected on screening and run-in failures  
All patients who have signed informed consent but are not entered into the treatment run-in 
period will have the disposition page for the screening epoch, demographics, 
inclusion/exclusion, and SAE data collected.  Adverse events that are not considered SAEs 
will be followed by the investigator and collected only in the source data. These patients are 
considered screening failures. 
All patients that sign informed consent and take treatment run-in study drug will have the visit 
specific CRFs and Run-in disposition (Visit 199) collected. The reason for patient 
discontinuation during the treatment run-in period must be carefully documented in the 
appropriate CRF.  These patients are considered treatment run-in failures.  
For all patients who have signed informed consent and receive study treatment all AEs 
occurring after informed consent is signed will be recorded on the Adverse Event CRF.  
Re-screening  
A patient who enters screening but is determined not to be eligible to enter the treatment run-
in epoch 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 up to two times. A minimum of 2 weeks must elapse between 
re-screenings. The patient must provide new written informed consent before each time they 
are re-screened. 
No re-screening of patients that are discontinued from the treatment run-in period will be 
allowed. 
6.2 
Patient demographics/other baseline characteristics  
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, 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. 
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 care giver. This information should be captured in the 
source document 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. 
The duration of randomized treatment exposure will be calculated based upon the start and 
stop dates recorded in the CRF. 


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6.4 
Efficacy 
The primary composite endpoint consists of the following components: 
• CV death 
• HF hospitalization (including first and recurrent hospitalizations) 
The secondary endpoints are: 
• KCCQ clinical summary score at 8 months 
• NYHA functional classification at 8 months 
• composite renal endpoint, defined as:  
1. renal death or 
2. reaching end stage renal disease (ESRD) or 
3. ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline 
• All-cause mortality 
A clinical endpoint committee (CEC) will be responsible for adjudicating and classifying all 
death events (CV vs. non-CV) and for determining whether pre-specified endpoint criteria 
were met for non-fatal events. The detailed definitions of the endpoints, required 
documentation and the adjudication process will be provided to all sites in a separate endpoint 
manual. 
6.4.1 
Appropriateness of efficacy assessments  
These measurements are standard and have been used in previous HF trials. The definition of 
CV endpoints is consistent with the FDA CV endpoints draft guidelines (Hicks et al 2012).  
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. 
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 102 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 CRF. Significant findings made after signing the 


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informed consent which meet the definition of an AE must be recorded on the AE section of 
the CRF. 
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 (e.g., OMRON) or a standard 
sphygmomanometer with an appropriately sized cuff on the non-dominant arm. Guidelines for 
the management of BP are provided in Appendix 4. 
6.5.3 
Height and weight  
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. 
Waist/hip circumference (to the nearest centimeter [cm] in indoor clothing) will be measured 
at Visit 199/201 and the final study visit (Visit 299). 
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 (hematology, blood chemistry, and urine) for the assessment 
of safety in this study will be performed at Visit 1, 199/201, 203, 205 and then at yearly 
intervals (Visits 209, 213, 217 and 221) until the end of the study.  Complete blood chemistry 
measurement will be performed at Visit 103. Abbreviated laboratory evaluations will be 
performed as indicated in Table 6-1. In Japan, patients will have abbreviated central 
laboratory evaluations at V201J1, V202J8, V202J12, V206, V208, V210, V212, V214, V216, 
V218 and V220 (Table 6-1).  In India, the serum potassium for all patients will be assessed at 
V201I1 using the central laboratory; a local laboratory assessment may be performed at the 
discretion of the investigator. 
In addition to the required central laboratory assessments, a local laboratory may be used for 
the assessment of potassium and eGFR during the treatment run-in period as indicated in 
Table 6-1. The results from the local laboratory during the treatment run-in period and at Visit 
199/201 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 CRF. 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.  
All central laboratory results will be communicated to the investigators and the sponsor, with 
the exception of biomarkers, of which only the Visit 1 NT-proBNP will be reported (Section 
6.6.3).  
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator in the patient’s CRF and additional laboratory evaluations 
should be performed, as judged appropriate by the investigator. If the laboratory abnormality 


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induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or 
medical condition must be entered on the AE CRF. 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 (Section 7.2). 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. 
Table 6-2 
Routine laboratory examinations 
Hematology 
Biochemistry 
Urine measurements 
Hematocrit  
Hemoglobin 
Platelet count 
Red blood cell count (RBC) 
White blood cell count (WBC) 
WBC differential 
Red blood cell distribution width 
(RDW) 
Mean corpuscular volume 
(MCV) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
 
Alanine aminotransferase (ALT) 
Albumin (Alb) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase 
(AST) 
Blood urea nitrogen (BUN)* 
Calcium 
Chloride 
Creatinine* 
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 >2x ULN) 
Total protein 
Uric acid 
Urinalysis 
*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, fractioned bilirubin (if total 
bilirubin >2x ULN), AST, ALT, alkaline phosphatase, sodium, glucose (plasma), hemoglobin 


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A1C, lipid profile, potassium, chloride, calcium, total protein, albumin, and uric acid will be 
measured. Potassium, BUN and creatinine will be obtained at study visits where abbreviated 
laboratory evaluations are scheduled.     
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 
Urine assessments 
Urinalysis with dipstick measurements for specific gravity, pH, total protein, bilirubin, 
ketones, leukocytes and blood will be performed. 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 at Visit 1, Visit 199/201, annual visits, and Visit 
299. Interpretation of the tracing must be made by a qualified physician and documented on 
the ECG section of the CRF. Each ECG tracing should be labeled with the study 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 CRF page. 
6.5.6 
Pregnancy and assessments of fertility  
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test at 
Visit 1. 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. If positive, the patient must 
discontinue study drug until after the pregnancy and lactation period. 
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.  


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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” (e.g., 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 
Resource utilization  
Analyses will be undertaken, as appropriate, to assess the effects of treatment on Healthcare 
Resource Utilization (RU) parameters.  
These measures may include hospitalization (e.g. number of hospital days), physician visits, 
other drugs used, and laboratory tests and procedures performed.  
At Visit 202 and each subsequent scheduled visit, the level of health care resource utilization 
will be assessed through procedures during hospital stays. The frequency and duration of any 
inpatient hospitalization will be recorded along with the primary reason for the hospital 
admission and discharge. All attempts will be made to collect RU variables in all patients 
throughout the duration of the study to avoid selection bias. There may also be circumstances 
when the collection of such data after completion of the study may be warranted. 
6.6.2 
Health-related Quality of Life  
HF symptoms reduction and reduction in physical limitation 
The KCCQ is a self-administered questionnaire that requires 4-6 minutes to complete. It 
contains 23 items, covering physical function, clinical symptoms, social function, self-
efficacy and knowledge, and Quality of Life (QoL).  
The HF symptoms and physical limitation domains scores show the best correlation for 
improvements following a chronic heart failure (CHF) exacerbation (Green et al 2000). Thus, 
one of the secondary endpoints is a clinical summary score based on the HF symptoms and 
physical limitation domains scores of the KCCQ at 8 months. All other domains will be 
analyzed as exploratory endpoints. 
The KCCQ is available in a number of validated translations. Patients in whose language a 
validated translation of the KCCQ is not available will be exempt from completing this 
instrument. 


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Clinical composite assessment 
The clinical composite assessment is one of the exploratory endpoints of this study. It is 
derived from the patient global assessment and the NYHA class, combined with the 
occurrence of major adverse clinical events as defined by CV death and hospitalization for HF. 
The patient global assessment is a seven-point patient self-evaluation scale. At Visit 201, the 
investigator should call the patient’s attention to how he/she feels about his/her condition at 
that time and explain that periodically throughout the study the patient will be asked to rate 
how he/she feels compared to at the randomization visit (Visit 201). This evaluation is 
combined with the NYHA class, a reliable instrument for rating HF patients’ functionality, 
and with major adverse clinical events as defined by CV death and hospitalization for HF to 
arrive at an overall evaluation of whether a patient is considered to have improved, worsened, 
or remain unchanged after a pre-specified period of time (Packer 2001). 
Assessment of HF signs and symptoms/NYHA class will be conducted at all visits. 
EuroQol (EQ-5D) 
The EuroQol (EQ-5D) instrument assesses the current health status of patients. It consists of 
five domains and one visual analogue scale. This instrument assesses morbidity, self-care, 
usual activity, pain, and anxiety and depression of patients. 
The EQ-5D is available in a number of validated translations. However, patients in whose 
language a validated translation of the EQ-5D is not available will be exempt from completing 
this questionnaire. 
6.6.3 
NT-proBNP 
NT-proBNP measurements will be performed by the central lab in all patients at Visits 1, 
101/102 (whichever occurs first), 103, 199/201, 203 and 205. 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. 
6.6.4 
Echocardiography 
All patients must have a qualifying echo for study entry defined as either a locally obtained 
echo performed within 6 months prior to Visit 1 or 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. For patients enrolled in India, all ejection fractions must be 
performed using 2D volumetric methods.  
For a subset of approximately 1200 patients at selected centers, the qualifying echoes will be 
sent to a core laboratory for assessment.  The details of the echo procedures will be outlined in 
the manual provided to all participating sites. 
6.6.5 
Atrial fibrillation 
The exploratory endpoint of new onset atrial fibrillation will be assessed in patients with no 
history of AF at baseline. This will be assessed at study visits by the investigator submitting 


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ECG tracings demonstrating the occurrence of atrial fibrillation  to the clinical endpoint 
committee for adjudication (see Section 6.5.5 and Section 8.5). 
Atrial fibrillation is common in HF and can contribute to the symptomatic and hemodynamic 
decline of the patient (Agostoni et al 2008, Clark et al 1997). Activation of the RAS system 
may contribute to the development of atrial fibrillation  by promoting atrial fibrosis and 
detrimental hemodynamics (Healey et al 2005). Prior clinical studies have yielded conflicting 
results on the benefit of RAS inhibition for primary prevention of AF (Khatib et al 2013). In 
PARAMOUNT (CLCZ696B2214), there was a greater reduction in left atrial size in the 
LCZ696 group compared to the valsartan group (Solomon et al 2012). This atrial reverse 
remodeling may be a result of the beneficial effects of RAS inhibition and increased NPs and 
its second messenger cGMP resulting from neprilysin inhibition in the presence of RAS 
blockade.  
6.6.6 
 Cognitive function assessment 
Cognitive impairment is common in patients with heart failure (HF) (Hajduk et al 2013). 
Available literature suggests that treatment of hypertension and improved cardiac function 
and cerebral blood flow in HF patients might improve cognitive function (Almeida & Tamai 
2001; Birns et al 2006; Zuccala et al 2005; Jesus et al 2006). On the other hand, NEP 
inhibition may inhibit the breakdown of amyloid β (Aβ), a peptide linked to cognitive 
impairment (Hersh & Rodgers 2008). In a two week cynomolgus monkey CSF study, short 
term LCZ696 treatment resulted in increases in CSF Aβ1-40, 1-42, and 1-38 levels. No 
increase in Aβ levels in brain was observed. In a chronic toxicology study, young (2-4 year 
old) cynomolgus monkeys treated for 39-weeks with LCZ696 at 300 mg/kg/day had no 
compound-related microscopic brain changes or increases in brain or cerebral vascular Aβ 
content or plaque formation. A two week clinical study in healthy human subjects did not find 
increases in Aβ1-40 and Aβ1-42 (although an increase in Aβ1-38 was observed), despite 
relevant concentrations of the NEPi, LBQ657, in the CSF. These findings suggest that 
degradation and transport mechanisms other than neprilysin, including enzymes such as 
angiotensin-converting enzyme (ACE), endothelin-converting enzyme (ECE) and insulin-
degrading enzyme (IDE), may play a compensatory role in the clearance of CSF Aβ 
fragments in humans.  
In the recently completed PARADIGM-HF (Study LCZ696B2314), in which 8442 patients 
were randomized to LCZ696 or enalapril for a median follow-up of 27 months, there were no 
differences between the two treatments in cognitive impairment or dementia-related adverse 
events. However cognitive function was not assessed in this trial. Therefore, global cognitive 
function will be assessed as an exploratory endpoint in the current protocol to evaluate the 
effect of LCZ696 compared to valsartan on cognition. 
In the current study the effects of RAAS inhibition alone with valsartan is compared to the 
effects of combined RAAS and NEP inhibition with LCZ696 on cognitive function using the 
Mini-Mental State Examination (MMSE) instrument. The MMSE is the most commonly used 
instrument for assessing cognitive function in adults. It is a comprehensive screening tool that 
can be administered by non-specialist staff. It is a 30-point questionnaire that tests various 
aspects of a patient’s cognition, including orientation to time and place, recall, attention, and 


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repetition. The instrument will be administered at randomization, annually thereafter, and at 
end of study visit (V299). 
The MMSE is available in a number of validated translations. Patients in whose language a 
validated translation of the MMSE is not available will be exempt from completing this 
instrument. 
6.6.7 
Biomarker substudy 
Biomarkers related to cardiac and renal function/injury and associated comorbidities and their 
consequences in the HFpEF population will be obtained from blood and first morning void 
(FMV) urine in a subset of approximately 1500 - 2000 patients as indicated in Table 6-1 as 
part of a substudy. Biomarkers will be used to elucidate the effect of study drugs as well as to 
explore risk. Blood biomarkers of potential interest may include, but are not limited to: NT-
proBNP, BNP, ST2, high-sensitivity troponin, Galectin 3, Cystatin C and/or other relevant 
markers.  FMV urine biomarkers may include markers such as cGMP and creatinine. The list 
of blood and urine biomarkers may change during the course of the study as new or more 
relevant biomarkers are determined. Biomarker analysis may also occur retrospectively after 
study close with biomarker decisions dependent on study outcome and/or new biomarkers 
relevant to the HFpEF patient population or drug mechanism. 
The results of the biomarkers analyzed during the conduct of the study will be blinded to the 
site and the Novartis clinical study team with the exception of the Visit 1 NT-proBNP.   
6.6.8 
Pharmacokinetics substudy  
Approximately 400 of the patients participating in the biomarker substudy (Section 6.6.7) will 
also participate in the PK substudy during the randomized treatment period at selected study 
sites. Plasma levels of valsartan, AHU377, and LBQ657 will be determined from these 
patients.  
On the morning of Visit 199/201 (end of treatment run-in/randomization) prior to starting the 
double blind study drug, participating patients will have a trough (Cmin ) PK sample taken.  
Patients should be instructed to take their last dose of treatment run-in study drug at 
approximately at 19:00 (7 PM) on the night prior to the visit that the trough PK sample will be 
obtained.    
On the morning of Visit 203 a total of 3 samples will be collected. Patients should be 
instructed not to take their morning dose of study drug prior to the clinic visit. The samples 
will be collected at the following intervals (Appendix 6): 
• Sample #1: pre-dose trough (immediately before the administration of study drug) 
• Sample #2: 0.5 to 2 hours post-dose 
• Sample #3: 3 to 5 hours post-dose 
If the PK samples are not taken at Visit 203, they will be taken at Visit 205. The site should 
make every effort to collect sample as close to the interval periods as possible. The exact time 
of the treatment administration, dose level of study medication, sample number, and time of 
sample collection will be recorded for each sample collected on the Pharmacokinetic Sample 
CRF. 


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Patients participating in the PK substudy are not required to provide all three required blood 
samples during the same study visit. Samples should always be taken when the patient is 
expected to be at steady state, i.e., has been receiving the study drug regularly on the same 
dose level as prescribed for at least 1 week.  
Special instructions on preparation, labeling, storage, and shipment of PK samples will be 
provided to the sites in a separate document. 
6.6.9 
Pharmacogenetics/Pharmacogenomics 
Pharmacogenetics/pharmacogenomic substudies will be conducted in countries where 
approval is granted.  
6.6.9.1 
Pharmacogenetics 
The study includes an optional pharmacogenetic component to be conducted at all 
participating sites and requires a separate signed informed consent if the patient agrees to 
participate. The Investigator where this component of the study is conducted will offer this 
option to the patient. 
This study will identify inherited genetic factors which may (1) be related to the causes and 
consequences of CHF, its’ pathophysiology and associated comorbidities, (2) predict response 
to treatment with LCZ696, (3) predict genetic predisposition to side effects. The goal is to 
develop a better understanding of CHF and how subjects respond to LCZ696. The genetic 
markers (or polymorphisms) that may be studied relate to the etiology of or modifiers of CHF 
include ACE I/D, which was reported to be associated with event-free survival in patients 
with HF. The specific genetic markers to be assessed may evolve during the course of the 
study as new or more relevant markers are determined relating to, for instance, ventricular 
structure or prediction of mortality or as new markers relevant to the HFpEF patient 
population develop. Additional polymorphisms may be considered at any time within the 
restricted scope of these studies as described. Analyses may occur retrospectively after study 
close.  
The ApoE4 gene has been identified as a genetic marker that predicts predisposition to 
cognitive decline and Alzheimer’s disease (Corder et al 1993). To control for this 
predisposing factor, patients will be asked to provide blood samples for genotyping which will 
include assessment of their ApoE4 genotype so that genetic predisposition is taken into 
account when assessing the cognitive function of the study participants.   
Recent advances in genotyping technologies have made genome-wide approaches possible. 
Genome wide studies may also be undertaken to identify genes that may be associated with 
HF or response to therapy as described above. 
Sample collection: One blood sample will be collected from participating patients at Visit 
103, or at any visit thereafter when consent is obtained. The protocol for the preparation of the 
samples for pharmacogenetics will be detailed in the study lab manual. The samples will be 
shipped to the central lab for DNA extraction. The extracted DNA will then be transferred to 
Novartis Pharmaceuticals Corporation for pharmacogenetic analysis and storage.  


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Any DNA derived from the sample that remains after analysis will be double-coded (see 
Section 8.3) and may be stored for up to 15 years to address scientific questions related to 
LCZ696, CHF or HFpEF. 
6.6.9.2 
Pharmacogenomics 
This study includes an optional pharmacogenomics component to be conducted at all 
participating sites and requires a separate signed informed consent if the patient agrees to 
participate. The investigator where this component of the study is conducted will offer this 
option to the patient.  
The pharmacogenomic samples will be obtained with the intention of assessing the effects of 
LCZ696 and valsartan on peripheral cellular and circulating plasma mRNAs, miRNAs and 
other oligonucleotides. Having access to these data could in turn assist: i) pre-treatment 
molecular stratification of disease, ii) evaluation of longitudinal treatment-induced molecular 
effects, and iii) the enrichment of responders to treatment at baseline. 
Sample collection: One blood sample will be collected at two timepoints/visits: i.e. prior to 
treatment with single-blind run-in study drug at Visit 103 and at Visit 203 (or Visit 205) 
during the double blind treatment epoch. RNA will be obtained from cellular components and 
from plasma. The protocol for the preparation of the samples for pharmacogenomics testing 
will be detailed in the study lab manual. 
Any RNA or other oligonucleotides derived from the sample that remains after analysis will 
be double-coded and may be stored for up to 15 years to address scientific questions related to 
LCZ696, CHF or HFpEF.  
7 
Safety monitoring  
7.1 
Adverse events  
An AE is any untoward medical occurrence (i.e., 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. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
An untoward medical occurrence may be a study endpoint as well as meeting the definition 
for an AE. Specific guidance on the appropriate recording and reporting of events that meet 
the criteria for both a study endpoint and an AE are provided in Section 7.3.  
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test, or other assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  


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• they require therapy.  
Clinically significant abnormal laboratory values or test results should 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 AEs. Alert ranges for labs and other test abnormalities are included in 
Appendix 1. 
AEs should be recorded in the AE CRF under the signs, symptoms or diagnosis associated 
with them accompanied by the following information. 
• the severity grade  
o mild: usually transient in nature and generally not interfering with normal 
activities 
o moderate: sufficiently discomforting to interfere with normal activities 
o severe: prevents normal activities 
• its relationship to the study treatment (no/yes) 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
• whether it constitutes an SAE  
• action taken regarding study treatment  
• whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any AE (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: 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o 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  
o 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  
o social reasons and respite care in the absence of any deterioration in the patient’s 
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• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e. further observation only); study drug dosage adjusted/temporarily 
interrupted; study drug(s) permanently discontinued; concomitant medication given; non-drug 
therapy given. The action taken to treat the AE should be recorded on the AE CRF.  
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should 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. 
Novartis may request additional information on specific AEs 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. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study drug. This information should 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 event reporting  
To ensure patient safety all SAEs, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence.  
At a minimum, 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. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 


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submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Follow-up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the investigational treatment, a Novartis Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. If the SAE is considered Suspected Unexpected 
Serious Adverse Reactions (SUSARs), Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported.  All SUSARs will be collected and 
reported to the competent authorities and relevant ethics committees (ECs) in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
7.3 
Protocol specific unblinding rules for SUSARs that are also efficacy 
endpoints 
In studies such as this one, where the efficacy endpoints potentially meet the requirements for 
SUSAR reporting, the integrity of the study may be compromised if the endpoints are 
systematically unblinded for expedited reporting to competent authorities/relevant ECs and 
investigators. In such cases, regulations allow an exemption from SUSAR unblinding and 
expediting aimed at ensuring the validity of an outcome study (European Commission 
ENTR/CT12 Guideline 2006; FDA Guidance 2012). Therefore, the following rules for 
unblinding SUSARs during the study period will be applied. 
7.3.1 
Primary and secondary endpoints 
The primary and secondary endpoints (atrial fibrillation, CV death, heart failure 
hospitalization, myocardial infarction and stroke) will not be unblinded even if they meet the 
definition of a SUSAR.  Novartis will not expedite a report to competent authorities/relevant 
ECs and will not issue an IN. However, non-CV death, a secondary endpoint for the study, 
will be unblinded if it meets the criteria for a SUSAR.  
If specifically requested by a local Health Authority, pre-specified endpoints that also meet 
criteria for SUSARs will be expedited to this Health Authority as blinded reports.  
Investigator notifications will not be issued for these events.   
7.3.2 
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 they will not be unblinded and will not be reported as SUSARs to regulatory agencies, 
ECs, or investigators during the study. These events will be presented in the clinical study 
report (CSR) at the end of the study.  


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If specifically requested by a local Health Authority, 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 Health Authority 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 Health Authority will be expedited to the Health 
Authority 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 
 
7.3.3 
Exploratory endpoints and other SAEs that meet the definition of 
SUSARs 
Exploratory endpoints that meet SUSAR criteria, and all other SAEs that do not meet the 
criteria in Section 7.3.1 and Section 7.3.2 but do meet SUSAR criteria will be unblinded and 
reported to regulatory agencies, ECs, or investigators during the study. 
Monitoring of safety data by the Data Monitoring Committee 
An external independent Data Monitoring Committee (DMC) (Section 8.4) will be appointed 
to monitor the safety of study participants and to ensure that the program is being conducted 
with highest scientific and ethical standards. This DMC will review the endpoint and SAE 
data throughout the trial in a semi-unblinded manner. Should the DMC make 
recommendations on the conduct of the trial that are considered to have significant bearing on 
the benefit-risk of the trial, these will be communicated by Novartis to HAs, ECs and 
investigators within an appropriate timeframe and implement any additional actions required. 
7.4 
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.  
Liver events are divided into two categories: 


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• Liver events of special interest (AESI) which consist of LFT elevations 
• Medically significant liver events which are considered as SAEs and which consist of 
marked elevations of LFTs and / or pre-specified AEs. 
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver events.  
Any liver event which meets the criteria for “medically significant” event as outlined in 
Table 14-1 of Appendix 2 should follow the standard procedures for SAE reporting as 
described in Section 7.2.  
Every liver event as defined in Table 14-1 of Appendix 2 should be followed up by the 
investigator or designated personnel at the trial site as summarized below. Detailed 
information is outlined in Table 14-2 in Appendix 2. 
• 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 should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 
7.5 
Pregnancy reporting  
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
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 should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report 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 CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 


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Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
8.2 
Data collection  
Designated investigator staff will enter the data required by the protocol into the EDC system. 
Designated investigator site staff will not be given access to the system until they have been 
trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control  
Novartis staff or Contract Research Organization (CRO) working on behalf of Novartis 
review the data entered into the CRFs 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. A 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 WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and AEs 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. 
Pharmacogenetic/pharmacogenomic samples 
To maximize confidentiality, all samples are coded with a unique number and no personal 
identifiers are on the sample tubes. DNA samples are double-coded to ensure added 
confidentiality. The process of double-coding allows Novartis to go back and destroy the 
sample at the patient’s request.  All information relating to the samples is stored in a secured 
database under the control of Novartis. In addition, the results obtained from these exploratory 
samples will be stored in a secured database that is separate from and not linked to the sample 
database. 
The use of pharmacogenetics/pharmacogenomics to search for biomarkers of disease and drug 
action is exploratory. Any results from this pharmacogenetic study will not be placed in the 
patient’s medical records. 
8.4 
Data Monitoring Committee  
An external data monitoring committee (DMC) independent of Novartis will be appointed to 
monitor the study conduct and to review the results of the interim analyses for efficacy and 
safety on a regular basis and determine if it is safe to continue the study according to the 
protocol. 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 Committees 
Clinical Endpoint Committee 
All events, which could potentially fulfill the criteria for the primary, secondary, or other 
endpoints will be assessed during the study and reported to the Clinical Endpoint Committee 
(CEC) for adjudication. 
The CEC will be responsible for classifying all death events and for determining whether pre-
specified endpoint criteria were met for the non-fatal events. Sites are instructed to take a 
conservative approach when reporting endpoints; if the investigator suspects an endpoint may 


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have occurred, it should report the event to the CEC for the final determination. The 
membership and responsibilities of the CEC Committee will be defined in a separate 
document provided to the sites. This document will include definitions for endpoints and 
guidelines on the endpoint reporting process. 
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. 
8.6 
Source documentation verification  
Novartis will select patients based on pre-defined criteria (e.g., enrollment based on elevated 
NT-proBNP alone or based on prior hospitalization for heart failure) for collection of select 
source documentation of medical history records for full medical review of adherence to the 
inclusion/exclusion criteria as needed to ensure the intended per protocol target patients are 
enrolled. Sites will be instructed to remove all personal identifiers linking the source 
documents to the patients prior to submission to a third party vendor via electronic email or 
fax. The third party vendor will then ensure anonymity of the documents, compile the medical 
history packets, translate the documents into English (if applicable), and forward them to 
Novartis for medical review. Only the patient’s study identification number will be used to 
ensure patient’s identity and confidentiality are preserved. The review will be conducted 
centrally by the global study clinical team and will focus on enrolled patients. The aim of this 
central medical review is to assess compliance with the protocol and provide additional 
training to the investigator sites if needed. 
9 
Data analysis  
This section describes a preliminary approach to data analysis. 
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. 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 
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The Safety (SAF) Population 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 
safety population 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 population 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. This baseline is the randomized treatment 
epoch baseline. 
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, and vital signs. BMI will be calculated as 
weight (kg) / height2 (m2) from the collected height and weight at Visit 1 (Screening Visit). 
Continuous variables will be summarized using n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized using frequency and 
percentage. 
The difference between treatment groups will be compared using the Chi-square test for 
categorical variables or using t-test for continuous variables. The p-values will be provided for 
descriptive purposes and will not be considered to define any formal basis for determining 
factors to be included in statistical models. If a substantial imbalance of treatment groups with 
respect to some variables does occur, supplemental analyses with addition of these variables 
in model may be performed to assess the potential impact on efficacy as appropriate. 
The FAS will be the patient population 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. 
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 safety population.  
The number and percentage of patients on different CV background medications (e.g., 
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. 


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9.4 
Analysis of the primary and secondary variable(s) 
9.4.1 
Variable(s) 
The primary and secondary objectives of this study are presented in Section 2.1 and Section 
2.2 
The primary efficacy variable is the cumulative number of primary composite events, i.e., the 
composite events of (total) HF hospitalizations and CV death, for a given subject, over time. 
The secondary efficacy variables are: 
1. 
Change from baseline in KCCQ clinical summary score for HF symptoms and physical 
limitations at Month 8. 
2. 
Change from baseline to Month 8 NYHA class. 
3. 
Time to first occurrence of the composite renal endpoint, defined as follows:  
• renal death, or 
• reaching ESRD, or 
• ≥50% decline in eGFR relative to baseline 
4. 
Time to all-cause mortality. 
The time point of Month 8 is defined as Week 32 in accordance with the assessment schedule 
(Table 6-1). 
9.4.2 
Statistical model, hypothesis, and method of analysis 
9.4.2.1 
Primary analysis 
The primary efficacy endpoint of the study consists of the times to recurrent hospitalization 
due to heart failure and death time due to CV reasons during the patient's follow-up. The 
comparisons between two treatment groups will be made using statistical procedures which 
deal with such multiple event time observations. For example, the semi-parametric 
proportional rates model (abbreviated as LWYY model) (Lin et al 2000) can be utilized for 
quantifying the treatment difference. 
Specifically, let λij (t, xij) be the individual rate of primary composite events for subject i in 
region j, given the patient has not died from a CV reason at time t. It is dependent on time 
from randomization (t) and treatment group (xij). Let xij=1 if the subject is in the LCZ696 
group and xij=0 if the subject is in the valsartan group.  
Under the proportional rates model, the individual rate function for the composite endpoint of 
CV death and total HF hospitalizations is assumed to be, λij(t, xij) = Yij (t)λ0j(t) exp(β0xij), 
where Yij (t)=1 if subject i in region j is at risk for HF hospitalization or CV death at time t 
and Yi j(t)=0 if subject i in region j is censored or died from a CV reason at time t- and λ0j(t) is 
the baseline rate function for the event in region j. 
The primary hypothesis to be tested is, H10: β0≥ 0 versus H1a: β0< 0, where exp(β0) is the 
relative risk or rate ratio (RR) of total hospitalizations for HF and CV death in the LCZ696 
group relative to the valsartan group given the patient has not died from a CV reason at time t, 
which is assumed to be constant over time and across regions.  


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The primary hypothesis could be equivalently written as:  
H10: Rate ratio LCZ696/valsartan ≥ 1 versus H1a: Rate ratio LCZ696/valsartan < 1,  
A rate ratio < 1 indicates an effect in favor of LCZ696. 
Note that exp(β0) can also be considered as a ratio of two mean cumulative frequencies of a 
subject having hospitalizations for HF and CV death when the rate ratio is constant over time 
and CV mortality is balanced between treatment groups. 
The primary hypothesis will be tested at a one-sided significance level of 0.02499 adjusted for 
interim analysis. The rate ratio and its 95% confidence interval will be estimated from the 
above proportional rates model through maximization of a partial likelihood score function. 
The resulting estimate of exp(β0) is identical to the one described by Anderson and Gill 
(Anderson and Gill 1982), but unlike Anderson-Gill, a robust variance estimator (sandwich 
estimator) is used to account for the dependency of within subject events. Note that having 
CV death is not considered as a censoring variable, but as a primary endpoint event and a 
conditional factor in this analysis. Time to non-CV death will be considered as a censoring 
variable. Any censoring due to non-CV death is assumed to be non-dependent in the analysis. 
The above presented analysis method based on LWYY provides a treatment comparison 
based on primary endpoint rate ratio conditional on not having died from a CV reason. A 
marginal interpretation of the estimates requires that any censoring of the primary composite 
events will be non-informative and may be challenging if there is an imbalance in CV 
mortality.  
As a part of the primary analysis, the two components in the composite endpoint (total HF 
hospitalizations and CV mortality) will be analyzed separately to quantify the respective 
treatment effects and check the consistency between the composite and the components.  
For the analysis of total HF hospitalizations component, occurrence of CV death can be 
regarded as semi-competing risk (informative censoring) and may introduce a bias in the 
treatment effect estimate for HF hospitalizations (dilution of effect size if the drug has a 
positive effect on both components). In order to address this concern and to account for the 
correlation between the two components, the joint modeling (frailty model) approach 
(Cowling et al 2006) will be used for the component analyses. The joint model is specified as 
follows. 
𝜆𝜆𝑖𝑖𝑖𝑖
𝐻𝐻(𝑡𝑡) = 𝑌𝑌𝑖𝑖𝑖𝑖 (𝑡𝑡)𝜆𝜆0
𝐻𝐻exp (𝛽𝛽0𝑥𝑥𝑖𝑖𝑖𝑖)𝜈𝜈𝑖𝑖𝑖𝑖 
𝜆𝜆𝑖𝑖𝑖𝑖
𝜏𝜏(𝑡𝑡) = 𝑌𝑌𝑖𝑖𝑖𝑖(𝑡𝑡)𝜆𝜆0 
𝜏𝜏exp (𝛾𝛾0𝑥𝑥𝑖𝑖𝑖𝑖)𝜈𝜈𝑖𝑖𝑖𝑖
𝛼𝛼 
𝜈𝜈𝑖𝑖𝑖𝑖~ 𝑓𝑓 (. ) 
where 
 is the rate function of the total hospitalizations for HF for subject i in region j 
and 𝜆𝜆0
𝐻𝐻  is its constant baseline and 
has a similar format as the model described above 
for the primary endpoint except for the multiplier 
 that is a subject-specific random effect 
factor (frailty); and 
 is the hazard function for the component of CV mortality for 


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subject i in region j and 𝜆𝜆0
𝜏𝜏 is its constant baseline and 
 is a frailty Cox proportional 
hazards model. The parameter α measures the association between 
 and 
. The 
frailty distribution f(.) will be pre-specified prior to the unblinding of the treatment codes. The 
parameters in the joint model, including the unknown power for the frailty, will be estimated 
through maximization of the corresponding likelihood. The model assumes that the 
correlation between total HF hospitalizations and CV death for each patient is completely 
explained by the covariates and the frailty and the two analysis variables corresponding to the 
two components are independent given the patient’s frailty and covariates.  
For the analysis of CV death, it will be analyzed using Cox’s proportional hazards model with 
a fixed treatment group factor and stratified by region. The analysis in the joint frailty model 
for this component will be considered as supportive whenever an inference is needed for it. 
In all the proposed analyses, it is acknowledged that the study will not be powered to achieve 
statistically significant results for the CV death. The inference on the total HF hospitalizations 
can only be made when both the composite endpoint and the total HF hospitalizations itself 
showed statistically positive results. 
Non-parametric estimates of HF hospitalization rates over time allowing for death as terminal 
event will be provided as well (Ghosh and Lin 2000). 
9.4.2.2 
Supportive analyses for primary efficacy 
The supportive analyses for the primary analysis results will be performed in two ways:  
1. Performing the primary analysis (the LWYY model) and the component analyses (the 
joint frailty model) on the PPS; 
2. Evaluating the impact of the informative censoring of CV death on the estimate of the 
relative rate reduction through performing additional analyses including: 
a. Checking of existence of any non-negligible imbalance in CV mortality between 
treatment groups through analysis for CV mortality alone; pooling PARADIGM-HF 
(CLCZ696B2314) and this study to assess any adverse signal on CV mortality, if it 
deems necessary; 
b. Providing a series of sensitivity analyses to investigate the robustness and consistency 
of the primary efficacy results:  
• Analysis using the WLW method (Wei et al 1989, Li and Lagakos 1997) on time 
to first (the conventional time-to-first event analysis) and time to 2nd, 3rd, 4th, 
5th, and 6th composite events; an average effect (stratified by event number) will 
be provided for each of those analyses. This analysis will partially evaluate the 
robustness of the overall estimate of effect size against the impact from an 
(expected) small subgroup of patients with higher number of hospitalizations for 
HF. If the patient's first event is a CV death, then his 2nd, 3rd,…, Kth event will 
be counted as CV death as well. This analysis avoids informative censoring by 
counting CV death repeatedly as event. It is acknowledged that some of the 
analyses, time-to-1st event, for example, may not be powered; 
• Analysis using a negative binomial regression model (McCullagh and Nelder 
1989) on total number of primary composite endpoints with an offset of 


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logarithm of time from randomization to censoring or death. The common rate 
ratio of composite events will be provided.  
• Analysis using a multi-state model (Castaneda and Gerritse 2010) to assess the 
hazard ratios of transition intensities between different states defined by 
hospitalization status and CV death. 
9.4.2.3 
Secondary analysis 
9.4.2.3.1 Analysis methods 
The four secondary hypotheses to be tested are: 
• Comparison of change from baseline in KCCQ clinical summary score at Month 8 
(denoted as H210, the parameter is the mean change from randomized treatment epoch 
baseline to Month 8 in KCCQ clinical summary score); 
• Comparison of change from baseline to Month 8 NYHA class (denoted as H220, the 
parameter is the category change from baseline to Month 8 in NYHA class); 
• Time from randomization to first occurrence of composite renal endpoint of renal death,  
ESRD, or ≥50% decline in eGFR relative to baseline (denoted as H230, the parameter is the 
hazard ratio for composite renal endpoints); 
• All-cause mortality (denoted as H240, the parameter is the hazard ratio for all-cause death). 
Changes from baseline in KCCQ clinical summary score at Month 8 will be analyzed based 
on a repeated measures ANCOVA model in which treatment, region, visit, and treatment-by-
visit interaction will be included as fixed-effect factors and baseline value as a covariate, with 
a common unstructured covariance matrix among visits for each treatment group. Treatment 
comparisons and effect size estimates at Month 8 will be provided. The analysis will be 
performed based on all available data up to Month 8 in the FAS and based on likelihood 
method with an assumption of missing at random for missing data. 
In addition, a responder analysis for KCCQ clinical summary score change from randomized 
treatment epoch baseline at Month 8 (defined as patients with at least 5 point change 
(deterioration or improvement) will be performed using a generalized mixed model with 
treatment, region, visit, and visit-by-treatment as fixed factors and baseline score as covariate, 
with a common compound symmetry covariance matrix among visits for each treatment group. 
Treatment comparisons and effect size estimates at Month 8 will be provided. The analysis 
will be performed based on all available data up to Month 8 in the FAS. The goal of the 
responder analysis is to assess the clinical relevance of the difference between the two groups 
in the mean change from randomized treatment epoch baseline. 
Change from baseline to Month 8 NYHA class will be analyzed using a repeated measures 
proportional cumulative odds model. The response variable is the category change from 
baseline to any given time points up to Month 8 (improved, unchanged, worsened). NYHA 
class change after patients who have died will be categorized into ‘worsened’. The model will 
include patient as a random effect and the randomized treatment phase baseline NYHA class, 
region, treatment, visit and treatment-by-visit interaction as fixed effect factors. This model 
assumes that the treatment effect sizes across measurement categories are the same. Model 
fittings will be based on likelihood with all available data up to Month 8. As supportive 


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analysis, the same model will be performed on data with no imputation for missing data in 
NYHA class change due to death. 
Time-to-first occurrence of composite renal endpoint events will be analyzed using the Cox 
proportional hazard model with treatment as a fixed effect factor, stratified by region. The 
estimated hazards ratio and the corresponding two-sided 95% confidence interval will be 
provided. 
All-cause mortality will be analyzed using Cox’s proportional hazards model with a fixed 
treatment group factor and stratified by region. 
9.4.2.3.2 Multiplicity adjustment 
The secondary hypotheses will be tested and statistical inferences will be made only if the 
primary hypothesis is rejected. The four secondary efficacy hypotheses will be tested for 
superiority of LCZ696 to valsartan for the FAS. For each secondary variable, the null 
hypothesis of no treatment difference between LCZ696 and valsartan will be tested against 
the alternative hypothesis that LCZ696 is more effective than valsartan. 
The sequentially rejective multiple test procedures (Bretz et al 2009) will be used for testing 
the hypotheses of the primary endpoint and the first three secondary endpoints as indicated in 
Figure 9-1, to control the alpha level. The all-cause mortality (H240) will be tested at a full 
level of alpha, after the rejection of the primary hypothesis, considering as a hard-endpoint.  
In Figure 9-1, the fractions marked in the graph denote the weights or proportions of alpha to 
be added to the alphas in the next nodes according to where the arrows point once the current 
node of hypothesis is rejected. 
• The initial allocation of (local) significance levels are α, 0, 0, and 0 for the comparisons of 
the primary endpoint and the first three secondary endpoints, respectively.  
• The general algorithm for the testing procedure goes as follows: Test the hypotheses H10, 
H210, H220, and H230 each at its local significance level defined above. If a hypothesis can 
be rejected, reallocate its level to one of the other hypotheses according to a pre-specified 
rule represented by the weighted graph in Figure 9-1. Update the reallocation weights in 
the reduced graph (the rejected hypothesis is removed from the graph) and repeat the 
testing step for the remaining no-rejected hypotheses with the updated local significance 
levels. This possibly leads to further rejected null hypotheses with associated reallocation 
of the local significance levels. The procedure is repeated until no further hypothesis can 
be rejected. The reallocation of the local alpha levels is fully determined by the initial 
graph given in Figure 9-1 and the update algorithm for this sequentially rejective multiple 
test procedure (Bretz et al 2009). 
o In the notation of Bretz et al 2009, a weight of ε for an edge indicates an 
infinitesimally small weight. If a hypothesis (vertex) with such an outgoing edge is 
rejected and the vertex removed, no significance level is passed on along such an edge 
as long as there are other outgoing edges with positive weights. If after removal of 
another vertex only infinitesimal outgoing edges remain, then the algorithm of Bretz et 
al 2009 turns them into edges with positive weights that sum to 1. In this specific 
procedure, this implies that no significance level is passed from the secondary null 
hypotheses for KCCQ (H210) or NYHA class (H220) to the secondary null hypothesis 


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for composite renal endpoint (H230) until both KCCQ and NYHA class null hypotheses 
have been rejected. To ensure the sum of weights on all outgoing edges of a vertex is 1 
when such edges are present, some edges are given a weight of 1 – ε. 
Figure 9-1 
Illustration of weights for alpha relocation in the sequentially rejective 
multiple test procedure for the secondary hypotheses 
 
The power analyses for each hypothesis in Figure 9-1 are presented in Section 9.7.  
For publications the secondary variables may be assessed using a full level of alpha without 
consideration of multiplicity adjustment.  
9.4.2.4 
Subgroup analyses for primary and secondary objectives 
Subgroup analyses will be performed for the primary and secondary endpoints based on the 
FAS. To explore beneficial effects in subgroups or homogeneity of beneficial effects among 
subgroups, the estimated effect sizes, their two-sided 95% confidence intervals, and within 
subgroup p-value and p-value for the test for the treatment-by-subgroup interaction will be 
provided for each of the subgroups based on the analysis models. The analysis models will 
include treatment, subgroup, and treatment-by-subgroup as fixed-effect factors, except for 
NHYA. No adjustment for multiple comparisons will be made. Therefore, p-values from these 
subgroup analyses have to be interpreted with caution since there is a non-negligible chance 
of false-positive findings. 
• Age group (<65 vs. ≥65 years; <75 vs. ≥75 years)  
• Gender (male/female)  
• Race 
• Region  
• Diabetic at baseline (yes/no) 
• Baseline SBP (≤median vs. >median) 


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• Baseline LVEF (≤median vs. >median) 
• Baseline NT-proBNP (≤median vs. > median) 
• Baseline eGFR (<60 vs ≥60 mL/min/1.73 m2) 
• AF at baseline (yes/no) 
• Use of MRAs at baseline (yes/no) 
• ACEI intolerant patients (yes/no) 
9.4.3 
Handling of missing values/censoring/discontinuations 
The primary efficacy variable, the recurrent extended composite events and time to new onset 
of AF variables are related to the number of events or time to event occurred within a certain 
time window. The censoring will be the major source of missing data. This type of missing 
data will be handled by assuming some dependence structures between the censoring 
mechanism and the event generating mechanism. The dependence structures will be pre-
specified in the analysis plan. A variable is considered to be censored at each analysis time 
point if at least one of the following applies at or prior to the analysis time point: 
• Withdrawal of informed consent, 
• Lost to follow-up, or 
• Death  
The censoring date will be defined as the following (whichever occurs first): 
• Date when the patient withdrew informed consent 
• Date of the patient’s last visit before analysis cut-off date 
• Date of death 
For the analysis of KCCQ clinical summary score, if a patient dies, a worst score (score of 0) 
will be imputed for the clinical summary score at all subsequent scheduled visits after the date 
of death where the clinical summary score would have been assessed. 
For the analysis of NYHA, the analysis will be based on the likelihood approach. The missing 
at random (MAR) for missing data is assumed. An unbiased analysis will be produced under 
MAR. 
9.5 
Analysis of exploratory variables 
Exploratory objectives are defined in Section 2.3.  
9.5.1 
Exploratory variables 
Below are the variables for the exploratory analyses:  
1. Time from randomization to occurrences of the composite endpoint events of CV death, 
total non-fatal HF hospitalizations, total non-fatal strokes, and total non-fatal myocardial 
infarctions (MIs). Total is defined as the first and all recurrent events;  
2. Change in clinical composite assessment (NYHA, global patient assessment, and clinical 
events defined as CV death and HF hospitalization) at 8 months; 
3. Patient global assessment at 8 months; 


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4. Changes from baseline in health-related QoL (assessed by the overall summary score, 
clinical summary score, and individual scores of the sub-domains from the KCCQ 
[relative to the beginning of treatment run-in and randomization epochs] and assessments 
of the EQ-5D for health status); 
5. Number of HF events per-subject;  
6. Number of worsening HF events or CV death per-patient; 
7. Number of all-cause hospitalizations per-subject and number of cause specific 
hospitalizations per-subject; 
8. Number of days alive and out of hospital at 12 months, and during the study duration; 
9. Rate of change in eGFR (eGFR slope); 
10. Time from randomization to NODM; 
11. Number of days staying in intensive care unit (ICU), number of re-hospitalizations for HF, 
and number of ER visits for HF; 
12. Indicator of 30 day HF rehospitalization (after a prior HF hospitalization); 
13. Number of rehospitalizations within 30 days after discharge; 
14. Time between HF hospital readmissions; 
15. Changes in pre-specified biomarkers (e.g., cardiac, vascular, renal, collagen, metabolism, 
and/or inflammatory biomarkers) from baseline to predefined time-points (in a subset of 
patients); 
16. Variables to characterize the PK of valsartan, AHU377, and LBQ657 at steady-state in 
patients receiving LCZ696 using population modeling and/or non-compartmental based 
methods; 
17. Change from baseline in MMSE summary score at year 2 (week 96); 
18. Time from baseline to new onset  atrial fibrillation; 
19. Echocardiographic parameters in a subset of patients 
9.5.2 
Analysis methods 
In general, exploratory variables will be analyzed in the FAS unless specified otherwise. 
Statistical tests will be performed at the two-sided significance level of 0.05. To better satisfy 
the normality assumption, the log-transformation will be taken on each biomarker prior to 
statistical analysis. There will be no multiplicity adjustment for any analysis of exploratory 
variables. 
Analysis of time-to-event data 
Time-to-event variables include:  
• Time to new onset of DM; 
• Time to new onset of AF; 


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• Time to the composite endpoint events of CV death, total HF hospitalizations, total non-
fatal strokes, and total non-fatal myocardial infarctions (MIs). 
Time-to-event variables will be analyzed using the Cox proportional hazard model with 
treatment as a fixed effect factor, stratified by region. The estimated hazards ratio and the 
corresponding two-sided 95% confidence interval will be provided.  
The composite endpoint of CV death, total HF hospitalizations, total strokes, and total MIs 
will be analyzed using the same proportional rates model used for the primary endpoint. In the 
component analysis, the four components will be grouped into two components: CV death and 
the composite of total HF hospitalizations, total strokes, and total MIs. 
Analysis of continuous variables 
Continuous variables, which are assumed to be normally distributed, are: 
• Rate of change (slope) in eGFR from baseline to endpoint; 
• Changes in health-related quality of life (assessed by clinical summary score, overall 
summary score and individual scores of the sub-domains from the KCCQ and scores of 
the EQ-5D for health status (EQ-5D index derived from EQ-5D descriptive system and 
EQ-5D VAS) from baseline to pre-defined time-points; 
• Changes from baseline to pre-defined time-points in pre-selected biomarkers (e.g., cardiac, 
vascular, renal, collagen, metabolism, and/or inflammatory biomarkers); 
• Days alive out of the hospital during the first 12 months, and during the study duration. 
• Change from baseline in MMSE summary score at week 96. 
For the rate change in eGFR, the eGFR slope will be estimated from a repeated measures 
ANCOVA model including treatment, region, time (when the eGFR is assessed in months), 
and treatment-by-time as fixed effects with random intercept and slope (time) and a common 
unstructured covariance. The least-squared means of slopes for within and between treatment 
groups, and the corresponding two-sided 95% confidence intervals will be provided.  
Changes from randomized treatment epoch baseline in KCCQ scores, similarly for changes 
from baseline in EQ-5D VAS and EQ-5D index, will be analyzed based on a repeated 
measures ANCOVA model in which treatment, region, visit, and treatment-by-visit 
interaction will be included as fixed-effect factors and baseline value as a covariate, with a 
common unstructured covariance matrix among visits for each treatment group. Treatment 
comparisons and effect size estimates at different visits will be provided. The analysis will be 
performed based on all available data up to 3 years in the FAS and based on likelihood 
method with an assumption of missing at random for missing data.  
KCCQ score obtained at the beginning of treatment run-in epoch is used as the run-in baseline 
and the analysis of KCCQ changes using a repeated measures ANCOVA model as described 
above will be repeated again using run-in baseline. 
For pre-selected biomarkers, change from baseline to a pre-defined time-point (Week 4 and 
Month 8) in logarithmic scale will be analyzed using a similar repeated measures ANCOVA 
model as described above. 


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For days alive out of the hospital during the first 12 months, it will be treated as a continuous 
variable. The mean difference between treatment groups will be compared using an 
ANCOVA model with factors of region and treatment group. Days alive out of the hospital 
during the study duration will be similarly analyzed as appropriate. 
The change from baseline in the summary score of MMSE will be analyzed using a repeated 
measures ANCOVA model in which treatment, region, baseline hypertension status, baseline 
diabetes status, visit (Week 48, and Week 96) and treatment-by-visit interaction are included 
as fixed-effect factors and baseline age, MMSE baseline value and visit by MMSE baseline 
interaction as covariates, with a treatment-specific unstructured covariance matrix among 
visits for each treatment group. The adjusted mean changes at week 96 within each treatment, 
the difference in mean changes at week 96 between two treatments, its 95% confidence 
interval obtained from the above model will be presented. The analysis will be performed 
based on all available data up to 96 weeks for patients with both baseline and at least one 
post-baseline MMSE assessment, and based on likelihood method with an assumption of 
missing at random (MAR) for missing data. In case that if there is any a problem with model 
convergence, the factors of baseline hypertension and diabetes status may be dropped from 
the modeling. 
With a total of approximately 2500 patients expected to be eligible for the above analysis, 
there is more than 90% probability that the lower bound of the 95% confidence interval of the 
between-treatment difference of mean MMSE summary scores at Week 96 is ≥ -0.5 (exclude 
a between-treatment difference of 0.5 or more reduction), assuming that there is no true 
between-treatment difference and the common standard deviation is 3. A between-treatment 
difference of 0.5 or less is not considered clinically meaningful. 
To investigate the sensitivity of the analysis results based on the MAR assumption, analyses 
based on multiple imputations, such as those  using a pattern mixture model approach,  may 
be performed, which assumes that missing MMSE scores after death, HF hospitalizations, or 
stroke were missing not at random (MNAR).  
Similar analyses as above will also be performed in the subset of patients who have ApoE4 
genotype assessment done.  
In addition, changes from baseline in the summary score of MMSE will also be analyzed 
using a repeated measures ANCOVA model in which treatment, geographic region, baseline 
hypertension status, baseline diabetes status, visit (Weeks 48, 96, 144, 192, 240), and 
treatment-by-visit interaction are included as fixed-effect factors, and baseline age, baseline 
MMSE value and visit by MMSE baseline interaction as covariates, with a common 
unstructured covariance matrix among visits for each treatment group. Treatment comparisons 
and effect size estimates and their 95% confidence intervals at different visits (only for visits 
at Week 48, 96, 144) and averaged over-all-visits will be provided. The analysis will be 
performed based on likelihood method with an assumption of missing at random for missing 
data.  
Similar repeated measure ANCOVA model will be fitted in the subgroup of patients who have 
ApoE4 genotype assessment done.  
A descriptive summary of MMSE absolute score and change from baseline over time will be 
tabulated and plotted. 


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All analyses in MMSE score will be performed in the FAS for patients who have participated 
in the cognitive function assessment sub-study. 
Analyses of categorical and ordinal variables 
Binary variables include: 
• Indicator of 30 day HF rehospitalization (after a prior in-study HF hospitalization). 
• Indicator of KCCQ scores ≥ 5 points change (deterioration or improvement)  
Binary variable of 30 day HF rehospitalization will be analyzed using logistic regression with 
treatment and region as fixed-effect factors. For 30 day hospital readmission, the analysis set 
will be restricted to patients who had hospitalization for HF at least once during double blind 
period. 
A responder analysis for KCCQ score change from randomized treatment epoch baseline at 
scheduled visits (defined as patients with at least 5 point change (deterioration or 
improvement) will be performed using a generalized mixed model with treatment, region, 
visit, and visit-by-treatment as fixed factors and baseline score as covariate, with a common 
compound symmetry covariance matrix among visits for each treatment group. Treatment 
comparisons and effect size estimates at scheduled visits will be provided. The analysis will 
be performed based on all available data up to Year 3 in the FAS. The goal of the responder 
analysis is to assess the clinical relevance of the difference between the two groups in the 
mean change from randomized treatment epoch baseline. 
KCCQ score obtained at the beginning of treatment run-in epoch is used as the run-in baseline 
and the responder analysis of KCCQ as described will be repeated again using run-in baseline. 
Ordinal variables include: 
• Assessment in the clinical composite assessment (improved, unchanged, and worsened) at 
post-randomization visits 
• Change in NYHA class from randomization  
• Changes in HF signs and symptoms from randomization  
• Patient global assessment at 8 months 
The first three variables will be analyzed, at Month 8, 1 year, 2 years, and 3 years, using a 
repeated measures proportional cumulative odds model. The model will include patient as a 
random effect and the randomized treatment phase baseline category (only for NYHA class 
and HF signs and symptoms), region, treatment, visit (all available post-randomization visits) 
and treatment-by-visit interaction as fixed effect factors. This model assumes that the 
treatment effect sizes across measurement categories are the same. The visit-wise effect size 
estimates and their 95% confidence intervals will also be provided. The analysis will be based 
on all available data in the FAS and likelihood method with an assumption of missing at 
random for missing data. The patient global assessment at 8 months will be analyzed similarly 
but using a non-repeated measures proportional cumulative odds model. 
Analysis of count data 
Count data include: 


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• Number of HF events  
• Number of worsening HF events or CV deaths 
• Number of hospital admissions  
• Number of days/stays in ICU 
• Number of re-hospitalizations 
• Number of ER visits for HF 
• Number of 30 day hospital readmissions (after a prior in-study HF hospitalization) 
Count variables will be analyzed using a negative binomial model (McCullagh and Nelder 
1989) with the count data as the dependent variable and treatment group and region as fixed-
effect factors and log(follow-up duration) as the off-set. The model estimated event rates 
(intensities) and their 95% confidence intervals will be provided by treatment group. The 
treatment comparison will be performed through the estimated ratio of risk rates. The 
estimated reduction in event rate (ratio LCZ696/valsartan) and its 95% confidence interval 
will also be provided. As mentioned before, for 30 day hospital readmission, the analysis set 
will be restricted to patients who had hospitalization for HF at least once during double blind 
period. This implies that the baseline treatment group balance obtained from the 
randomization may be broken. 
Subgroup of ACEI intolerant patients 
The primary and secondary variables as well as the symptom based variables, such as the 
NYHA class, clinical composite assessment, and so on, will also be analyzed using methods 
proposed above for the sub-group of ACEI intolerant patients. 
9.5.3 
Safety variables 
The safety and tolerability assessments are listed below: 
• Identified and potential risks 
• 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 frequency 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 


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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 (e.g., 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 safety set. There will be no formal statistical 
inference analysis. 
9.5.4 
Resource utilization 
Data relating to resource utilization will be used for the purpose of economic evaluation 
which will be carried out and reported as a separate activity. 
9.5.5 
Health-related Quality of Life 
The reduction in combination of HF symptoms and physical limitation scores assessed by the 
clinical summary score of the KCCQ and the other KCCQ sub-domains will all be analyzed 
using a repeated measures ANCOVA model. Within treatment group and between treatment 
groups comparisons will all be conducted based on this model.  
Assessments of EQ-5D VAS and EQ-5D index will also be analyzed similarly. 
9.5.6 
Pharmacokinetics 
Steady-state PK time profile of valsartan, AHU377, and LBQ657 will be analyzed by 
graphical methods to determine the appropriate structural PK model to fit the data. Following 
this, a population PK model will be developed using the plasma time profile patient-level data 
from this study and/or in combination with PK data from other studies with LCZ696 to 
quantify the PK of valsartan, AHU377, and LBQ657 and test for significant covariates that 
influence their PK. 
9.5.7 
Pharmacogenetics 
The exploratory pharmacogenetic studies are designed to investigate the association between 
genetic factors (genotypes) and clinical assessments (phenotypes) which are collected during 
the clinical trial. Alternatively, if the number of subjects enrolled in the study is too small to 
complete proper statistical analyses, these data may be combined, as appropriate, with those 
from other studies to enlarge the data set for analysis. 
9.5.8 
Pharmacogenomics 
The analysis of pharmacogenomic data (miRNA) will be performed by the Biomarker 
Development group. Quality control of all individual samples and molecular data will be 


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conducted. The analysis of genomic data per se will be assisted by the use of “in house’ and 
commercial expert applications and databases. A range of statistics based approaches will be 
applied to the data. 
9.5.9 
Biomarkers 
NT-proBNP will be collected in all patients at Visits 1, 101/102 (whichever occurs first), 103, 
199/201, 203 and 205. Additional biological markers will be collected in a subset of patients. 
For the FAS, summary statistics by treatment group will be performed for the baseline values, 
the post-baseline values, and the change from baseline, with biomarker baseline defined as 
values at Visit 101 or 102, whichever occurs first. 
9.6 
Interim analyses 
One interim analysis for efficacy is planned. The cut-off time for this interim analysis will be 
when about two-thirds of the target number of primary events have been reported and 
adjudication-confirmed, approximately 1231 of adjudication-confirmed composite of 
hospitalizations for HF and CV death. In the interim analysis, the analysis dataset will 
comprise all patients who were randomized before the cutoff date. Bonferroni multiplicity 
adjustment will be adopted for the statistical comparisons between treatments. An alpha of 
0.001 (one-sided alpha) will be spent for the comparison of primary endpoint at the interim 
analysis and the rest of alpha  (one-sided 0.024 for the current specified boundary) will be 
utilized for it at the final analysis. In the interim analysis, the study may be stopped for 
superior efficacy only when the primary endpoint and CV death both are significant at level of 
0.001 (one-sided). 
If the study is stopped early for claiming superior efficacy at the interim analysis, the 
secondary endpoints will be tested using the same hierarchical testing procedure as described 
before with an overall alpha level used for the primary endpoint at the interim analysis  (one-
sided alpha of 0.001 for the current specified boundary).  
Interim safety assessments are planned to be performed every six months. No further alpha 
adjustment will be made for these interim safety assessments. 
Interim analyses will be performed by an independent statistician who will not be involved in 
the trial conduct. The results will be reviewed by the independent DMC. 
9.7 
Sample size calculation 
9.7.1 
Sample size for the primary analysis 
Sample size is calculated through simulations for the proportional rates model. The control 
group rate of total hospitalizations for HF and rate of mortality are estimated in two steps in 
order to get a reasonable estimate for the selected patient population.  
First we estimate the rates from the candesartan group of the CHARM-Preserved study 
(Yusuf et al 2003) for patients with EF >45%, using a joint model that joins the Poisson 
regression model and the exponential regression model together through a shared gamma 
frailty (Cowling et al 2006). An independent uniform censoring on the events are assumed 
during the follow-up. With the given frailty between HF hospitalization and CV death, the 


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estimated baseline intensity in the Poisson model= 0.00032 HF hospitalizations/day per 
patient and the estimated hazard rate in the exponential model = 0.000136 CV deaths/day per 
patient. The estimated gamma shape parameter (the frailty parameter that is also assumed to 
be 1/scale) is 0.193. These specified parameter values produce approximately an annualized 
rate of 0.083 for time to first primary event and an annualized rate of 0.036 for CV mortality.  
Second, we adjust these estimated rates up by 8% (and then increasing the corresponding 
Poisson intensity rate and hazard rate) based on the results from the recent completed HF 
studies and publications, which are believed to reflect a higher risk patient population than 
that in the CHARM-Preserved study. This leads an annualized rate of 0.09 for time to first 
primary event and an annualized rate of 0.04 for CV mortality for a high risk patient 
population.  
The target reduction in RR for the primary endpoint is chosen to be about 22%, which 
approximately corresponds to a reduction of 30% for HF hospitalization and a reduction of 
10% for CV death, given the gamma frailty defined above between these two components. 
With the CHARM-Preserved data structure for EF >45%, the specified rates will produce an 
approximately 15% reduction for time-to-first event analysis, see Table 9-1. 
The patient enrollment is assumed to be uniform lasting 2 years and 5 months and the 
minimum follow-up is to be 2 years and 2 months. 
In Table 9-1, sample sizes and powers are estimated through simulations for the framework 
defined above. Three thousand trial replicates are generated for each scenario with different 
sample sizes in the simulations. Both the power and type I error rate are estimated for the 
selected proportional rates model (LWYY). For our study, with a one-sided alpha level of 
0.025, a total of 4600 patients will provide more than 90% of power for the LWYY method. 
This will require approximately 1847 primary events (see the row in table below with sample 
size = 4600 and HR = 0.9 and RR = 0.7). The type I error rates were preserved well in the 
cases we examined. 
Table 9-1 
Sample size and power estimations through simulations 
Sample 
size 
Simulation specs 
Expected  
no. of composite 
events 
Estimated HR or RR 
Power 
HR for 
death 
RR for total 
hosp for HF 
 
Time to 1st 
composite 
event 
LWYY 
LWYY 
 4600 
0.9 
0.7 
1847  
0.859 
0.778 
0.95  
 
 
0.75 
1882  
0.881 
0.814 
0.85  
 
1.0 
0.7 
1846  
0.876 
0.784 
0.94 
 
 
0.75 
1885  
0.900 
0.822 
0.82  
3000 simulation runs were performed for each scenario. 
9.7.2 
Sample size re-estimation 
A blinded sample size re-estimation will be considered around the time at the efficacy interim 
analysis. The pooled intensity/hazard rates for hospitalization for HF and CV death will be 


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estimated using the same joint shared-gamma-frailty model (with one treatment group) used 
for the simulations for the sample size calculations in the above sections. The differences 
between the model parameter estimates used for the sample size calculations and the new ones 
obtained in the interim analysis will then be evaluated. Sample size simulations based on the 
new estimates will be performed using the same assumptions used in the initial sample size 
calculations. The new sample size and/or the duration of follow up will be determined based 
on the new simulations in order to preserve the target power and to achieve the required 
number of events in an acceptable timeframe. 
9.7.3 
Powers for the secondary analyses 
9.7.3.1 
Power for change in KCCQ clinical summary score at 8 months 
For the change from randomized treatment epoch baseline to Month 8 in clinical summary 
score assessed by KCCQ, the planned sample size will provide 83% power to detect a 
treatment difference of 2 points at the two-sided significance level of 0.05, assuming a 
standard deviation of 22 (observed in PARADIGM study). This estimation has taken into 
consideration that approximately 10% of patients may be excluded from analysis due to no 
KCCQ assessment done, based on PARADIGM experience. 
9.7.3.2 
Power for NYHA class 
From the PARAMOUNT (CLCZ696B2214) study, which is the phase II pilot study with a 
similar HFpEF population, after 9 months of treatment with valsartan, the incidence rates in 
each category distribute as follows in Table 9-2. 
Table 9-2 
PARAMOUNT NYHA incidence rates 
 
LCZ696 
Valsartan 
 
Baseline 
Class I 
Class II 
Class 
III/IV 
Baseline 
Class I 
Class II 
Class 
III/IV 
Class I 
1 ( 0.8) 
0 ( 0.0) 
1 (100.0) 
0 ( 0.0) 
1 (0.8) 
0 ( 0.0) 
1 (100) 
0 ( 0.0) 
Class II 
100 (78.7) 
16 (16.0) 
80 (80.0) 
4 ( 4.0) 
102 (81.6) 
9 ( 8.8) 
89 (87.3) 
4 ( 3.9) 
Class III 
26 (20.5) 
0 ( 0.0) 
13 (50.0) 
13 (50.0) 
22 (17.6) 
0 ( 0.0) 
8 (36.4) 
14 (63.6) 
From this table, there are approximately 7% of patients (16/100=16% vs. 9/102=8.8%) within 
class II and 14% of patients (13/26=50% vs. 8/22=36.4%) in class III improved from baseline 
to 9 months endpoint in LCZ696 compared with valsartan.  
Our power evaluation is based on this data and takes the incidence rates in valsartan group as 
the rates in the comparator group. A one-sided alpha of 0.025 is used to control the type I 
error. Table 9-3 shows powers for a sample size of 4600 patients. 
Table 9-3 
Powers for NYHA class comparisons 
 
Improved from Baseline to endpoint in Class III 
Improved from baseline to 
endpoint in Class II 
10% 
12% 
14% 
16% 
5% 
98% 
99% 
99% 
>99% 
7% 
>99% 
>99% 
>99% 
>99% 


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Improved from Baseline to endpoint in Class III 
9% 
>99% 
>99% 
>99% 
>99% 
The results in this table are based on simulations with 100000 replicates. 
9.7.3.3 
Power for composite renal endpoint 
With an expected hazard reduction of 30% (LCZ696 over valsartan) in composite renal 
endpoint, an annual first occurrence of renal events rate of 0.63% (or 1%), an average follow-
up of 3.375 years, and a two-sided alpha of  0.05, forty-six  hundred patients will provide a 
power of  36% (or  52%). When the hazard reduction is about 35%, forty-six hundred patients 
will provide a power of 47% (or 66%) when the annual event rate is 0.63% (or 1%). Note that 
the power provided here is conditional power, when the null hypotheses for the primary 
endpoint, the secondary endpoints of KCCQ change and NYHA class change at month 8 are 
all rejected. 
The power estimations are mainly based on data observed from recently completed 
PARADIGM-HF trial. In that trial, the observed annual event rate for composite renal 
endpoint is 0.63% and the hazard reduction of LCZ696 over enalapril is 37%. 
9.7.3.4 
Power for all-cause mortality 
With a reduction of 20% in mortality, an annual all-cause mortality rate of 5% (25% increase 
from CV mortality), an average follow-up of 3.375 years, and a two-sided alpha of 0.05, 
forty-six hundred patients will provide a power of 81%. When the reduction is about 15%, 
forty-six hundred patients will provide a power of 56%. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented 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 Code of Federal Regulations Title 
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), 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/Research Ethics Board (IRB/IEC) approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should 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 (i.e., all of the procedures described in the 


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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 should be informed that taking the study drug 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 should not 
be entered in the study. 
This study includes an optional pharmacogenetic and pharmacogenomic component which 
requires a separate signature if the patient agrees to participate.  It is required as part of this 
protocol that the Investigator presents this option to the patient at all participating sites where 
this component of the study is conducted.  The process for obtaining informed consent should 
be exactly the same as described above for the main informed consent. 
Declining to participate in pharmacogenetic and/or pharmacogenomic assessments will in no 
way affect the patient’s ability to participate in the main research study.  
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or ethics committee approval will be 
obtained. 
10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. 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 Clinical 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 
Novartis assures that 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. 


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11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the 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 it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
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. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations. 
12 
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life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J 
Heart Fail; 9(1):83-91. 
Li QH, Lagakos SW (1997) Use of Wei-Lin-Weissfeld Method for the Analysis of a 
Recurring and Terminating Event. Statistics in Medicine 16:925-940. 
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functions of recurrent events. J R Stat Soc; B, 62:711–730. 
Mangiafico S, Costello-Boerrigter LC, Andersen IA, et al (2012) Netural endopeptidase 
inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular 
therapeutics. Eur Heart J; 34:886-893. 
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management of arterial hypertension: the Task Force for the Management of Arterial 
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Martinez-Rumayor A, Richard AM, Burnett JC, Januzzi JC (2008) Biology of the natriuretic 
peptides. Am J Cardiol; 101(sup):3A-8A. 
Massie BM, Carson PE, McMurray JJ, et al for the I-PRESERVE Investigators (2008) 
Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med; 
359(23):2456-67. 
Masson S, Latini R, Anand IS, et al for the Val-HeFT Investigators (2008) Prognostic value of 
changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure 
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enalapril in heart failure. N Engl J Med; 371(11):993-1004. 
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infarction complicated by heart failure, left ventricular dysfunction, or both: the VALIANT 
echo study. Eur Heart J; 30:56-65. 
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individual patient data meta-analysis. Eur Heart J; 33(14):1750-7. 
Neaton JD, Gray G, Zuckerman BD, et al (2005) Key issues in end point selection for heart 
failure trials: composite end points. J Card Fail; 11(8):567-75. 
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of carvedilol on the morbidity of patients with severe chronic heart failure: results of the 
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activity in heart failure with preserved ejection fraction. Circulation; 126(7):830-9. 
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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 for the CHARM Investigators and Committees (2003) 
Effects of candesartan in patients with chronic heart failure and preserved left-ventricular 
ejection fraction: the CHARM-Preserved trial. Lancet; 362:777-781.  
Ziegler P, Glotzer T, et al (2012). Detection of previously undiagnosed atrial fibrillation in 
patients with stroke risk factors and usefulness of continuous monitoring in primary stroke 
prevention. Am J Cardiol; 110:1309-1314. 
Zile MR, Gottdiener JS, et al (2011) Prevalence and significance of alterations in cardiac 
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Zuccalà G, Onder G, Marzetti E,et al; GIFA Study Group (2005) Use of angiotensin-
converting enzyme inhibitors and variations in cognitive performance among patients with 
heart failure. Eur Heart J;26(3):226-33. 
13 
Appendix 1: Clinically notable laboratory values  
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 
14 
Appendix 2: Liver event definitions and follow-up 
requirements 
Table 14-1 
Liver event definitions 
 
Definition/ threshold 
AE of special interest 
 
Laboratory values 
ALT or AST > 3 x ULN 
 
ALP > 2 x ULN 
 
TBL > 1.5 x ULN 
Medically significant event 
 


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(SAE) 
Laboratory values 
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction]) 
 
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction]) 
 
TBL > 3 x ULN 
 
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and 
TBL > 2 x ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 x ULN) 
AEs 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT 
* 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 
Table 14-2 
Liver event follow up requirements 
Criteria 
Event type 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
 
ALT or AST 
> 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 5 to ≤ 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 x ULN 
accompanied by 
symptomsb 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 x ULN  
AESI 
Central laboratory to report to 
Investigator discretion 


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Criteria 
Event type 
Actions required 
Follow-up monitoring 
(patient is 
asymptomatic) 
Investigator & Novartis 
Repeat LFT once or twice in the 
week 
If elevation persists, establish 
causality 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 3 x ULN  
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
ALP (isolated) 
> 5 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, report to 
Novartis as an SAE 
Establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
> 2 to ≤5 x ULN  
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
week. If elevation persists, 
establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 2 x ULN  
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
TBL (isolated) 
> 3 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 3 x ULN 
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Novartis 
Repeat LFT once or twice in the 
week. If elevation persists, 
establish causality 
investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 1.5 x ULN 
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
Preferred terms 
Jaundice 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize the patient 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
“Drug-related 
hepatic 
Medically 
significant 
Discontinue the study drug  
hospitalization if clinically 
Investigator discretion 


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Criteria 
Event type 
Actions required 
Follow-up monitoring 
disorders - severe 
events only” SMQ 
AE 
appropriate 
Report to Novartis as an SAE 
Establish causality 
a Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN 
b General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia 
c 
Resolution is defined as an outcome of one of the following: return to baseline values, stable 
values at three subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a 
maximum of 6 months, liver transplantation, and death. 
15 
Appendix 3: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 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) 
• Confirm potassium concentration in a non-hemolyzed sample 
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
tomatoes, coffee, etc.)  
• Correct metabolic acidosis if necessary.  
• 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: 
o MRAs (if they are believed to be the most likely cause of hyperkalemia) 
o Potassium-sparing diuretics (e.g. amiloride and triamterene) including in 
combination products with thiazide or loop diuretics  
o Potassium supplements, e.g., potassium chloride 
o Salt substitutes  


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o Non-steroidal anti-inflammatory drugs (NSAIDs) 
o Cyclo-oxygenase-2 (COX-2) inhibitors 
o Trimethoprim and trimethoprim-containing combination products, such as 
Bactrim® and Septra® (trimethoprim/sulfamethoxazole fixed combination) 
o 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 
• 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.  
• 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 drug, 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 drug 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 drug 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 drug 
• Confirm potassium concentration in a non-hemolyzed sample 
• Urgently evaluate patient and treat hyperkalemia as clinically indicated  
• Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L (mEq/L) 
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee. 
16 
Appendix 4: Guidelines for the management of blood 
pressure  
Guidelines 
1. 
Investigator should monitor BP closely  
2.  
If symptomatic hypotension occurs: 
a. Correct any treatable cause, e.g. hypovolemia 


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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 drug is 
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 drug 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. 
17 
Appendix 5: 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 baseline (Visit 1) (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 
Action situation  
If a patient’s eGFR decreases by ≥40% from baseline (Visit 1) (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 drug. If the investigator judges that 
study drug has to be stopped, he/she will have to contact the Novartis medical monitor or 
his/her designee. Thereafter, serum creatinine assessments will have to be repeated at least 


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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. 
18 
Appendix 6: Blood log for PK sample collection 
 
Visit 
Visit name 
Timepoint 
Volume 
Sample 
Number 
Dose 
reference ID 
199  
Treatment run in 
Predose 
2 mL 
1 
1 
203a 
Week 16 
0 hours pre-
dose 
2 ml 
2 
2 
203b 
Week 16 
0.5 - 2 hours 
post-dose 
2 ml 
3 
2 
203c 
Week 16 
3-5 hours 
post-dose 
2 ml 
4 
2 
205a 
Week 48 
0 hours pre-
dose 
2 ml 
5 
3 
205b 
Week 48 
0.5 - 2 hours 
post-dose 
2 ml 
6 
3  
205c 
Week 48 
3 - 5 hours 
post-dose 
2 ml 
7 
3  
a, b, c: If the samples are not collected at Visit 203, the samples at the same time points can be 
collected at Visit 205 

SAP_001.pdf: 
Clinical Development
LCZ696D
Clinical Trial Protocol CLCZ696D2301 / NCT01920711
A multicenter, randomized, double-blind, parallel group, active-
controlled study to evaluate the efficacy and safety of LCZ696 
compared to valsartan, on morbidity and mortality in heart failure 
patients (NYHA Class II-IV) with preserved ejection fraction
RAP Module 3 – Detailed Statistical Methodology
Author:
Document type:
RAP Documentation
Document status:
Amendment 3
Release date:
May 28, 2019
Number of pages:
58
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
1
Introduction .........................................................................................................................9
2
Analysis set..........................................................................................................................9
3
Subgroup definitions and subgroup analyses ....................................................................11
3.1
Subgroups ..............................................................................................................11
3.2
Subgroup analyses .................................................................................................12
4
Definitions of baseline, post baseline, analysis cut-off, and close-out..............................13
5
Missing date handling........................................................................................................15
6
Subject disposition, background and demographic characteristics, medical history ........16
6.1
Subject disposition.................................................................................................16
6.2
Background and demographic characteristics .......................................................17
6.3
Medical history......................................................................................................18
7
Study medication...............................................................................................................18
7.1
Run-in phase..........................................................................................................18
7.1.1
Duration of treatment exposure.............................................................18
7.1.2
Dose level..............................................................................................20
7.2
Double-blind phase................................................................................................20
7.2.1
Duration of treatment exposure.............................................................20
7.2.2
Dose levels ............................................................................................21
7.2.3
Other exposure analyses........................................................................22
7.2.4
Treatment exposure in subgroups .........................................................22
7.3
Study exposure.......................................................................................................23
8
Concomitant medication....................................................................................................24
9
Efficacy evaluation............................................................................................................25
9.1
Event counting for efficacy ...................................................................................25
9.2
Variables................................................................................................................25
9.3
Statistical hypothesis, model, and method of analysis ..........................................28
9.3.1
Primary analysis....................................................................................28
9.3.2
Secondary analysis................................................................................35
9.3.3
Exploratory analysis..............................................................................39
9.3.4
General handling of missing data in the efficacy analyses ...................46
10 Safety evaluation ...............................................................................................................47
10.1
Allocation of AEs ..................................................................................................47
10.2
Analysis for the identified and potential risks in the risk management plan.........48
10.3
Adverse events (AEs) ............................................................................................50


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10.4
Laboratory data......................................................................................................51
10.4.1
General laboratory data.........................................................................51
10.4.2
Specific laboratory data.........................................................................52
10.5
Vital signs..............................................................................................................52
10.6
Electrocardiogram (ECG)......................................................................................53
11 Resource utilization...........................................................................................................53
12 Interim analyses.................................................................................................................53
13 Power and sample size considerations ..............................................................................54
13.1
Power for the primary endpoint.............................................................................54
13.2
Sample size re-estimation......................................................................................55
13.3
Power for secondary endpoints..............................................................................55
13.3.1
Power for the change in KCCQ clinical summary score at 8 months...55
13.3.2
Power for NYHA class..........................................................................56
13.3.3
Power for composite renal endpoint .....................................................56
13.3.4
Power for all-cause mortality................................................................57
14 References .........................................................................................................................57


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Document History – Changes compared to previous version of RAP module 3 (Final 
Draft version 1.0, October 16, 2013).
Version
Date of 
change
Page
Changes
Final version 
2.0
(Amendment 
1 to Final 
Draft 1.0, 
dated Oct 16, 
2013)
9/15/20
16
7
(Analysis sets) Several items in exclusions from analysis sets due 
to PDs have been changed due to the changes in the PD list and 
the reconsideration of the analysis sets.
10
(Subgroup analyses) Subgroup defined by the randomization 
baseline eGFR values and NYHA classifications are added; 
Definition of regions has been changed according to the countries 
involved in the study. 
12
Baseline for biomarkers has been corrected to visit 101/102. 
MMSE has been added to the list to be collected at randomization 
baseline.
Analysis cut-off date has been updated for the new sample size.
10
South Africa and Israel have been moved to Asia/Pacific and 
other under the new definition of region.
Slovenia is added to Central Europe. Countries not participating 
the study are removed.
15, 
16, & 
21
The ACEi intolerant subgroup summary for background and 
demographic characteristics has been removed. Baseline LVEF 
<= median subgroup summary has been added.
17 to 
19
The exposure duration calculation formulas for the dose level 2 in 
sub-run-in phase have been corrected.  The dose level 3 was 
erroneously included in the calculation for the run-in and has 
been removed. More exposure duration analyses for dose down-
and up-titration are added.
20
Formula of “Daily dose for each patient” are updated to reflect 
BID.
24 to
26
Secondary analysis (based on the protocol amendment 2):
(1) The extended composite endpoint variable (CV death, total 
HF hospitalizations, total non-fatal strokes, and total non-fatal 
MIs) and time to new onset Atrial fib are moved to the 
exploratory analysis from the secondary analysis; KCCQ 
clinical summary score at month 8 and time to 1st composite 
renal impairment endpoint have been added to the secondary 
analysis. In total we still have four secondary endpoints.
Exploratory analysis:
(2) The extended composite endpoint variable is added;
(3) Number of worsening HF events or CV death per-subject has 
been replaced by number of total worsening HF events and 
CV death per-subject. The definition of worsening HF event is 
given;
(4) Number of days alive and out of hospital (DAOOH) during the 
randomized, double-blind study period and percentage of 
DAOOH over potential follow-up time is added;


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(5) Time to 1st occurrence of composite renal impairment event is 
removed;
(6) Time to new onset AF is moved here;
(7) Number of ICU stays is added;
(8) Cardiac related biomarkers are added to the analysis list;
(9) Change from baseline in MMSE summary score at year 2 
(week 96) is added;
(10) Indicator of presence of AF >5 minutes (for the AF substudy) 
is removed;
(11)AF burden measured by the total AF duration over total 
monitoring time is removed
(12)Echocardiographic parameters (in a subset of patients) are
removed.
27
The 0.02499 in “The primary hypothesis will be tested at a one-
sided significance level of 0.02499 adjusted for the interim 
analysis.” has been corrected to 0.024. Nelsen-Aalen estimate 
has been moved to Page 30.
27
In the primary analysis model, “ties = breslow” has been changed 
to “ties = efron” as requested by the FDA. The general baseline 
rate and hazard functions are changed to constant baseline rate 
and hazard in the joint shared frailty model, to simplify the 
modeling based on the experience from PARADIGM-HF. Piece-
wise constant baseline rate and hazard functions will be used for 
the sensitivity analysis. The BIC criterion will be used to select the 
number of pieces. The marginal time-to-CV death analysis has 
been added to use Cox’s regression analysis. The following 
sentence “The inference on the total HF hospitalizations can only 
be made when both the composite endpoint and the total HF 
hospitalizations itself showed statistically positive results” has 
been removed in order to reduce the confusion about how to 
make the primary inference.
31
A new supportive analysis of performing the LWYY model on HF 
hospitalizations alone has been added. A pooled-weighted effect 
size from this analysis and the Cox’s regression analysis on CV 
death has also been added.
32
R codes for multi-state model have been modified.
On-treatment LWYY analysis is added as supportive analysis to 
the primary efficacy.
33 to 
35
Due to the change in the secondary objectives, the endpoints and 
the testing scheme in the multiple hypotheses testing procedure 
for the secondary efficacy analysis have been changed
accordingly. 
35 to 
36
The analysis specifications for the KCCQ CSS (mean change and 
responder analyses) at Month 8 have been added. The analysis 
for composite renal impairment has been added. The analyses for 
the extended composite endpoint and new onset AF have been 
removed from secondary analyses.
Missing NYHA class change due to death will be imputed as 
worsened.


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37 to 
43
For the exploratory analyses, the following analyses are updated
according to protocol amendment (PA) 2:
1.
Time to new onset AF;
2.
Time-to-recurrent-composite event of CV death, total HF 
hospitalizations, total strokes, and total MIs;
3.
Analyses for changes in health-related quality of life 
change (KCCQ scores and EQ-5D);
4.
Analysis for rate of change in eGFR;
5.
Analysis of biomarkers;
6.
Analysis of days alive out of hospital;
7.
Analysis of MMSE;
8.
Analysis of count data.
The details for the analysis for MMSE are added.
The subgroup analysis for MMSE is also specified.
39
Analysis related to pharmacokinetics parameters are added. 
45
In Table 10-2:
1.
Hyperkalemia related AE by baseline hyperkalemia status 
is removed.
2.
Symptomatic hypotension related are removed.
3.
Cutoff for SBP is updated to 100 from 90 mmHg.
4.
Risks deleted: gastric lesions, stimulation of lipolysis, QT-
prolongation.
5.
Risks added: embryo-fetal toxicity/lethality, 
neonatal/infantile toxicity, statin drug-drug interaction.
47
Analysis for cognitive impairment has been explicitly listed in the 
analysis for change in cognitive function.
50 to 
51
For interim analysis, the following modifications have been made 
according to the protocol amendments (PA) 2 and 3.
1.
Move the interim efficacy analysis to occur after 
approximately two-thirds of the target number of primary 
composite events (i.e., ~1231 primary composite events) 
rather than half as previously defined; (PA 2)
2.
Eliminate the futility analysis; (PA 2)
3.
The statistical stopping rules for superiority of LCZ696 
over valsartan is modified from one-sided p-value of 
<0.0001 for the primary endpoint to one-sided p-value of 
<0.001 for both the primary endpoint and CV death at the 
interim efficacy analysis. (PA 3)


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51, 52
According to the protocol amendment 3, the total sample size has 
been readjusted from 4300 to 4600 to increase the statistical 
power from 81% to close to 85% to detect a 25% reduction in 
recurrent heart failure hospitalizations. The sample size re-
estimation was based on a recent analysis on recurrent heart 
failure hospitalization in the PARADIGM-HF, which showed that 
LCZ696 resulted in approximately a 25% reduction in recurrent 
heart failure hospitalizations relative to enalapril. The target 
number of primary events is also increased to 1847, which 
corresponds to conducting the interim efficacy analysis when 
~1231 primary composite events have been confirmed by 
adjudication. As described in Table 13-1, a 25% reduction in 
recurrent heart failure hospitalizations is expected to correspond 
to an overall 19% reduction in the primary endpoint (CV deaths 
and total recurrent heart failure hospitalization). 
53, 54
For the secondary endpoints, the powers are also updated 
according to the new sample size.
54
Reference of Andersen and Gill (1982) is added.
Amendment 
of final 
version 2.0 
(Amendment 
2 to Final 
Draft 1.0, 
dated Oct 16, 
2013)
8/1/201
8
10
Slovenia is added to Central Europe. Countries not participating 
the study are removed.
20
Formula of “Daily dose for each patient” are updated to reflect 
BID.
32
On-treatment LWYY analysis is added as supportive analysis to 
the primary efficacy.
39
Analyses related to pharmacokinetics parameters are added. 
45
In Table 10-2:
1.
Hyperkalemia related AE by baseline hyperkalemia status 
is removed.
2.
Symptomatic hypotension related are removed.
3.
Cutoff for SBP is updated to 100 from 90 mmHg.
4.
Risks deleted: gastric lesions, stimulation of lipolysis, QT-
prolongation.
5.
Risks added: embryo-fetal toxicity/lethality, 
neonatal/infantile toxicity, statin drug-drug interaction.


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Version
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Amendment 
3 
(Amendment 
3 to Final 
Draft 1.0, 
dated Oct 16, 
2013)
5/28/20
19
10
(Table 2-1) Protocol deviations leading to exclusion from analysis 
sets are updated. 
Removed:
1.
History of severe pulmonary disease (exclusion criteria);
2.
LVEF ≥45% not measured by echocardiogram (echo) 
during the screening epoch, or within 6 months prior to
Visit 1 (inclusion criteria);
3.
Lack of evidence for left atrial (LA) enlargement or left 
ventricular hypertrophy (LVH) as defined by the protocol
(inclusion criteria).
Added:
1.
Most recent LVEF measured <45 by ECHO, or LVEF % 
not measured;
2.
NYHA class I Visit 1.
11
(Subgroup analyses) Subgroup of atrial fibrillation based on 
history prior to randomization is added in addition to the existing 
atrial fibrillation based on ECG at randomization.
14
Analysis cut-off date information is added.
32
Analysis of time to first primary composite event (CV death or 
hospitalization for HF) was added as supportive analysis to the 
primary efficacy objective. Analysis includes:
1.
Cox proportional hazards model;
2.
Additionally, Log-rank test will be performed.
34
CV death component in primary LWYY analysis is replaced with 
the following as supportive analyses to the primary efficacy 
objective:
1.
Death due to CV or unknown cause;
2.
All-cause death. 
Time-dependent systolic blood pressure (SBP) covariate adjusted 
LWYY and Cox analyses are added as supportive analyses to the 
primary efficacy objective.
39
Component analysis (joint frailty model) for item 2 is removed.
41
Pharmacokinetics related analyses will be presented in a 
separate report.
42
The subgroup analysis for MMSE is specified with more 
interaction terms.
48
In Table 10-2:
1.
Risks deleted: change in bone growth/bone mineral 
density.
2.
Risks updated or added: neonatal/infantile toxicity 
through exposure from breast milk, 
anaphylaxis/anaphylactoid reactions, malignancy.
55
Table 13-1: one typo is corrected. 
#
Besides the above noted changes, some minor edits to the text 
are also made to correct some words or order of texts.


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Statistical and analytical plans
1
Introduction
Data will be analyzed according to the data analysis section 10 of the study protocol which is 
available in Appendix 16.1.1 of the CSR.  Important information is given in the following 
sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
2
Analysis set
The following analysis populations will be defined for statistical analysis:

Screened set (SCR) – All patients who signed the informed consent. The screened set  
includes only unique screened patients, i.e., in the case of re-screened patients only the 
chronologically last screening data is counted. 

Enrolled set (ENR) (run-in phase) – All patients who received at least one dose of 
run-in study drug. 

Valsartan run-in set (VRS) – All patients who are in the ENR and received at least 
one dose of run-in valsartan.

LCZ696 run-in set (LRS) – All patients who are in the ENR and received at least one 
dose of run-in LCZ696.

Randomized set (RAN) – All patients who received a randomization number, 
regardless of receiving trial medication.

Full analysis set (FAS) – All randomized patients. This is the primary efficacy 
population applied in efficacy analyses for all efficacy endpoints. Following the intent-
to-treat principle, patients are analyzed according to the treatment they have been 
assigned to at randomization. However, patients who did not qualify for randomization 
but were inadvertently randomized into the study and did not receive study medication 
may be excluded from FAS. Further exclusions from the FAS may only be justified in 
exceptional circumstances (e.g., serious GCP violations). These potential incidences 
imply the possibility that the FAS may be smaller than the RAN.

Per protocol set (PPS) – A subset of the FAS, consists of all randomized patients in 
FAS who received at least one dose of study drug during the double blind period of the 
study and have no major protocol deviations. Major protocol deviations are those
affecting the primary endpoint analyses, which will be identified prior to the final 
database lock.

Safety set (SAF) – All randomized patients who received at least one dose of study drug
during the double blind period of the study. Patients will be analyzed according to 
treatment received. Treatment received will be considered identical to the randomized 
treatment if the patient has received at least one dose of the randomized treatment.


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The following Table 2-1 contains a sample of current study specific important protocol 
deviations that lead to exclusion from analysis sets in the study. The final list may be different 
from this and will be signed before DBL.
Table 2-1
Specification of protocol deviations which lead to exclusion from 
analysis sets
Category
Description of Protocol 
Deviation 
Inclusion / 
Exclusion in 
analyses
Identification 
method 
Person 
responsible for 
identification
General
GCP issue present at site
Excluded from 
PPS,FAS
Manual
Field monitor 
(FM)
Blind broken locally
Excluded from 
PPS
Manual
FM
Informed consent missing 
Excluded from 
PPS, FAS, SAF, 
RAN
Manual
FM
Study 
treatment
Patient randomized but no 
study medication taken.
Excluded from 
SAF
Programmable
TDM
Patient was mis-randomized 
(patient randomized in error 
and no DB study medication 
taken).
Excluded from 
PPS, FAS, SAF 
Manual
FM
Exclusion 
criteria
History of dilated 
cardiomyopathy, including 
peripartum
cardiomyopathy, 
chemotherapy induced 
cardiomyopathy, or viral
myocarditis.
Excluded from 
PPS
Manual 
FM
Heart transplant or 
ventricular assistance device 
(VAD) or intent to transplant 
(on transplant list) or implant 
a VAD
Excluded from 
PPS
Manual
FM
Inclusion 
criteria
NYHA class I at Visit 1
Excluded from 
PPS
Programmable
TDM
Most recent LVEF measured 
<45 by ECHO, or LVEF % 
measured by non-ECHO 
methods
Excluded from 
PPS
Manual
FM
Lack of 1) HF hospitalization 
(defined as HF as the major 
reason for hospitalization or 
treatment for HF lasting ≥12 
hours and including 
intravenous [IV] diuretics at a 
healthcare facility) within 9 
months prior to Visit 1, OR  
2) lack of elevated NT-
Excluded from 
PPS
Manual
FM


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Category
Description of Protocol 
Deviation 
Inclusion / 
Exclusion in 
analyses
Identification 
method 
Person 
responsible for 
identification
proBNP > 300 pg/ml for 
patient not in AF on Visit 1 
ECG or > 900 pg/ ml for 
patient in AF on Visit 1 ECG
3
Subgroup definitions and subgroup analyses
3.1
Subgroups
Subgroups will be formed for the analyses for the FAS or SAF depending on the parameters 
under consideration to explore the consistency of treatment effects and safety profiling between 
the subgroups and the overall population. 
In general, subgroups will be defined based on baseline information. In this study, since we 
have a run-in phase to test patients’ tolerability to the study drugs before they can enter the 
double-blind phase, we have defined two baselines (Section 4): the run-in baseline and the 
double-blind baseline. Subgroups may be formed using one of these baselines according to their 
analysis purposes. 
In Table 3-1, we have listed all subgroups defined for this study and the ways to derive them. 
In different analysis, such as efficacy analysis or safety analysis, a different subset of them will 
be selected. Also note that only important parameters or variables in these analyses may have 
subgroup analyses. The details about the parameters having subgroup analyses will be presented 
in the corresponding sections below. Also, additional subgroups may be formed later for 
regional or country-wise analyses per request for exploratory purposes.
Table 3-1
Specification of subgroups
Subgroup 
Method of 
Derivation  
Disposition 
/Background 
& demo. 
/Exposures
Efficacy
(Primary and 
secondary)
Health 
economics 
(KCCQ and 
EQ-5D 
only)
Safety
Age groups: <65, 
≥65; <75, ≥75 years
Screening
x
x
x
x
Gender
Screening
x
x
x
Race (Caucasian, 
Black,  Asian, 
Other)  
Screening
x
x
x
Region *
Derived 
(pooled 
countries or 
country), using 
x
x
x
x


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Screening 
data
Diabetic at baseline 
(yes/no) 
Randomizatio
n (Derived)
x
x
Baseline LVEF  ≤ 
median,>median
Screening
x
x
Atrial Fibrillation
based on ECG at 
baseline: yes/no
Randomizatio
n
x
x
Atrial Fibrialtion 
based on prior 
history at baseline: 
yes/no
Randomizatio
n
x
x
Baseline NT-
proBNP:  ≤ median 
and > median
Screening
x
x
SBP ≤ 
median,>median
Screening
x
Use of Aldosterone 
antagonist at 
baseline: yes/no
Randomizatio
n (Derived)
x
x
ACEi intolerant: 
yes/no
Screening
x
Baseline eGFR (<60 
vs ≥60 mL/min/1.73 
m2)
Randomizatio
n (Derived)
x
NYHA classification 
at baseline I/II vs 
III/IV
Randomizatio
n
x
UK
x
* North America: USA, Canada
Latin America (including Central America): Argentina, Brazil, Colombia, Guatemala, Mexico, Peru 
Western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, 
Norway, Spain, Sweden, Switzerland, UK
Central Europe: Bulgaria, Croatia, Czech Republic, Hungary, Poland, Rep. of Slovakia, Romania, 
Russia, Serbia, Turkey, Slovenia
Asia/Pacific and other: Israel, South Africa, Australia, China, India, Japan, Rep of Korea, Philippines, 
Singapore, Taiwan. 
3.2
Subgroup analyses
Subgroup analyses will be performed depending on the analysis purposes. Subgroups selected 
and types of analyses are specified in Table 3-1 and will be detailed later in the sequel sections. 
In principle, there will be no adjustment for multiple comparisons for subgroup analyses.


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4
Definitions of baseline, post baseline, analysis cut-off, and 
close-out
Single-blind run-in phase (Treatment run-in epoch)
The single-blind run-in phase (or run-in phase) is defined as the period between the start of the 
study drug (in general it should be Visit 101 or Visit 102) and the time prior to randomization
(Visit 201). The run-in phase will be divided further into the valsartan run-in phase and the 
LCZ696 run-in phase. The start of the valsartan phase is the date the patient receives the run-in 
dose of valsartan. In principle, the day before a patient receives the first dose of LCZ696 (any 
dose level) will be the end of the valsartan run-in phase and the day the patient receives the first 
dose of LCZ696 will be the start day for the LCZ696 run-in phase for that patient. If the date of 
the start day of receiving LCZ696 is missing, then the date of Visit 103, which is the protocol 
specified run-in drug switching day, will be used as the start date for the LCZ696 phase. If the 
date of the last dose of valsartan run-in medication falls on the same day of the first dose of 
LCZ696 run-in medication, this day will be considered the end of the valsartan run-in phase 
and the following day will be considered as the start of the LCZ696 run-in phase. The LCZ696 
run-in phase ends at the time when the patient receives the randomization drug. During these 
two run-in phases, patients will be on the run-in medications in a single blind manner.
Randomized treatment phase
The randomized treatment phase begins at the time of randomization and ends with the last 
study drug intake or the death of the patient, whichever comes earlier. During the randomized 
treatment phase, patients will return for scheduled clinic visits. For all related safety analyses 
randomized treatment starts with the first intake of randomized, double-blind study drug. 
Temporary discontinuation of the study drug will not be counted as randomized treatment phase 
discontinuation. 
Post-randomized treatment phase
The post-randomized treatment phase (usually after unscheduled, permanent study drug 
discontinuation) begins after last study drug intake + 1 day and ends on the date last seen (or 
vital status confirmed by indirect contact).
Double-blind (DB) phase (Randomized treatment epoch)
The double-blind phase is the combination of the randomized treatment phase and the post-
randomized treatment phase.
Baseline for run-in phase 
The treatment run-in baseline is defined as the last available measurement prior to or at time of 
Visit 101 or Visit 102, whichever is earlier. For some parameters, values may be only collected 
at screening (Visit 1). For them the treatment run-in baseline will be at screening.


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Baseline for double blind phase
The baseline for the double blind phase is defined depending on the parameter considered. In 
general, the baseline for the double blind phase is defined as the last available measurement 
during the LCZ696 run-in phase and randomization (generally Visit 199 or Visit 201). For the 
parameters that are not designated to have measurements collected during the LCZ696 run-in 
or randomization, the run-in baseline may be used as the baseline for the double blind phase. 
The following parameters will have the double blind phase baseline at randomization visit:
NYHA class, HF signs and symptoms, vital signs, waist/hip circumference, eGFR, safety 
laboratory values, endpoints, 1st morning urine (sub-study patients only), lab assessments, 
patient global assessment (it is assumed that patients will assess their health status comparing 
to that at randomization), KCCQ  scores and EQ-5D assessments and MMSE.      
The following parameters will have their double blind phase baseline measured only at 
screening visit (Visit 1), i.e., prior or at Visit 101 or 102:
Height, (HF, diabetes, liver, and other) medical histories, demography, echocardiogram, and 
inclusion/ exclusion criteria.
NT-proBNP will be collected in all patients at Visits 1, 101/102 (whichever occurs first), 103, 
199/201, 203 and 205. Additional biological markers will be collected in a subset of patients. 
For these biomarkers, the baseline will be defined as values at Visit 101 or 102, whichever 
occurs first.
Unscheduled visit
Only for the analysis of safety laboratory evaluation will unscheduled measurements be taken 
into account. For efficacy evaluations, measurements from unscheduled visits will generally 
not be used, unless specifically specified.
Analysis cut-off date (Study endpoint for analysis)
The trial was designed to be terminated when 4600 patients have experienced a total of about 
1847 confirmed primary composite events of heart failure hospitalization and CV death. If the 
assumptions of the study design were kept unchanged, the analysis cut-off date will be a 
predicted date when either the targeted 4600 patients have experienced 1847 primary composite 
events during a period of 2.42 years of enrollment plus 2.17 years of minimum follow-up or a 
study termination date has been decided based on other study termination decisions. Analysis 
cut-off date is determined to be Apr 30, 2019 based on prediction analysis.
Final visit
The final visit will be the last time a patient’s study record has been taken. For a patient who is 
still alive and in the study the final visit will be his/her last clinical visit. For a patient who died 
or is determined to be lost to follow-up before the analysis cut-off date, the final visit will be 
his/her death/lost-to-follow-up day. For a patient who is alive but no longer has regularly 
scheduled clinic visits and whose study records only can be obtained by telephone or indirect 
contact, the final visit will be the day the study records being taken.


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Close-out
Close-out is a final study period (about two-to-three months) consisting of arranging patients’ 
final visits and completing study conduct, starting from the date (close-out date) when all the
study sites are informed to schedule patients’ final visits for those still alive.  The close-out 
process will start before the analysis cut-off date. The final visit for each patient may occur 
prior to or immediately after the analysis cut-off date, depending on the timing the final visits 
can be scheduled in each site.
5
Missing date handling
Visit date missing
In any analysis or evaluation, if the visit date(s) is used but is missing, then the date(s) calculated 
based on the planned date(s) in the schedule specified in the protocol should be used to impute 
the missing date(s).
Event date missing or partially missing
If the date of an event is not known or is incomplete, the imputation rules are:
a) If the day of the event is unknown, then the 15th day of this month will be imputed for a 
missing day;
b) If only the month is unknown, then July will be used for imputation of the missing;
c) If only the year of the event is known, then the 1st of July will be imputed for a missing day 
and month;
d) The above rules are only for general case. If there is additional information available for the 
missing date, then the information should be used and the imputation of missing date should 
be treated differently. For example, if an event occurs between two visits and its date is 
missing, then the date in the middle of these visits may be used.
Medication stop date missing
If medication stop date is unknown or is incomplete, the imputation rules are:
a) If only the day field of the drug stop is missing, then the missing date is imputed by using 
the 15th of the month;
b) If year and month are missing, then use the next scheduled visit date (using the protocol 
specified visit schedule) from the previous last non-missing visit date to replace the missing 
drug stop date;
c) If the drug stop date is completely missing, then:
a.
If patient had fatal AEs (identified  as either start or end date is equal to the date of 
death and the AE is flagged as an SAE), handling rules are (in the specified order):
i. AE end date is not missing: use the AE end date to replace the missing drug 
stop date;


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ii. AE end date is completely missing but AE onset date not missing: use the 
AE onset date to replace the missing drug stop date;
iii. AE end date is partially missing (only day field is missing): use Novartis 
standard procedure to impute the AE end date, and then use the imputed AE 
end date to replace the missing drug stop date;
iv. AE end date is completely missing and AE onset date is partial missing 
(missing the date field only): impute the AE onset date using Novartis 
standard procedure, and then use the imputed AE onset date to replace the 
missing drug stop date;
v. If both AE onset and end dates are completely missing, then use the last 
previous non-missing visit date plus 35 days to replace the missing drug stop 
date.
b. If patients had no fatal AEs, handling rules are the same with the case where year 
and month are missing.
6
Subject disposition, background and demographic 
characteristics, medical history
6.1
Subject disposition
The number and percentage of patients successfully screened will be presented. In addition, the 
reasons for screen failures will be provided. For patients who are screened more than once, the 
information from the last screen will be used in the summary. The analysis set is the SCR.
The number and percentage of subjects enrolled, completed, and failed in run-in will be 
summarized for the valsartan run-in and LCZ696 run-in separately. The reasons for run-in 
failures will be provided. The analysis set is the ENR. The same information for the valsartan 
run-in phase (VRS) and the LCZ696 run-in phase (LRS) will also be summarized.
The number of subjects randomized (RAN) and included in the full analysis set (FAS) will be 
presented by treatment group. The number and percentage as well as the reasons that subjects 
had been excluded from the RAN will be summarized by treatment group. The number and 
percentage of subjects in the FAS who completed the study (“Study completer” see Figure 6-
1), who discontinued the study and the reasons for discontinuation will be presented for each
treatment group. The number and percentage of subjects with protocol deviations as well as the 
criteria leading to exclusion from analysis sets will be presented in separate tables for the FAS. 
Study completer is defined as the one died or having vital status available after the close-out 
date.
Furthermore, the number of subjects enrolled and randomized per region and per country will 
be presented descriptively for the ENR and the FAS, respectively.
Figure 6-1
Definition of study completer
Last visit after start of close-out = completer


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Died before close-out = completer
Died during close-out = completer
Follow-up* obtained during close-out w/o office visit = completer
No follow-up* at least to start of close-out = lost to follow-up
Run-in
Close-out
CD
BL
Randomization
Start of 
close-out
Analysis 
cut-off
*: Follow-up means patient’s vital/medical status information. It may be obtained through indirect contact.
As described in Section 3, the disposition analysis will be repeated for the following subgroups:

Age group <65, ≥65 years

Age group <75, ≥75 years

Gender (male, female)

Race (Caucasian, Black, Asian, Other)

Region

Baseline LVEF <=median, > median
6.2
Background and demographic characteristics
For the run-in phase, summary statistics will be provided by total number of patients based on 
the ENR for background and demographics, disease characteristics, and cardiovascular risk 
factors for the run-in phase baseline, including the following parameters: age, age group (<65 
years vs. ≥65 years; <75 years vs. ≥75 years), sex, race, ethnicity, weight, height, body mass 
index (BMI) (mean summary and frequencies in ≤30, >30 and ≤35, and > 35), category of prior 
CHF medication, prior HF hospitalization, etiology of HF (ischemic vs. non-ischemic), NYHA 
class, NT-proBNP, BNP, history of MI, history diabetes, history of hypertension, device use, 
eGFR (mean summary and frequencies in < 60 and ≥ 60), LVEF (mean summary and 
frequencies in < 50 and ≥ 50), vital signs, and echocardiography parameters. BMI will be 
calculated as weight (kg) / height2 (m2) from the collected height and weight at Visit 1 
(Screening Visit).
Similarly, for the double blind phase, summary statistics will be provided by treatment group 
and total based on the FAS for the above mentioned parameters plus: category of other select 
cardiovascular medications, duration of heart failure, medical history (including history of MI, 
diabetes mellitus, hypertension, atrial fibrillation/flutter, stroke). The summary will be based 
on the data collected at the double blind phase baseline, if available. Biomarkers will use their 
baseline at Visit 101/102.


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Continuous variables will be summarized using n, mean, standard deviation, median, minimum, 
the first quartile, the third quartile, and maximum. For in-text tables, minimum and maximum 
will not be presented. Categorical variables will be summarized using frequency and percentage.
As described in Section 3, the background and demographic characteristics analysis will be 
repeated for the following subgroups and for the FAS:

Age group <65, ≥65 years

Age group <75, ≥75 years

Gender (male, female)

Race (Caucasian, Black, Asian, Other)

Region

Baseline LVEF <=median, > median
For baseline comparability analysis, categorical variables will be analyzed by Cochran-Mantel-
Haenszel Chi-square test (Fleiss 1981) and continuous variables will be analyzed by F-test. The 
results of these analyses will be presented in Appendix 16.1.9 only. For categorical variables, 
the number and percentage of subjects with missing data will be provided but those subjects 
who are included in the missing category will not be in the denominator for the Cochran-
Mantel-Haenszel Chi-square test.
Note that these tests of comparability are performed for descriptive purposes only, and will not 
serve as a basis for determining entry of explanatory variables into the respective models.  
However, when these tests yield statistically significant results referring to a p-value less than 
0.05, they can be used as supportive information in interpreting the statistical analyses 
performed on the primary and secondary efficacy variables.
6.3
Medical history
Any condition entered on the relevant medical history / current medical conditions CRF will be 
coded using the most updated version of MedDRA dictionary. Medical history includes heart 
failure history and cardiovascular disease history, and other medical history in this study, which 
are collected at Visit 1 (Screening visit). The number and percentage of subjects with each 
medical condition will be provided by treatment group and system of organ class for the ENR 
set and for the FAS set.
7
Study medication
7.1
Run-in phase
7.1.1
Duration of treatment exposure
The duration of the run-in study treatment exposure will be summarized (n, mean, standard 
deviation, minimum, Q1, median, Q3 and maximum) by treatment in a sequential manner: the 
valsartan run-in phase (VRS) followed by the LCZ696 run-in phase (LRS) and (frequency and 


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percentage of patients) by exposure duration category in each phase. The exposure duration 
categories are defined for each phase as:
For the valsartan run-in phase:

0 days 

0 - 1 week 

1 - 2 weeks

>2 weeks
For the LCZ696 run-in phase:

0 days 

0 - 1 week 

1 - 2 weeks

2 – 4 weeks

> 4 weeks 
The valsartan run-in phase, as defined in Section 4, starts at the date when the patient receives 
the run-in valsartan and ends at the day prior to receiving LCZ696 or when the patient 
discontinued, whichever comes first. The LCZ696 run-in starts at the date when the patient 
receives the run-in LCZ696 and ends at the day prior to randomization or when the patient 
discontinued, whichever comes first. 
The mean duration of each run-in treatment phase (valsartan and LCZ696) will be computed 
based on each sub run-in set for overall duration and for each up-titration dose levels 1 and 2
(40 mg BID, 80 mg BID, and 80 mg matching placebo BID for valsartan; and 50 mg matching 
placebo BID, 100 mg matching placebo BID, and 100 mg BID LCZ696, respectively) using the 
following algorithm: 

Overall valsartan run-in: valsartan run-in treatment duration (days) = min(date the 
patient died in run-in, date failed in valsartan run-in, date received the first run-in 
LCZ696 drug – 1) – date received the first run-in valsartan + 1;

Overall LCZ696 run-in: LCZ696 run-in treatment duration (days) = min(date the patient 
died after receiving the first run-in LCZ696, date failed in LCZ696 run-in, date 
randomized –1) – date received the first run-in LCZ696 + 1.
In each sub run-in phase:
•
Run-in dose level 1 for valsartan: Run-in dose level 1 valsartan treatment duration (days) 
= min(treatment start date of valsartan run-in dose level 2 medication – 1, date run-in 
failure date, date died) – run-in valsartan dose level 1 medication date + 1;
•
Run-in dose level 2 for valsartan: Run-in dose level 2 valsartan treatment duration (days) 
= min(treatment start date of LCZ696 run-in dose level 2 medication – 1, date run-in 
failure date, date died) – run-in valsartan dose level 2 medication date + 1;


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•
Run-in dose level 2 for LCZ696: Run-in dose level 2 LCZ696 treatment duration (days) 
= min(randomization date – 1, date failed run-in, date died)  – run-in LCZ696 dose level 
2 medication date + 1.
Time from the first study dose to its first top dose will also be summarized for valsartan and 
LCZ696, if necessary.
The above specified analysis will be repeated for the SAF to investigate the run-in drug 
administration profile for patients who eventually enter the double blind phase.
7.1.2
Dose level
Doses and dose levels in the run-in phase are:
Table 7-1
Study drug dispensed for the treatment run-in epoch by study visit 
Study visit
Dose level
LCZ696
Valsartan
101a
1
50 mg matching placebo b.i.d.
40 mg b.i.d.
102
2
100 mg matching placebo b.i.d.
80 mg b.i.d.
103
2
100 mg b.i.d.
80 mg matching placebo b.i.d.
Number and percentage of patients will be summarized by dose level (or visit) and treatment.
This analysis will be repeated for the SAF.
7.2
Double-blind phase
7.2.1
Duration of treatment exposure
The duration of the treatment exposure for a patient, regardless of temporary interruptions of 
usage of the study drug, is defined as 

date of last study drug intake – first study drug date (usually the randomization date) + 
1.

Duration of the treatment exposure will be summarized by treatment group descriptively 
(i.e. n, mean, standard deviation, min, Q1, median, Q3, max) and the number 
(percentage) of patients will be summarized by exposure duration category:

< 2 week   

2 to < 8 weeks   

8 weeks to < 4 months   

4 months to < 1 year  

1 to < 2 years 

2 to < 3 years 

3 to < 4 years 

4 to < 5 years 

> 5 years.


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Overall patient-years on-treatment and average patient-years on-treatment will be computed 
based on the duration of the treatment exposure as follow: Overall patient years 
= 
25
.
365
/
1

n
i
i
exposure
treatment
of
duration
,
where n is the total number of patients in the SAF. Average patient-years on-treatment = overall 
patient-years on-treatment/n.  They will be summarized by treatment group.
The durations on each dose level, time from randomization to the first dose down-titration, and 
time from the first dose down-titration to the start of the next up-titration for patients with dose 
down- and up-titration will also be summarized by treatment group. 
Duration of total exposure to study drug (excluding interruptions) will be computed as 

date of last study drug intake – first study drug date (usually day after randomization 
date) + 1 – number of days of treatment interruption.
The duration of total exposure to study drug will be summarized by treatment group (mean, 
standard deviation, median, minimum and maximum) as well as frequencies per duration 
category defined below. 

< 2 week   

2 to < 8 weeks   

8 weeks to < 4 months   

4 months to < 1 year  

1 to < 2 years 

2 to < 3 years 

3 to < 4 years 

4 to < 5 years 

> 5 years  
Percentage exposure to study drug for each patient is defined as the ratio of the total exposure 
to study drug divided by the treatment exposure x 100. The percentage exposure to study drug
will be summarized by treatment group (mean, standard deviation, median, minimum and 
maximum).
The time from randomization to the permanent discontinuation of study drug, excluding 
treatment discontinuation caused by death, will be summarized by Kaplan-Meier curve by 
treatment group.
7.2.2
Dose levels
Doses and dose levels in the double blind phase are:


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Table 7-2
Study drug dose levels during randomized treatment epoch
Dose level
LCZ696 Treatment Arm
Valsartan Treatment Arm
3
200 mg b.i.d. 
160 mg b.i.d. 
2
100 mg b.i.d. 
80 mg b.i.d. 
1
50 mg b.i.d. 
40 mg b.i.d. 
Average dose and dose level will be summarized by visit and overall study and treatment group 
(mean, standard deviation, median, minimum and maximum). Average dose will be calculated 
as, in each treatment group, at a given visit: 
Sum of reported doses (including zero dose for interruption) / Total number of patients.
The formula for the average dose level is similar. The overall average (daily) dose will be 
calculated as:
1. Daily dose for each patient = 
∑
(.	 
  
  )×(
  ×)


∑
(.	 
  
  )


2. Average daily dose for each patient over patients in each treatment group.
For the average overall dose level, the formula is similar, replacing “dose level i×2” “ by i.
Frequency and percentage of patients at each dose level will be summarized by visit and 
treatment group. 
The last recorded treatment on the drug administration form will be presented with the number 
and percentage of patients on each dose level, including off-treatment. The average dose related 
to the last recorded treatment will be also be summarized by treatment group, for both cases of 
including all patients in the SAF and excluding off-treatment patients. 
7.2.3
Other exposure analyses
The number and percentage of patients with down titrations will be summarized together with 
the study specific reasons for down titration. This summary will be repeated for down titrations 
to no treatment.
The number and percentages of treatment interruption episodes and the reasons for permanent 
treatment discontinuation and treatment interruption episodes (any and >14 days) will be 
summarized by treatment group.
7.2.4
Treatment exposure in subgroups
The above treatment exposure analyses in Section 7.2.1 will be repeated for the following 
subgroups:

Age group <65, ≥65 years

Age group <75, ≥75 years

Gender (male, female)

Race (Caucasian, Black, Asian, Other)

Region


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
Baseline LVEF <=, > median 
7.3
Study exposure
As defined before (Section 4) the double-blind study phase = the on-randomized treatment 
phase + the post-randomized-treatment phase. The study exposure here means the exposure for
the double blind study phase. The summary of the exposure for the study phase will be 
computed for the FAS.
The duration of the on-treatment phase exposure (duration of study drug exposure, regardless
of temporary discontinuation of study drug) will be computed for the FAS using the following 
formula:

Date of last study drug intake – randomization date + 1.
The duration of the post-treatment phase will be computed for patients in the FAS who complete 
the last scheduled visit of the double-blind phase or have the vital status available using the 
following algorithm:

Duration of the post-treatment phase (days) = date last seen (or vital status confirmed 
by indirect contact) - date of the visit at which the study medications was permanently 
stopped + 1
The overall duration of the double blind study phase will be computed for patients in the FAS.

Duration of the double blind study phase (days) = date last seen (or vital status 
confirmed by indirect contact) – randomization date + 1
The durations of the on-treatment, post-treatment phase, and overall double blind study phase 
will be summarized by treatment group (n, mean, standard deviation, median, minimum Q1, 
Q3, and maximum) and the number and percentage of patients, in terms of the duration of the 
overall double blind study phase, will also be summarized by exposure duration category. 
The study exposure duration categories are defined as 

< 2 week   

2 to < 8 weeks   

8 weeks to < 4 months   

4 months to < 1 year  

1 to < 2 years 

2 to < 3 years 

3 to < 4 years 

4 to < 5 years 

> 5 years  


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8
Concomitant medication
Medications will be identified using Novartis Drug and Therapy Dictionary, NovDTD which is 
a modified Novartis internal version of Q3 2004 WHO Drug Reference List (DRL)   including 
Anatomical Therapeutic Chemical (ATC) code.
For the run-in phase, the run-in concomitant medication information will be summarized based 
on the ENR.
Prior and run-in concomitant medications taken at any time between the screening visit and the 
randomization visit will be summarized in sequential format by treatment of valsartan for the 
VRS and LCZ696 for the LRS based on the latest version of dictionary.  Medications will be 
presented in alphabetical order, by ATC codes and grouped by anatomical main group (the 1st
level of the ATC codes). Tables will show the overall number and percentage of patients 
receiving at least one drug of a particular ATC code and at least one drug in a particular 
anatomical main group. 
Prior medications are defined as drugs taken prior to first dose of run-in study medication. 
Any medication given at least once between the day of first dose of run-in study medication and 
the last day prior to randomization visit will be a run-in concomitant medication, including 
those which were started pre-screening and continued into the run-in phase Prior or run-in 
concomitant medication will be identified based on recorded or imputed start and end dates of 
taking medication. The rules for imputing incomplete (start and end) dates are described in 
Section 5.
The concomitant medication information for the double blind phase will be summarized based 
on the SAF.
Concomitant medications taken at any time since the randomization visit will be summarized 
by treatment group based on the latest version of the dictionary. As before, medications will be 
presented in alphabetical order, by ATC codes and grouped by anatomical main group (the 1st 
level of the ATC codes). Tables will also show the overall number and percentage of subjects 
receiving at least one drug of a particular ATC code and at least one drug in a particular 
anatomical main group. 
Any medication given at least once between the day of first dose of randomized study 
medication and the last day of study visit will be a double-blind concomitant medication, 
including those which were started pre-randomization visit and continued into the double blind 
treatment phase. 
The following important classes of concomitant heart failure and CV medications administered
during run-in and during double-blind phase will be summarized separately in a similar way as 
described above. 
•
ARBs
•
ACE inhibitors
•
Diuretics
•
Beta blockers
•
Aldosterone antagonists    
•
Cardiac glycosides (Digoxin/digitalis glycoside)


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•
Calcium antagonists
•
Other vasodilators 
•
Anticoagulants
•
Antiarrhythmic agents
•
Aspirin
•
Other antiplatelet agents
•
Statins 
•
Nitrates
•
Other lipid lowering agents
The classes of medications will be defined in a separate EXCEL sheet with ATC preferred term
and WHO drug code. This EXCEL sheet will be stored in CREDI at the RAP level after the 
content is agreed to by the Global Program Medical Director (GPMD) and prior to CDBL
9
Efficacy evaluation
Efficacy evaluation will focus on the double blind phase and be based on the FAS. Endpoint 
events collected during run-in will not be utilized in the comparison of the efficacy endpoint. 
The endpoint events related to the primary or secondary objectives collected during run-in will 
be simply summarized with adjustment for treatment exposure duration using the annualized 
event rates, according to the designed sequential sub-run-in periods. In case a baseline is needed 
for the evaluation, the run-in phase baseline will be referred to.
9.1
Event counting for efficacy
All events occurring prior to or at the analysis cut-off date will be included in the efficacy 
analyses.
Only adjudicated and confirmed events will be counted in the primary and secondary analyses. 
Event information received after the analysis cut-off date will not be included in the primary 
and secondary efficacy analyses, but they will be included in the investigator reported event 
analysis.
For a patient who did not complete the study, i.e. who was lost to follow-up or withdrew consent, 
if the vital status for the patient can be retrieved from public information (or vital status can be 
confirmed by indirect contact), the last known alive date defined for the analysis will be the last 
alive date obtained from the retrieved information.
9.2
Variables
The variables defined in this section are only for the double blind period. The baseline referred 
to in the variable definitions below is always the double blind phase baseline, unless otherwise 
indicated. For variables related to changes at Month 8, Month 8 refers to Week 32.


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Primary variable:

Cumulative number of primary composite events, i.e., the composite events of (total) 
HF hospitalizations and CV death, for a given subject, over time.
Secondary variables:

Change from baseline in KCCQ clinical summary score at Month 8;

Change from baseline to Month 8 NYHA class;

Time from randomization to first occurrence of composite renal endpoint event, defined
as either:
o
Renal death, or
o
a 50% decline in estimated glomerular filtration rate (eGFR) relative to 
baseline, or
o
reaching end stage renal disease (ESRD);

Time to all-cause mortality.  
Exploratory variables:

Cumulative number of events of the extended composite endpoint of CV death, total HF 
hospitalizations, total non-fatal strokes, and total non-fatal MIs, for a given subject, over 
time;

Change in clinical composite assessment (NYHA, global patient assessment, and 
clinical events defined as CV death and HF hospitalization) at Month 8;

Patient global assessment at Month 8;

Changes from baseline in health-related QoL (assessed by the total score, clinical 
summary score, and individual scores of the sub-domains from the KCCQ and 
assessments of the EQ-5D for health status);

Number of HF events per-subject; 

Number of total worsening HF events and CV death per-subject. A subject will be 
defined as having a CV death or worsening HF event when the subject has:
1. CV death or
2. A hospitalization for HF or
3. Received intravenous (IV) decongestive therapy (IV diuretics, IV neseritide or other 
natriuretic peptide, IV inotropes, and IV nitroglycerin [NTG]), and does not result 
in formal inpatient hospital admission, regardless of the setting (i.e. in an emergency 
room (ER) setting, in the physician’s office, an outpatient treatment facility, etc.);

Number of all-cause hospitalizations per-subject and number of cause specific 
hospitalizations per-subject;

Number of days alive and out of hospital (DAOOH) at Month 12;


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
Number of days alive and out of hospital (DAOOH) during the randomized, double-
blind study period and percentage of DAOOH over potential follow-up time (defined 
as date of end of study minus date of randomization plus 1);

Rate of change in eGFR (eGFR slope);

Time from randomization to new onset diabetes mellitus (NODM);

Time to new onset of atrial fibrillation (AF);

Number of days staying in intensive care unit (ICU), number of stays in intensive care 
unit (ICU), number of re-hospitalizations for HF, and number of ER visits for HF;

Indicator of 30 day HF rehospitalization (after a prior HF hospitalization during 
double blind phase);

Number of rehospitalizations within 30 days after discharge;

Time between HF hospital readmissions;

Changes in pre-specified biomarkers (e.g., cardiac, vascular, renal, collagen, 
metabolism, and inflammatory biomarkers) from baseline to predefined time-points (in 
a subset of patients);

Variables to characterize the PK of valsartan, AHU377, and LBQ657 at steady-state in 
patients receiving LCZ696 using population modeling and/or non-compartmental 
based methods;

Change from baseline in Mini-Mental State Examination (MMSE) summary score at 
year 2 (week 96).
Among the variables above, some of them or their components need to be adjudicated to 
confirm the reported types and occurrences based on the unified criteria for analyses. The 
adjudication of these events is based on an adjudication process through an independent 
Endpoint Adjudication Committee. The following events will be assessed by the Endpoint 
Adjudication Committee during the study:

All death events;

Unplanned hospitalization for HF;

MI;

Stroke;

Renal dysfunction (including occurrence of end stage renal disease);

Others (new onset atrial fibrillation (NOAF), NODM)
In the analysis, as specified before, only adjudicated events will be utilized if the events 
included in the analysis are required to be adjudicated. However, in the sensitivity analysis, the 
investigator reported events may also be used.


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As specified before, all events and endpoints occurred or measured prior to or at the specified 
analysis time-points (such as Month 8, Month 12, etc.), including the analysis cut-off date, will 
be counted, unless otherwise specified.
Censoring variables:
Number of events and time-to-event variable are usually subject to censoring. The censoring 
can be caused by withdrawal of consent, lost to follow-up, other competing events, or 
administrative reasons (interim or analysis cutoff date). Below are the rules for deriving 
censoring variables in the analyses (primary, secondary, exploratory):

For all-cause death, the censoring will occur at minimum (date of withdrawal of consent, 
last known alive date, analysis cutoff date)

For CV death, the censoring will occur at minimum(date of withdrawal of consent, last 
known alive date, analysis cutoff date, date when patient died for non-CV causes)

For a non-mortality and non-composite endpoint, the censoring will occur at 
minimum(date of withdrawal of consent, date of lost to follow-up, analysis cutoff date, 
date when patient died)

For a composite endpoint, the censoring will occur at the earliest censoring date among 
the components.
In some additional analyses, one may be interested in all events occurring before major protocol 
deviations. In such cases, the events occurred after having major protocol deviations need to be 
censored. The censoring variables are:

Minimum (the censoring time defined for the primary, secondary, exploratory analyses, 
date of the first major protocol deviation). 
9.3
Statistical hypothesis, model, and method of analysis
9.3.1
Primary analysis
All adjudication confirmed primary events occurred between randomization and the analysis 
cut-off date will be included in the primary analysis.
9.3.1.1
Analysis for primary endpoint
The primary efficacy endpoint of the study consists of the times to recurrent hospitalization due 
to heart failure and death time due to CV reasons during the patient's follow-up. The 
comparisons between two treatment groups will be made using statistical procedures which deal 
with such multiple event time observations. The semi-parametric proportional rates model 
(abbreviated as LWYY model) (Lin et al 2000) will be utilized for quantifying the treatment 
difference.
Specifically, let (, ) be the individual rate of primary composite events for subject  in 
region , given that the patient has not died from a CV reason at time . It is dependent on the 
time from randomization () and treatment group (). Let  = 1 if the subject is in the 
LCZ696 group and  = 0 if the subject is in the valsartan group. 


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Under the proportional rates model, the individual rate function for the composite endpoint of 
CV death and total HF hospitalizations is assumed to be, #, $ = %()&()exp(*&), 
where %() = 1 if subject  in region  is at risk for HF hospitalization or CV death at time 
and %() = 0 if subject  in region  is censored or died from a CV reason at time  −and 
&() is the baseline rate function for the event in region . (%() = ,(min(0, 1) ≥), 
where 0 and 1 are CV death time and censoring time for subject  in region . ,(. ) is an 
indication function.)
The primary hypothesis to be tested is, H10: *& ≥0 versus H1a: *& < 0, where exp(*&) is the 
relative risk or rate ratio (RR) of total hospitalizations for HF and CV death in the LCZ696 
group relative to the valsartan group given the patient has not died from a CV reason at time , 
which is assumed to be constant over time and across regions. 
The primary hypothesis could be equivalently written as: 
H10: Rate ratio LCZ696/valsartan ≥ 1 versus H1a: Rate ratio LCZ696/valsartan < 1, 
A rate ratio < 1 indicates an effect in favor of LCZ696.
Note that exp(*&) can also be considered as a ratio of two mean cumulative frequencies of a 
subject having hospitalizations for HF and CV death when the rate ratio is constant over time 
and CV mortality is balanced between treatment groups.
The primary hypothesis will be tested at a one-sided significance level of 0.024 adjusted for the 
interim analysis. The rate ratio and its 95% confidence interval will be estimated from the above 
proportional rates model through maximization of a partial likelihood score function. The 
resulting estimate of exp(*&) is identical to the one described by Anderson and Gill (Anderson 
and Gill 1982), but unlike Anderson-Gill, a robust variance estimator (sandwich estimator) is 
used to account for the dependency of within subject events. Note that having CV death is not 
considered as a censoring variable, but as a primary endpoint event and a conditional factor in 
this analysis. The “conditional factor” means that the rate of the composite endpoint at time t is 
evaluated conditional on the patient being at risk of CV death at time . Time to non-CV death 
will be considered as a censoring variable. Any censoring due to non-CV death is assumed to 
be non-dependent in the analysis.
The above presented analysis method based on LWYY provides a treatment comparison based 
on primary endpoint rate ratio conditional on not having died from a CV reason. A marginal 
interpretation of the estimates requires that any censoring of the primary composite events will 
be non-informative and may be challenging if there is an imbalance in CV mortality.
The LWYY analysis can be carried out using the following SAS code:
proc phreg data=primary_data covs(aggregate);
model (time_start, time_rec)*status_rec(0)=treat/ties=efron rl;
id sid1a;
run;
where primary_data is the input dataset, time_start is the previous event stop time and 
time_rec is the current event stop time, the censoring variable status_rec (0 for censored 


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and 1 for event) should take the value 1 if the last event is a CV death and 0 if it is censored for 
any non-CV death reasons for the given patient; sid1a is the subject ID.
As a supportive part of the primary analysis, the two components in the composite endpoint 
(total HF hospitalizations and CV mortality) will be analyzed separately to quantify the 
respective treatment effects and check the consistency between the composite and the 
components. 
For the analysis of total HF hospitalizations component, occurrence of CV death can be 
regarded as semi-competing risk (informative censoring) and may introduce a bias in the 
treatment effect estimate for HF hospitalizations (dilution of effect size if the drug has a positive 
effect on both components). In order to address this concern and to account for the correlation 
between the two components, the joint modeling (frailty model) approach (Cowling et al 2006) 
will be used for the component analyses. The joint model is specified as follows.

4() = % ()&
4exp(*&)5

6 () = %()&
6 exp(7&)5
8
5~ : (. )
where 
4() is the rate function of the total hospitalizations for HF for subject i in region j and  
&
4 is its constant baseline and 
4() has a similar format as the model described above for the 
primary endpoint except for the multiplier 5 that is a subject-specific random effect factor 
(frailty); and 
6 () is the hazard function for the component of CV mortality for subject i in 
region j and  &
6 is its constant baseline and 
6 () is a frailty proportional hazards model. The 
parameter α measures the association between 
4() and 
6 (). The frailty distribution :(∙) is 
taken to be the Gamma distribution with shape = < and scale = 1/<. The parameters in the joint 
model, including the unknown power for the frailty, will be estimated through maximization of 
the corresponding likelihood. The model assumes that the correlation between total HF 
hospitalizations and CV death for each patient is completely explained by  and the frailty 
and the two analysis variables corresponding to the two components are independent given the 
patient’s frailty and .
For the analysis of CV death, it will be analyzed using Cox’s proportional hazards model with 
a fixed treatment group factor and stratified by region. The analysis in the joint frailty model 
for this component, which is actually subject specific, will be considered as supportive for the 
analysis for CV death whenever an inference is needed for it.
In all the proposed analyses, it is acknowledged that the study will not be powered to achieve 
statistically significant results for the CV death. 
The proposed joint frailty model assumes a constant baseline intensity and constant baseline 
hazard model for the recurrent HF hospitalization and CV death components, respectively. The 
marginal model for the recurrent hospitalizations for heart failure of this joint frailty model is a 
negative binomial model. 
As a sensitivity analysis, the constant baseline intensity function &
4 and constant baseline 
hazard function &
> will be replaced by piece-wise constant functions (i.e. multiple-step 


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functions). The number of steps in the step functions will be selected based on the Bayesian 
Information Criterion (BIC). The partitions of these constant step intervals can be obtained 
based on the equally-divided percentiles (Liu and Huang 2008). 
The joint model will be estimated using SAS PROC NLMIXED. The below SAS code
illustrates the program for a piece-wise constant intensity and hazard baseline function with 10 
steps:
proc nlmixed data=data_joint qpoints=5 corr;
parms / data=inpar;
bounds r01 r02 r03 r04 r05 r06 r07 r08 r09 r10 h01 h02 h03 h04 h05 h06
h07 h08 h09 h10 alpha >=0;
/* g is Gamma distributed with mean 1 and variance 1/alpha*/
p=cdf('NORMAL', nu);
if p > .999999 then p=.999999;
g2=quantile('GAMMA', p, alpha);
g=g2 * 1/alpha;
/* baseline hazard and cum baseline hazard, recurrent events */
base_haz_r=r01*event_r1+r02*event_r2+r03*event_r3+r04* event_r4 +
r05*event_r5+r06*event_r6+r07*event_r7+r08*event_r8
+r09 * event_r9 + r10 * event_r10;
cum_base_haz_r=r01*dur_r1+r02*dur_r2+r03*dur_r3+r04*dur_r4 +
r05*dur_r5+r06*dur_r6+r07*dur_r7+r08*dur_r8+r09*dur_r9 +
r10 * dur_r10;
/* baseline hazard and cumulative baseline hazard for death */
base_haz_d=h01*event_d1+h02*event_d2+h03*event_d3+h04*event_d4 +
h05*event_d5+h06*event_d6+h07*event_d7+h08*event_d8+
h09 * event_d9 + h10 * event_d10;
cum_base_haz_d=h01 * dur_d1 + h02 * dur_d2 + h03 * dur_d3 +
h04 * dur_d4 + h05 * dur_d5 + h06 * dur_d6 + h07 * dur_d7 +
h08* dur_d8 +h09 * dur_d9 + h10 * dur_d10;
mu1= beta1 * trt + log(g);/* for recurrent event */
mu2= alpha1 * trt + gamma * log(g); /* for death event */
loglik1=-exp(mu1) * cum_base_haz_r;
loglik2=-exp(mu2) * cum_base_haz_d;
/*log likelihood for recurrent event */
if status_rec = 1 then loglik=log(base_haz_r) + mu1 ;
/*log likelihood for death */
if status_rec = 2 then loglik=loglik1 +log(base_haz_d)+mu2+loglik2;
/*log likelihood for censoring */
if status_rec = 0 then loglik=loglik1 + loglik2;
model time_stop ~ general(loglik);
random nu ~ normal(0, 1) subject = sid1a;
ods output ParameterEstimates=jm.est FitStatistics=jm.fit;
run;


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where data_joint is the input dataset, jm.est and jm.fit for the parameter estimates and 
model fitted statistics. The dataset inpar contains the initial guesses for r01-r10, h01-h10  
and the other model parameters. The input dataset data_joint should include the values of 
event indicators event_r1- event_r10 and event_d1- event_d10  and durations dur_r1-
dur_r10 and dur_d1- dur_d10.
A non-parametric estimate of the primary endpoint event rates (Nelson-Aalen estimates) will 
be provided. Non-parametric estimates of conditional HF hospitalization rates (Nelson-Aalen 
estimates), given the patient has not died due to a CV reason, over time (Cook and Lawless 
1997) and of unconditional HF hospitalization rates over time allowing for death as terminal 
event will be provided as well (Ghosh and Lin 2000).
9.3.1.2
Supportive analyses for primary efficacy
The supportive analyses for the primary analysis results will be performed in two ways: 
1) Evaluating the impact of the informative censoring of CV death on the estimate of the 
relative rate reduction through performing additional analyses including:
a. Checking of existence of any non-negligible imbalance in CV mortality between 
treatment groups through analysis for CV mortality alone. This analysis will be 
performed using Cox’s proportional hazards model for time-to-CV death. If it deems 
necessary, pooling appropriate patient (sub-) population from PARADIGM-HF 
(CLCZ696B2314) and this study will be performed using the same Cox model to 
further assess any adverse signal on CV mortality between treatments;
2) Providing a series of sensitivity analyses to investigate the robustness and consistency of 
the primary efficacy results:
b. Performing the primary analysis (the LWYY model) and the component analyses (the 
joint frailty model) on the PPS;
c. Analysis using the WLW method (Wei et al 1989, Li and Lagakos 1997) on time to 
first (the conventional time-to-first event analysis) and time to 2nd, 3rd, 4th, 5th, and 
6th composite events; an average effect (stratified by event number) will be provided 
for each of those analyses. This analysis will partially evaluate the robustness of the 
overall estimate of effect size against the impact from an (expected) small subgroup of 
patients with higher number of hospitalizations for HF. If the patient's first event is a 
CV death, then his 2nd, 3rd,…, Kth event will be counted as CV death as well. This 
analysis avoids informative censoring by counting CV death repeatedly as event. It is 
acknowledged that some of the analyses, time-to-1st event, for example, may not be 
powered;
d. Analysis using a negative binomial regression model (McCullagh and Nelder 1989) on 
total number of primary composite endpoints with an offset of logarithm of time from 
randomization to censoring or death. The common rate ratio of composite events will 
be provided;
e. Analysis using a multi-state model (Castaneda and Gerritse 2010) to assess the hazard 
ratios of transition intensities between different states defined by hospitalization status 
and CV death;


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f.
Performing the analysis for recurrent heart failure hospitalizations using the same 
LWYY model used for the primary endpoint with the conditional rate ratio. A 
weighted-pooled effect size and its 95% CI, using the results from this analysis and the 
Cox regression analysis for CV death outlined in 1), will also be provided. The 
estimated optimal weights will be obtained through the estimated covariance matrix of 
the two estimates of the component effect sizes.
3) Evaluating treatment effect on time to first primary composite event (cardiovascular death 
or hospitalizations for heart failure). The time to first primary composite event will be 
analyzed using Cox proportional hazards model with treatment as fixed factor and stratified 
by region. Additionally, a 1og-rank test will be performed.
4) Some additional supportive analyses may be performed.
Analysis using the multi-state models
The multi-state model utilized in this study is described in Figure 9-1. The transition intensities 
are defined as follows.
ℎ
@4() = %
4()A&
@4()exp (B) for being hospitalized for heart failure (H) at time  from the 
state of event free (E);
ℎ
@C() = %
C()A&
@C()exp (*) for experiencing CV death (D) at time  from the state of 
event free (E);
ℎ
44() = %
4()A&
44()exp (7) for being re-hospitalized for heart failure (H) at time  after 
being previously hospitalized for heart failure (H);
ℎ
4C() = %
C()A&
4C()exp (D) for experiencing CV death (D) at time  after being 
previously hospitalized for heart failure (H);
where  and  stand for subject  in rejoin , %
∙()s are the at-risk (to D or to H) indicators, and 
 is the treatment group indicator defined above taking value 0 or 1.
Figure 9-1
Scheme of the multi-state model


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In this model, we have assumed that the transition intensities for recurrent hospitalization for 
HF are proportional; and that all transition intensities for recurrent hospitalization for HF to CV 
death are proportional. We have four transition intensities to be modeled.
The data structure for analysis has a form below:
patid time_start time_stop status from
to transition time treatment region
1     0.00        8.70      0      E  H1
E -> H
8.70    1       1
1     0.00        8.70      0      E  D    E -> D   8.70    1       1
2     0.00        6.30      0     E   H1   E -> H 
6.30    0       1
2     0.00      
6.30      1      E  D    E -> D   6.30    0       1
3     0.00        2.25      1     E  H1   E -> H 
2.25    1       2
3     0.00        2.25      0      E  D    E -> D   2.25    1       2
3     2.25        6.75      1      H1
H2   H -> H 
4.50    1       2
3     2.25        6.75      0      H1
D    H -> D   4.50    1       2
3     6.75      11.36      0      H2
H3   H -> H 
4.61    1       2
3     6.75      11.36      0      H2 D    H -> D   4.61    1       2
4     0.00        2.25      1      E   H1   E -> H   2.25    0       2
4     0.00        2.25      0      E   D    E -> D   2.25    0       2
4     2.25        6.75      1      H1  H2   H -> H   4.50    0       2
4     2.25        6.75      0      H1 D    H -> D   4.50    0       2
4     6.75      11.36      0      H2 H3   H -> H   4.61    0       2
4     6.75      11.36      1      H2 D    H -> D   4.61    0       2
where status is 0 for censored and 1 for event.
The below R code can be used for the analysis.
> library(survival)
> fit1 <- coxph(Surv(start, stop, status) ~ factor(transition_trt) + 
cluster(patid) + strata(transition_region) , data=recurent_data)
or 
> fit1 <- coxph(Surv(start, stop, status) ~ factor(trt) + cluster(patid) + 
strata(region) 
, 
data=recurent_data, 
subset=(transition=='E2H'))where 
transition_region is the derived from combination of  transition and region, 
transition_trt is the derived from combination of transition and trt.
On-treatment LWYY analysis 
On-treatment analysis is referring to the supportive analysis for the primary endpoint based on 
the FAS and with events censored after premature discontinuation of study drug. Specifically, 
the patient-specific follow-up period will be truncated at the date of last study drug intake + 29 
days. Accordingly, the date of last study drug intake + 29 days will be used as censoring if 
smaller than the censoring date defined in Section 9.2.
Various death components used in composite endpoint
The LWYY analysis will be repeated replacing the CV death component in the primary 
endpoint with the following (less disease-specific) components as supportive analyses:

Death due to CV or unknown cause;


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
All-cause death
Time-dependent systolic blood pressure (SBP) covariate adjusted analyses
The analyses will be performed as supportive analyses to explore whether the treatment effect 
is driven by SBP changes:

LWYY analysis for the primary composite endpoint of CV death and total heart 
failure hospitalizations;

Cox proportional hazards model mentioned in (3) for the first primary composite 
endpoint. 
9.3.1.3
Subgroup analysis
A full set of subgroups will be performed for subgroup analysis for the primary endpoint and 
its components, as outlined at Section 3. 
Subgroup analyses will be performed for the FAS. To explore beneficial effects in subgroups 
or homogeneity of beneficial effects among subgroups, the estimated rate ratio, two-sided 95% 
confidence interval, and within subgroup p-value and p-value for the test for the treatment-by-
subgroup interaction will be provided for each of the subgroups based on the proportional rates 
model in which treatment, subgroup, and treatment-by-subgroup are included as fixed-effect 
factors. Positive findings from these subgroup analyses have to be interpreted with caution since 
there is a non-negligible chance of false positives. Rate ratios from each subgroup will be 
graphically displayed using a forest plot.
9.3.2
Secondary analysis
9.3.2.1
Multiplicity adjustment among secondary comparisons
The four secondary hypotheses to be tested are:

Comparison of change from baseline in KCCQ clinical summary score at Month 8 (denoted 
as H210);

Comparison of change from baseline to Month 8 NYHA class (denoted as H220, the 
parameter is the category change from baseline to Month 8 in NYHA class);

Time from randomization to first occurrence of composite renal endpoint events (denoted 
as H230, the parameter is the hazard ratio forthe composite renal endpoint events);

All-cause mortality (denoted as H240, the parameter is the hazard ratio for all-cause death).
The secondary null hypotheses will be tested and statistical inferences will be made only if the 
primary null hypothesis is rejected. The four secondary efficacy hypotheses will be tested for 
superiority of LCZ696 to valsartan for the FAS.
The sequentially rejective multiple test procedures (Bretz et al 2009) will be used for testing the 
hypotheses of the primary endpoint and the first three secondary endpoints as indicated in 
Figure 9-2, to control the alpha level. The all-cause mortality (H240) will be tested at a full level 
of alpha, after the rejection of the primary hypothesis, considering as a hard-endpoint. 


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In Figure 9-2, the fractions marked in the graph denote the weights or proportions of alpha to 
be added to the alphas in the next nodes according to where the arrows point once the current 
node of hypothesis is rejected.

The initial allocation of (local) significance levels are α, 0, 0, and 0 for the comparisons of 
the primary endpoint and the first three secondary endpoints, respectively. 

The general algorithm for the testing procedure goes as follows: Test the hypotheses H10, 
H210, H220, and H230 each at its local significance level defined above. If a hypothesis can be 
rejected, reallocate its level to one of the other hypotheses according to a pre-specified rule 
represented by the weighted graph in Figure 9-2. Update the reallocation weights in the 
reduced graph (the rejected hypothesis is removed from the graph) and repeat the testing 
step for the remaining no-rejected hypotheses with the updated local significance levels. 
This possibly leads to further rejected null hypotheses with associated reallocation of the 
local significance levels. The procedure is repeated until no further hypothesis can be 
rejected. The reallocation of the local alpha levels is fully determined by the initial graph 
given in Figure 9-2 and the update algorithm for this sequentially rejective multiple test 
procedure.
o
In the notation of Bretz et al 2009, a weight of ε for an edge indicates an 
infinitesimally small weight. If a hypothesis (vertex) with such an outgoing edge is 
rejected and the vertex removed, no significance level is passed on along such an 
edge as long as there are other outgoing edges with positive weights. If after removal 
of another vertex only infinitesimal outgoing edges remain, then the algorithm of 
Bretz et al 2009 turns them into edges with positive weights that sum to 1. In this 
specific procedure, this implies that no significance level is passed from the 
secondary null hypotheses for KCCQ (H210) or NYHA class (H220) to the secondary 
null hypothesis for composite renal endpoint (H230) until both KCCQ and NYHA 
class null hypotheses have been rejected. To ensure the sum of weights on all 
outgoing edges of a vertex is 1 when such edges are present, some edges are given 
a weight of 1 – ε.



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Figure 9-2
Illustration of weights for alpha relocation in the sequentially rejective 
multiple test procedure for the secondary hypotheses
More specifically, the multiple testing procedure will be carried out in the following steps:
1). First the null hypothesis for the primary endpoint H10 is tested at full alpha (e.g. at 
one-sided level of 0.024). If not rejected, stop; if rejected, go to 2)
2). The null hypotheses for KCCQ (H210) and NYHA (H220) are tested at ½ alpha 
simultaneously. 
a.
If none of them are rejected, stop; 
b. if both of them are rejected, go to 3); 
c.
if only one of them is rejected (e.g. H210 for KCCQ), the other one (e.g. H220 for
NYHA) can be re-tested at full alpha. If this is still not rejected, stop; if this is 
rejected, go to 3);
3). The null hypothesis H230 for composite renal endpoint is tested at full alpha level.
Note: The power analyses for each hypothesis in Figure 9-2 are presented in the sections for the 
sample size discussions. 
For publications the secondary variables may be assessed using a full level of alpha without 
consideration of multiplicity adjustment. 
9.3.2.2
Analysis of change in KCCQ clinical summary score at Month 8
The KCCQ instrument includes multiple domains. Only the domains that address HF symptoms 
and physical limitations will be analyzed for the secondary objective. The clinical summary 
score of KCCQ is computed as the mean of the following two domain scores:

Physical limitation score

Total HF symptom score


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If a patient dies, a worst score (score of 0) will be imputed for the clinical summary score at all 
subsequent scheduled visits after the date of death where the clinical summary score would 
have been assessed.
Changes from baseline in KCCQ clinical summary score at Month 8 will be analyzed based on 
a repeated measures ANCOVA model in which treatment, region, visit, and treatment-by-visit 
interaction will be included as fixed-effect factors and baseline value as a covariate, with a 
common unstructured covariance matrix among visits for each treatment group. Treatment 
comparisons and effect size estimates at Month 8 will be provided. The analysis will be 
performed based on all available data up to Month 8 in the FAS and based on likelihood method 
with an assumption of missing at random (MAR) for missing data.
To investigate the sensitivity of the analysis results based on the MAR assumption, we will
perform an analysis using a pattern mixture model approach which assumes, besides the 
imputation with 0 for the KCCQ scores after death, that missing KCCQ scores after HF 
hospitalizations were missing not at random (MNAR). This sensitivity analysis would first 
create multiple (100) imputations of missing KCCQ values under a MAR assumption, resulting 
in multiple (100) complete data sets. The imputation model assumes a multivariate normal 
model for the 3 KCCQ measurements at baseline, Month 4 and Month 8. This model will be 
estimated separately within each treatment by region stratum.  For each completed data set, the 
imputed values at a given visit of patients who had a HF hospitalization since the preceding 
visit, a penalty factor (<1) would be multiplied to the imputed KCCQ scores to reflect that the 
MAR approach may have overestimated the missing KCCQ values. To the resulting 100 
datasets, the original analysis model described above will be fitted, yielding 100 sets of 
parameter estimates and associated covariance matrices. These are then combined by using 
Rubin’s rules to derive overall estimates, confidence intervals that adequately reflect missing 
data uncertainty as well as associated p-values. The analysis will be repeated for varying penalty 
factors in a range between 0.6 and 1.
In addition, a responder analysis for KCCQ clinical summary score change from baseline at 
Month 8 (defined separately for patients with at least 5 point deterioration and for patients with 
at least 5 point improvement) will be performed using a generalized mixed model with treatment, 
region, visit, and visit-by-treatment as fixed factors and baseline score as covariate, with a 
common compound symmetry covariance matrix among visits for each treatment group.
Treatment comparisons and effect size estimates at Month 8 will be provided. The analysis will 
be performed based on all available data up to Month 8 in the FAS. The goal of the responder 
analysis is to assess the clinical relevance of the difference between the two groups in the mean 
change from baseline. As an additional sensitivity analysis, the above specified analyses will 
also be performed for the missing data due to death without any imputation.
9.3.2.3
Analysis of NYHA class at Month 8
Change from baseline to month 8 NYHA class will be analyzed using a repeated measures 
proportional cumulative odds model. The response variable is the category change from 
baseline to any given time points (4 weeks and 16 weeks) up to Month 8 (32 weeks) (expressed 
as improved, unchanged, worsened). The NYHA class change after patients who have died will 
be categorized into ‘worsened’. The model will include patient as a random effect and the 
randomized treatment phase baseline NYHA class, region, treatment, visit and treatment-by-


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visit interaction as fixed effect factors. This model assumes that the treatment effect sizes across 
measurement categories are the same. The analysis will be performed based on all available 
data up to 8 months in the FAS and based on likelihood method with an assumption of missing 
at random (MAR) for missing data not due to death. The estimated between treatment effect 
(reductions in odds) with the associated two-sided 95% confidence interval at Month 8 will be 
provided. As supportive analysis, the same model will be performed on data with no imputation 
for missing data in NYHA class change due to death.
9.3.2.4
Analysis of time-to-first occurrence of composite renal endpoint event
Time-to-first occurrence of composite renal endpoint events will be analyzed using Cox’s 
proportional hazards model with a fixed treatment group factor and stratified by region. The 
estimated hazards ratio and the corresponding two-sided 95% confidence interval will be 
provided.
The Kaplan-Meier curves by treatment group will be presented. Additionally, the frequency and 
percentage of patients with composite renal endpoint events will be provided by treatment group.
Additional to the above major analysis for the composite renal endpoint, which is based on the 
criterion that dialysis for ≥ 30 days without known recovery of renal function, a supportive 
analysis with the same model defined above will be performed on a further restrictive endpoint 
which requires a verified continuation of dialysis for > 90 days.  
9.3.2.5
Analysis of time to all-cause mortality
As indicated above, all-cause mortality endpoint will be tested at a full level of alpha, after the 
rejection of the primary hypothesis, considering as a hard-endpoint.
It will be analyzed using Cox’s proportional hazards model with treatment factor and stratified 
by region. The estimated hazards ratio and the corresponding two-sided 95% confidence 
interval will be provided. The p-value for the score test will be utilized for inference.
The Kaplan-Meier curves by treatment group will be presented. Additionally, the frequency and 
percentage of all-cause mortality will be provided by treatment group.
9.3.2.6
Subgroup analysis for the secondary endpoints
Subgroup analysis for each of the secondary variables will also be performed similarly as 
described in Section 9.3.1.3 for the primary variable.
9.3.3
Exploratory analysis
In general, exploratory variables (Section 9.2) will be analyzed in the FAS unless specified 
otherwise. Statistical tests will be performed at the two-sided significance level of 0.05. To 
better satisfy the normality assumption, the log-transformation will be applied to data on each 
biomarker prior to statistical analysis. There will be no multiplicity adjustment for analysis of 
exploratory variables.
9.3.3.1
Analysis for time-to-event variables
There are two types of time-to-event exploratory variables:


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
Time-to-first-event variables
o
Time to new onset of DM;
o
Time to new onset of AF event.

Time-to-recurrent-event variable
o
composite endpoint of CV death, total HF hospitalizations, total strokes, and 
total MIs
Time-to-first event variables will be analyzed using a Cox proportional hazards model with 
treatment factor and stratified by region. The estimated hazards ratio and the corresponding 
two-sided 95% confidence interval will be provided. The Kaplan-Meier estimates may also be 
provided by treatment group, in tables and graphs. 
New onset of AF refers to the adjudication-confirmed AF experienced after randomization. For 
this endpoint, only patients who have no investigator-reported medical history of AF prior to 
screening visit and no adjudication-confirmed AF between screening and randomization visits 
will be included in the analysis population. 
For time-to-recurrent-event variable, the composite endpoint of CV death, total HF 
hospitalizations, total strokes, and total MIs will be analyzed using the same proportional rates 
model (LWYY). In the component analysis, the four components will be grouped into two 
components: CV death and the composite of total HF hospitalizations, total strokes, and total 
MIs. The estimated rate ratios and the corresponding two-sided 95% confidence intervals will 
be provided for the composite endpoint and its two grouped components.
9.3.3.2
Analysis of continuous variables
Continuous variables, which can be analyzed using the linear models with or without 
transformation on the responses, are:

Rate of change (slope) in eGFR from baseline to endpoint;

Changes in health-related quality of life (assessed by clinical summary score, total score 
and individual scores of the sub-domains from the KCCQ and scores of the EQ-5D for 
health status (EQ-5D index derived from EQ-5D descriptive system and EQ-5D VAS) 
from baseline to pre-defined time-points;

Changes (in log-scale when skewed) from baseline to pre-defined time-points in pre-
selected biomarkers (e.g., cardiac, vascular, renal, collagen, metabolism, and 
inflammatory biomarkers);

Summarize pharmacokinetics (PK) parameters at steady-state using population 
modelling;

Days alive out of the hospital during the first 12 months (48 weeks), and during the 
entire double-blind period;

Change from baseline in MMSE summary score at year 2 (week 96).


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Analysis for rate of change (slope) in eGFR
For the rate change in eGFR, the eGFR slope will be estimated from a repeated measures 
ANCOVA model including treatment, region, time (when the eGFR is assessed in months), and 
treatment-by-time as fixed effects with random intercept and slope (time) and a common 
unstructured covariance. The least-squared means of slopes for within and between treatment 
groups, and the corresponding two-sided 95% confidence intervals will be provided.
Analysis of changes in health-related quality of life change 
Changes from baseline in KCCQ mean scores (for all 10 scores), similarly for changes from 
baseline in EQ-5D VAS and EQ-5D index (if available), will be analyzed based on a repeated 
measures ANCOVA model in which treatment, region, visit, and treatment-by-visit interaction 
will be included as fixed-effect factors and baseline value as a covariate, with a common 
unstructured covariance matrix among visits for each treatment group. Treatment comparisons 
and effect size estimates, including two-sided 95% confidence intervals, at different visits will 
be provided. The analysis will be performed based on all available data up to 3 years in the FAS 
and based on likelihood method with an assumption of missing at random (MAR) for missing 
data.
In addition, a responder analysis for KCCQ clinical summary score change from baseline at 
various visits (defined separately for patients with at least 5 point deterioration and for patients 
with at least 5 point improvement) will be performed, refer to the section for the analysis for 
categorical data.
In the analyses of the KCCQ scores, including the responder analysis, both the worst-case 
imputation (score of 0) and no imputation for missing data due to death (including subsequent 
visits) analyses will be performed.
For the patients with KCCQ data collected at screening and run-in visits, the above specified 
analyses, including the responder analysis, will be repeated using the run-in epoch baseline. 
Changes from baseline and actual values will also be presented by visit and treatment group for 
KCCQ scores (both from run-in epoch baseline and from randomized epoch baseline) and EQ-
5D (VAS) (from randomized epoch baseline) assessments using descriptive statistics of N, 
mean and SD, and will be graphically displayed using line plots.
Note that since the EQ-5D descriptive system contains ordinal variables (the dimensions of 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with each having 
3 levels (no problems, some problems, severe problems)), besides the continuous scores of 
index and VAS, frequencies and percentages of patients in each category will be provided by 
treatment group and visit.
Analysis in biomarkers
For pre-selected biomarkers, the log-transformed ratio to baseline will be calculated for each 
subject at every post-dose time point i.e. log (post-dose value/baseline). The change from 
baseline to a pre-defined time-point (Week 16 and Week 48) in logarithmic scale will be 
analyzed using a similar repeated measures ANCOVA model as described above. Estimates of 
treatment difference sizes and their two-sided 95% confidence intervals will be provided. These 


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estimates and confidence intervals will be back-transformed for presentation. In addition, the 
following summary statistics will be presented over time by treatment for each variable:

The summary statistics: n, mean, SD, median, minimum, maximum, Q1 and Q3 will be 
presented for the baseline values, absolute post-dose values and change from baseline 
values. 

The geometric mean will be presented for the baseline values, absolute post-dose values 
and for the ratio to baseline values. The geometric mean of the ratio to baseline will be 
presented in terms of % change from baseline and will be calculated as follows:  
(exp(mean of the log-transformed ratio to baseline values) -1)*100

The Coefficient of Variation (CV) will be calculated for the baseline values, the absolute 
post-dose values and the ratio to baseline values.  
Analysis of pharmacokinetics (PK) parameters at steady state
The population-based PK parameters will be summarized at selected time-points by dose-level. 
The analysis set will be those in full analysis set (FAS) who participated in Pharmacokinetics 
sub-study.  

The summary statistics: n, mean, SD, median, minimum, maximum, Q1 and Q3 will be 
presented for the baseline values and absolute post-dose values. 

The geometric mean will be presented for the baseline values and absolute post-dose 
values. 

The Coefficient of Variation (CV) will be calculated for the baseline values and the 
absolute post-dose values.
Analysis of days alive out of hospital
For days alive out of hospital during the first 12 months, it will be treated as a continuous 
variable. The mean difference between treatment groups will be compared using an ANCOVA 
model with factors of region and treatment group. Estimate of treatment difference size and its 
two-sided 95% confidence interval will be provided.
As further exploratory analysis, the total number of DAOOH will be analyzed based on an 
ANCOVA with treatment group, region and potential follow-up time (dependent on time of 
randomization) as covariates. For patients who are lost to follow-up, the potential follow up 
time will be reduced accordingly. The percentage of DAOOH (relative to potential follow-up 
time) will be analyzed based on an ANOVA with treatment group and region as covariates.
Analysis of changes in MMSE summary score at 2 years
The change from baseline in the summary score of MMSE will be analyzed using a repeated 
measures ANCOVA model in which treatment, region, baseline hypertension status, baseline 
diabetes status, visit (Week 48 and Week 96) and treatment-by-visit interaction are included as 
fixed-effect factors and baseline age, MMSE baseline value and visit by MMSE baseline 
interaction as covariates, with a treatment-specific unstructured covariance matrix among visits 
for each treatment group. The adjusted mean changes at week 96 within each treatment, the 
difference in mean changes at week 96 between two treatments, its 95% confidence interval 
obtained from the above model will be presented. The analysis will be performed based on all 


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available data up to 96 weeks for patients with both baseline and at least one post-baseline 
MMSE assessment, and based on likelihood method with an assumption of missing at random 
(MAR) for missing data. In case that if there is any a problem with model convergence, the 
factors of baseline hypertension and diabetes status may be dropped from the modeling.
With a total of approximately 2500 patients expected to be eligible for the above analysis, there 
is more than 90% probability that the lower bound of the 95% confidence interval of the 
between-treatment difference of mean MMSE summary scores at Week 96 is ≥-0.5 (exclude a 
between-treatment difference of 0.5 or more reduction), assuming that there is no true between-
treatment difference and the common standard deviation is 3. A between-treatment difference 
of 0.5 or less is not considered clinically meaningful.
To investigate the sensitivity of the analysis results based on the MAR assumption, analyses 
based on multiple imputations, such as those using a pattern mixture model approach,  may be 
performed, which assumes that missing MMSE scores after death, HF hospitalizations, or stroke 
were missing not at random (MNAR). 
Similar analyses as above will also be performed in the subset of patients who have ApoE4 
genotype assessment done. For these analyses, additional factors such as ApoE4 status (yes/no) 
and the interactions of treatment by ApoE4 status, and ApoE4 by visit may be added in the 
modeling. The ApoE4 gene has been identified as a genetic marker that predicts predisposition 
to cognitive decline and Alzheimer’s disease (Protocol Section 6.6.9.1). This genetic marker is 
assessed at Visit 103 or at any visit thereafter when consent is obtained and is considered as the 
baseline characteristic of participating patient because it is unlikely for such genetic marker to 
change over a short period.  
In addition, changes from baseline in the summary score of MMSE will also be analyzed using 
a repeated measures ANCOVA model in which treatment, geographic region, baseline 
hypertension status, baseline diabetes status, visit (Weeks 48, 96, 144, 192, 240), and treatment-
by-visit interaction are included as fixed-effect factors, and baseline age, baseline MMSE value 
and visit by MMSE baseline interaction as covariates, with a common unstructured covariance 
matrix among visits for each treatment group. Treatment comparisons and effect size estimates 
and their 95% confidence intervals at different visits (only for visits at Week 48, 96, 144) and 
averaged over-all-visits will be provided. The analysis will be performed based on likelihood 
method with an assumption of missing at random for missing data. 
Similar repeated measure ANCOVA model will be fitted in the subgroup of patients who have 
ApoE4 genotype assessment done. 
A descriptive summary of MMSE absolute score and change from baseline over time will be 
tabulated and plotted. Changes in MMSE individual test domain scores from baseline over time 
will be tabulated as well.


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All analyses in MMSE score will be performed in the FAS for patients who have participated 
in the cognitive function assessment sub-study.
9.3.3.3
Analyses of categorical and ordinal variables
Binary variables include:

Indicator of 30 day HF rehospitalization (after a prior in-study HF hospitalization);

Responder for at least 5-point change in deterioration and responder for at least 5-point 
improvement for KCCQ scores. .
The 30-day HF rehospitalization will be analyzed using logistic regression with treatment and 
region as fixed-effect factors. For 30 day hospital readmission, the analysis set will be restricted 
to patients who had hospitalization for HF at least once during double blind period.
The responder analysis for KCCQ score changes from baseline (for both run-in epoch baseline 
and randomized epoch baseline) at various visits (defined separately for patients with at least 5 
point deterioration and for patients with at least 5 point  improvement) will be performed using 
a generalized mixed model with treatment, region, visit, and visit-by-treatment as fixed factors 
and baseline score as covariate, with a common compound symmetry covariance matrix among 
visits for each treatment group. Treatment effect size estimates and 95% CIs at various visits 
will be provided. The analysis will be performed based on all available data up to Year 3 in the 
FAS. 
Ordinal variables include:

Assessment in the clinical composite assessment (improved, unchanged, and worsened) 
at post-randomization visits;

Change in NYHA class from randomization;

Changes in HF signs and symptoms from randomization;

Patient global assessment at 8 months.
The first three variables will be analyzed, at Month 8, 1 year, 2 years, and 3 years, using a 
repeated measures proportional cumulative odds model. The model will include patient as a 
random effect and the randomized treatment phase baseline category (only for NYHA class and 
HF signs and symptoms), region, treatment, visit (all available post-randomization visits) and 
treatment-by-visit interaction as fixed effect factors. This model assumes that the treatment 
effect sizes across measurement categories are the same. The visit-wise effect size estimates 
and their 95% confidence intervals will also be provided. The analysis will be based on all 
available data in the FAS and likelihood method with an assumption of missing at random for 
missing data. The patient global assessment at 8 months will be analyzed similarly but using a 
non-repeated measures proportional cumulative odds model. The SAS procedure of GLIMMIX 
(SAS/STAT 9.3) can be used for the analysis. 
The clinical composite assessment at a selected visit is defined as:

Improved, if i) NYHA class decreases at least one level and Global Assessment is not 
worse at the selected visit and there is no major AE up to the selected visit; or ii) Global 


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assessment is improved and NYHA class does not increase at the selected visit and there 
is no major AE up to the selected visit.

Worsened, if i) NYHA class increases at the selected visit; or ii) Global Assessment is 
worse at the selected visit; or iii) experiences a major AE up to the selected visit.

Unchanged, if neither “Improved” nor “Worsened”. 
For Global Assessment, we converted the seven-category classification (recorded in the eCRF) 
to three-category classification in defining the clinical composite assessment: 

Markedly improved and Moderately improved to Improved; 

Moderately worsened and Markedly worsened to Worsened; 

Slightly improved, Unchanged, and Slightly worsened to Unchanged.
Major AEs are adjudication-confirmed CV death and heart failure hospitalizations.
9.3.3.4
Analysis of count data
Count data include:

Number of HF events;

Number of worsening HF events or CV deaths;

Number of hospital admissions;

Number of days/stays in ICU;

Number of stays in ICU;

Number of re-hospitalizations;

Number of ER visits for HF;

Number of 30 day hospital readmissions (after a prior in-study HF hospitalization).
Count variables will be analyzed using a negative binomial model (McCullagh and Nelder 1989) 
with the count data as the dependent variable and treatment group and region as fixed-effect 
factors and log(follow-up duration) as the off-set. The model estimated event rates 
(intensities/risk rate) and their 95% confidence intervals will be provided by treatment group. 
The treatment comparison will be performed through the estimated ratio of risk rates. The 
estimated reduction in event rate (ratio LCZ696/valsartan) and its 95% confidence interval will 
also be provided. Note that, in case when the follow-up durations depend on the treatments 
(potentially informative censorings), the estimated rate reduction should be interpreted with 
caution. However, when LCZ696 has a reduction in mortality, the rate reduction estimated from 
the negative binomial model will become conservative. As mentioned before, for 30 day 
hospital readmission, the analysis set will be restricted to patients who had hospitalization for 
HF at least once during double blind period. This implies that the baseline treatment group 
balance obtained from the randomization may be broken.
Descriptive statistics (n, mean, standard deviation, median, max, and min) will be provided for 
these variables by treatment group. For each variable, the annualized count for each patient is
calculated as the total counts during the study divided by the total duration of the double blind 


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treatment phase, multiplied by 365.25. The annualized counts will be summarized according to 
treatment groups.
9.3.3.5
Subgroup analysis 
Subgroup of ACEI intolerant patients
The primary and secondary variables as well as the symptom based variables, such as the 
clinical composite assessment, and so on, will also be analyzed using methods proposed above 
for the sub-group of ACEI intolerant patients.
Subgroup analysis for exploratory analysis
Subgroup analysis for the exploratory objectives will be performed for change in MMSE total
score from baseline and the EQ-5D assessments for Region (North America, Western Europe,
Central Europe, and the United Kingdom), age group, diabetes, AF, NT proBNP (<median or > 
median), and use of aldo antagonist at baseline.
9.3.4
General handling of missing data in the efficacy analyses
9.3.4.1
Time to event variables
For time-to-event variables, the censoring rules are presented in Section 9.2.
9.3.4.2
KCCQ clinical summary score
The clinical summary score is a mean of the physical limitation and total symptom scores. The
total symptom score is the mean of the symptom frequency and symptom burden scores. Each 
scale score (the physical limitation, symptom frequency or symptom burden) is calculated as 
the mean of its item scores and transformed to a 0–100 scale, with higher score indicating higher 
level of functioning. A score of 100 represents perfect health whereas a score of 0 represents 
dead. For patients who die, a worst score (score of 0) will be imputed for the clinical summary 
score at all subsequent scheduled visits after the date of death where the clinical summary score 
would have been assessed.
9.3.4.3
NYHA classification change over time
For categorical analysis in NYHA class change from baseline at month 8 or over time, missing 
NYHA classification due to death will be imputed as NYHA class worsened.
9.3.4.4
Other variables
For the variables other than those mentioned above, double blind post-baseline LOCF will be 
utilized for imputing missing data unless specific rules are mentioned in the analysis sections. 
If it deems necessary, multiple imputations method may be used in addition to the available 
data analysis for each variable when the missing at random assumption is considered reasonable.


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10
Safety evaluation
Safety will always be evaluated based on the VRS and LRS for run-in phase and the SAF for 
double-blind phase. Note that, in general, SAF is a subset of LRS and LRS is a subset of VRS.
The safety evaluation will include:

Specific identified and potential risk and safety factors evaluation

Adverse events

Laboratory evaluations 

Vital signs

Electrocardiogram
The following subgroups will be evaluated for safety, except for the specific identified and 
potential risk analysis:

Age group <65, ≥65 years

Age group <75, ≥75 years

Gender (male, female)

Race (Caucasian, Black, Asian, Other)

Region
10.1
Allocation of AEs
For AE reporting, the allocation of an AE in the different treatment phases is shown in Table 
10-1.  
If not otherwise specified (see below specific safety evaluation), all AEs with start date before 
final visit and SAEs within 30 days after final visit will be included in the AE analyses.
Table 10-1
Allocation of AEs
Screening 
(V1)
V101 or 
V102 – V103 
(val run-in)
V103 –
V199 (LCZ 
run-in)
V201(Ran
d) – CMP 
CMP –
CMP + 30d 
(SAE only)
Phase AE to be reported in
X
Reported by the site from Informed 
Consent
X
Report AE in valsartan run-in
X
Report AE in LCZ696 run-in
X
Report AE in DB
X
X2
Report as two separate AEs:
One with onset date X for valsartan run-
in and one with onset date X2 for 
LCZ696 run-in
(X)
X
X2
Report as two separate AEs:


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Screening 
(V1)
V101 or 
V102 – V103 
(val run-in)
V103 –
V199 (LCZ 
run-in)
V201(Ran
d) – CMP 
CMP –
CMP + 30d 
(SAE only)
Phase AE to be reported in
One with onset date X (X) for LCZ696 
(valsartan) run-in and one with onset 
date X2 for DB 
X, X2
Report as one AE:
One with onset date X for DB 
(X)
X
X
Report AE with onset date X (X) in 
LCZ696 (valsartan) run-in
X (SAE)
Report SAE in the 30 days follow-up
(X)
(X)
X
X2 (SAE)
Report as two separate AEs:
One AE with onset date X (X) for DB 
(valsartan or LCZ696 run-in) and one 
SAE with onset date X2 for the 30 days 
follow-up
X and (X) stands for onset and possible onset date of AE, respectively.
X2 stands for same AE but with an increased severity.
10.2
Analysis for the identified and potential risks in the risk 
management plan
The identified and potential risks for LCZ696 are listed in Table 10-2. Besides the specifically 
specified analyses for each risk, which are listed in the table, the following standard analysis 
will be applied to all risks. 
•
Incidence (absolute and relative frequency) rates in terms of patient regardless of study 
drug relationship by treatment group
•
Exposure adjusted incidence rates per 100 patient years regardless of study drug 
relationship, by treatment
•
Listing of subject numbers per risk.
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 risks in 
Table 10-2 are store in the LCZ696 Case Retrieval Strategy (2019).
Table 10-2
Identified and potential risks
Risks
Analysis 
Hyperkalemia
1. Frequency of hyperkalemia leading to treatment interruption and 
discontinuation regardless of study drug relationship, by treatment
2. Categorical analysis with frequency and percentage by treatment for 
patients with serum potassium ≥5.5 mEq/L, >6.0 mEq/L and >6.5 
mEq/L by treatment. 
Hypotension
1. Blood pressure summary (mean, standard deviation, median, and 
range) including measurement at each visit and change from baseline
will be provided by treatment
2. Summary with frequency and percentage by treatment for patients with:
a.
systolic blood pressure (SBP) <100 mmHg; 
b.
30 mmHg drop in SBP; 


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c.
simultaneous SBP <100 mmHg and 30 mmHg drop in systolic 
BP. 
Angioedema
Frequency and percentage by treatment (Standard statistical analysis )
Renal impairment
1. Summary for serum creatinine and eGFR by treatment
2. Summary for frequency and percentage by treatment for patients with: 
a.
eGFR decline by >25%, >40%, >50%, and >30 mL/min/1.73 
m2; 
b.
Serum creatinine increase by >50%; 
c.
Serum creatinine level >0.5 mg/dL, >2.0 mg/dL, >2.5 
mg/dL, >3.0 mg/dL
3. Subgroup analyses on the relationship between eGFR < 60 and >=60 
mL/min/1.73 m2 at baseline and incidence rate/severity of 
AEs/laboratory parameters indicating newly occurred/worsening of 
renal impairment. 
Hypersensitivity
Standard analysis 
Anaphylaxis/anaphylact
oid reactions
Standard analysis
Hepatotoxicity
1. Summary with frequency and percentage by treatment for patients with: 
a.
ALT or AST >3x ULN; 
b.
ALT or AST >5x ULN; 
c.
ALT or AST >8x ULN; 
d.
ALT or AST >10x ULN;
e.
ALT or AST >20x ULN;
f.
ALT or AST >3x ULN and TB >1.5x ULN;
g.
ALT or AST >3x ULN and TB >2x ULN; 
h.
ALT or AST >5x ULN and TB >2x ULN;
i.
ALT or AST >8x ULN and TB >2x ULN;
j.
ALT or AST >10x ULN and TB >2x ULN;
k.
ALT or AST >20x ULN and TB >2x ULN;
l.
ALP > 2 x ULN
m. ALP > 3 x ULN
n.
ALP > 5 x ULN
o.
TB > 1.5 x ULN
p.
TB > 2 x ULN
q.
TB > 3 x ULN
r.
ALP > 3x ULN and total bilirubin > 2x ULN
s.
ALP > 5x ULN and total bilirubin > 2x ULN
t.
ALT or AST > 3x ULN and total bilirubin > 2x ULN and ALP =< 
2x ULN
u.
(ALT or AST > 3x ULN and total bilirubin > 2x ULN and ALP =< 
2x ULN) or reported Hy’s Law case
v.
ALT or AST > 3x ULN and (nausea or vomiting or fatigue or 
general malaise or abdominal pain or (rash and eosinophilia))
w.
TB >3x ULN and AST or ALT are ≤3 x ULN and alkaline 
phosphatase ≤1.5x ULN; 
x.
AP >3x ULN and AST, ALT, TB are within normal range. 


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2.
A cross-tabulation of baseline and worst post-baseline values by below, 
within and above normal range categories will be provided. Shift tables 
will be provided for the parameters AST, ALT, TB and AP.
Embryo-fetal 
toxicity/Lethality
Standard analysis
Neonatal/infantile
toxicity through 
exposure from breast 
milk
Standard analysis
Statin drug-drug 
interaction
Standard analysis for patients who take statin during randomized treatment 
epoch (at baseline and post-baseline) 
Malignancy
Standard analysis
Cognitive impairment
Standard analysis 
10.3
Adverse events (AEs)
Any AE occurred during the study period will be included in AE summary tables as described 
in Section 10.1, i.e., AEs occurred in run-ins, double-blind period, and SAEs up to one-month 
after the study completion.
The incidence of treatment-emergent adverse events (new or worsened) will be summarized by 
primary system organ class, preferred term, severity, and relationship to study drug according 
to the Medical Dictionary for Regulatory Activities (MedDRA). 
The MedDRA version used for reporting the study will be described in a footnote.
Within each reporting phase (run-ins or double-blind, see Table 10-1), the following rules are 
applicable. If a subject reported more than one adverse event with the same preferred term, the 
adverse event with the greatest severity will be presented. If a subject reported more than one 
adverse event within the same primary system organ class, the subject will be counted only 
once with the greatest severity at the system organ class level, where applicable. Statistical 
analyses, which will only be performed for the double-blind or later phase, will include all post-
baseline AEs up to and including the analysis cut-off (AEs up to the final visit and SAEs up to 
30 days after the final visit for each patient) irrespective of how long after the last day of study 
treatment they occurred. 
The number and percentage of subjects reporting any adverse event during each reporting phase 
will be summarized by primary system organ class, preferred term and treatment. The most 
common adverse events reported (≥1 % in any group for each preferred term in the SOC-PT 
table) will be presented in descending frequency according to its incidence in the LCZ696 group 
starting from the most common event. 
Separate summaries, for each reporting phase (run-ins and double-blind), will be provided for 
study medication related adverse events, death, serious adverse event, other significant adverse 
events leading to study discontinuation and adverse events leading to dose adjustment.
Specific interested AEs will be summarized separately in addition to the above analysis. These 
specific interested AEs are: angioedema, hyperkalemia, hypotension, renal dysfunction, liver.


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Due to the different durations in the two sub-run-in phases, besides providing percentages, the 
annualized exposure duration adjusted event rates will also be provided.
In addition to the above standard analyses, for the double-blind phase, analysis for time-to-first 
selected AEs by treatment group will be performed using Kaplan-Meier estimate. The 
annualized exposure duration adjusted event rates will also be provided.
10.4
Laboratory data
10.4.1
General laboratory data
Laboratory data will be summarized for each reporting phase as described before: Run-ins based 
on the VRS and LRS and double blind period based on the SAF.
The summary of laboratory evaluations will be presented for three groups of laboratory tests: 
hematology, serum chemistry and urinalysis, which include hemoglobin, hematocrit, RBC 
count, WBC count, platelet count, blood urea nitrogen (BUN), creatinine, estimated glomerular 
filtration rate (eGFR), total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, 
potassium, chloride, calcium, phosphorus, total protein, albumin, and uric acid.
The eGFR is calculated according to the formula:
eGFR (mL/min/1.73 m2) = 175 x (Serum creatinine/88.4)-1.154 x (Age)-0.203 
                                                         x (0.742 if female) x (1.212 if black),
where serum creatinine is in μmol/L (SI unit) and age is non-rounded at the time of the 
laboratory sample in years.
Descriptive summary statistics (mean, median, standard deviation, min and max) for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post baseline values and will be calculated as:
•
change from baseline = post baseline value – baseline value
Note that baselines (for run-in and double blind phase) are defined in Section 4.
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group.
The number and percentage of subjects with clinically notable laboratory results after baseline 
will be presented. Clinically notable laboratory results, for those parameters where ranges are 
available, are given in Table 10-3 below. For the calculation the denominator are based on the 
evaluable post-baseline subjects who did not have the notable abnormality at baseline from the 
central laboratory.
Table 10-3
Clinical notable criteria for selected laboratory tests
Hematology


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RBC count
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Hematocrit
>50% increase, >20% decrease
WBC count
>50% increase, >50% decrease
Platelet count
>75% increase, >50% decrease
Blood Chemistry
ALT (SGOT)
>150% increase
AST (SGPT)
>150% increase
BUN
>50% increase
>14.28 mmol/L
Creatinine
>50% increase
>136.8 µmol/L
Total bilirubin
>100% increase
CPK
>300% increase
Alkaline phosphatase
>100% increase
Sodium
>5% decrease
Potassium
>20% increase, >20% decrease
≥6.0 mmol/L
>5.0 mmol/L
<3.5 mmol/L
Chloride
>10% increase, >10% decrease
Calcium
>10% increase, >10% decrease
Uric acid
>50% increase
In the above table increase and decrease are defined as compared to the baseline value. Here 
baseline is defined as the run-in baseline for the run-in phases and the double-blind baseline for 
the double-blind phase.
10.4.2
Specific laboratory data
Liver function test (LFT) data will be analyzed according to what specified in hepatotoxicity in 
Table 10-2 in Section 10.2.
Laboratory data related to renal impairment (serum creatinine, eGFR) will be analyzed 
according to what specified in renal impairment in Table 10-3 in Section 10.2.
10.5
Vital signs
Sitting systolic blood pressure, sitting diastolic blood pressure, sitting pulse rate and body 
weight will be summarized by treatment group and visit with standard summary statistics (mean, 
median, standard deviation, min, max), including changes from baseline. Baselines (run-in and 
double blind period) are defined in Section 4. Graphical mean plots with 95% CIs for these vital 
signs will also be provided.
The descriptive summaries will be presented by vital sign and treatment group and visit. Change 
from baseline will only be summarized for subjects with both baseline and post-baseline values 
and will be calculated as:


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•
change from baseline = post-baseline value – baseline value
The number and percentage of subjects with clinically notable vital signs changes from baseline 
will be presented. Clinically notable vital sign results are provided in Table 10-4 below.
Table 10-4
Clinically notable changes in vital signs
Vital Sign (unit)
Clinically notable criteria
Weight (kg)
decrease > 7% from Baseline
increase > 7% from Baseline
Sitting systolic blood pressure (mmHg)
<90 and decrease from baseline of >20
>180 and increase from baseline of >20
Sitting diastolic blood pressure (mmHg)
<50 and decrease from baseline of >15
>105 and increase from baseline of >15
Pulse (bpm)
<50 and decrease from baseline of > 15
>120 and increase from baseline of >15
10.6
Electrocardiogram (ECG)
The following quantitative variables will be summarized: heart rate,QRS duration, and QTc. 
Summary statistics (n, mean, SD, min .Q1, median, Q3, max) for the change from baseline 
(Visit 201) in ECG intervals by visit and treatment will be provided. QTc categorical summary 
will also be provided (for both Fridericia and Bazett corrctions) (for example, >500 ms, > 500 
ms (with RBBB), > 500 ms (without RBBB)) and categorical summary for maximum change 
from baseline for QTc (> 60 ms, > 60 ms (with RBBB), > 60 ms (without RBBB)).
In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, total) 
with the maximum on study result (normal, clinical significant, not available, total) will be 
provided for each variable. Clinically significant is defined if at least one abnormality: “atrial 
fibrillation, atrial flutter, LBB block, RBB block, pathological Q-waves, left ventricular 
hypertrophy, paced rhythm or other” is  answered “yes”.  
11
Resource utilization
Data relating to resource utilization will be used to describe medical resources used by the study 
participants.  Mainly descriptive statistics of resources utilization data will be provided by 
treatment group. 
12
Interim analyses
One interim analysis for efficacy is planned. The cut-off time for this interim analysis will be 
when about two-thirds of the target number of primary events have been reported and 
adjudication-confirmed, i.e., when approximately 1231 of composite of adjudication-confirmed 
hospitalizations for HFs and CV deaths are available. In the interim analysis, the analysis dataset 
will comprise all patients who were randomized before the cutoff date. Bonferroni multiplicity 
adjustment will be adopted for the statistical comparisons between treatments. An alpha of 
0.001 (one-sided alpha) will be spent for the comparison of primary endpoint at the interim 
analysis and the rest of alpha (one-sided 0.024 for the current specified boundary) will be 


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utilized at the final analysis. In the interim analysis, the study may be stopped for superior
efficacy only when the primary endpoint and CV death both are significant at level of 0.001 
(one-sided).
If the study is stopped early for claiming superior efficacy at the interim analysis, the secondary 
endpoints will be tested using the same hierarchical testing procedure as described in Section 
9.3.2.1 before with an overall alpha level used for the primary endpoint at the interim analysis 
(one-sided alpha of 0.001 for the current specified boundary). 
Interim safety assessments are planned to be performed every six months. No further alpha 
adjustment will be made for these interim safety assessments.
Interim analyses will be performed by an independent statistician who will not be involved in 
the trial conduct. The results will be reviewed by the independent DMC.
Investigators, Novartis employees, and others who are involved in the conduct of the trial will 
remain blinded to the treatment codes and interim analysis results until all monitoring decisions 
have been made and the database has been locked for the final analysis.
13
Power and sample size considerations
13.1
Power for the primary endpoint
Sample size is calculated through simulations for the proportional rates model. The control 
group rate of total hospitalizations for HF and rate of mortality are estimated in two steps in 
order to get a reasonable estimate for the selected patient population.
First we estimate the rates from the candesartan group of the CHARM-Preserved study (Yusuf 
et al 2003) for patients with EF >45%, using a joint model that joins the Poisson regression 
model and the exponential regression model together through a shared gamma frailty (Cowling 
et al 2006). An independent uniform censoring on the events are assumed during the follow-up. 
With the given frailty between HF hospitalization and CV death, the estimated baseline intensity 
in the Poisson model= 0.00032 HF hospitalizations/day per patient and the estimated hazard 
rate in the exponential model = 0.000136 CV deaths/day per patient. The estimated gamma 
shape parameter (the frailty parameter that is also assumed to be 1/scale) is 0.193. These 
specified parameter values produce approximately an annualized rate of 0.083 for time to first 
primary event and an annualized rate of 0.036 for CV mortality. 
Second, we adjust these estimated rates up by 8% (and then increasing the corresponding 
Poisson intensity rate and hazard rate) based on the results from the recent completed HF studies 
and publications, which are believed to reflect a higher risk patient population than that in the 
CHARM-Preserved study. This leads an annualized rate of 0.09 for time to first primary event 
and an annualized rate of 0.04 for CV mortality for a high risk patient population. 
The target reduction in RR for the primary endpoint is chosen to be about 22%, which 
approximately corresponds to a reduction of 30% for HF hospitalization and a reduction of 10% 
for CV death, given the gamma frailty defined above between these two components. With the 
CHARM-Preserved data structure for EF >45%, the specified rates will produce an 
approximately 15% reduction for time-to-first event analysis, see Table 13-1.


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The patient enrollment is assumed to be uniform lasting 2 years and 5 months and the minimum 
follow-up is to be 2 years and 2 months.
In Table 9-1, sample sizes and powers are estimated through simulations for the framework 
defined above. Three thousand trial replicates are generated for each scenario with different 
sample sizes in the simulations. Both the power and type I error rate are estimated for the 
selected proportional rates model (LWYY). For our study, with a one-sided alpha level of 0.025, 
a total of 4600 patients will provide more than 90% of power for the LWYY method. This will 
require approximately 1847 primary events (see the row in table below with sample size = 4600 
and HR = 0.9 and RR = 0.7). The type I error rates were preserved well in the cases we examined.
Table 13-1
Sample size and power estimations through simulations
Sample 
size
Simulation specs
Expected 
no. of composite 
events
Estimated HR or RR
Power
HR for 
death
RR for total 
hosp for HF
Time to 1st
composite 
event
LWYY
LWYY
4600
0.9
0.7
1847 
0.859
0.778
0.95 
0.75
1882 
0.881
0.814
0.85 
1.0
0.7
1846 
0.876
0.784
0.94
0.75
1885 
0.900
0.822
0.82 
3000 simulation runs were performed for each scenario.
13.2
Sample size re-estimation
A blinded sample size re-estimation will be considered around the time of the efficacy interim 
analysis. The pooled intensity/hazard rates for hospitalization for HF and CV death will be 
estimated using the same joint shared-gamma-frailty model (with one treatment group) used for 
the simulations for the sample size calculations in the above sections. The differences between 
the model parameter estimates used for the sample size calculations and the new ones obtained 
in the interim analysis will then be evaluated. Sample size simulations based on the new 
estimates will be performed using the same assumptions used in the initial sample size 
calculations. The new sample size and/or the duration of follow up will be determined based on 
the new simulations in order to preserve the target power and to achieve the required number 
of events in an acceptable timeframe.
13.3
Power for secondary endpoints
13.3.1
Power for the change in KCCQ clinical summary score at 8 months
For the change from randomized treatment epoch baseline to Month 8 in clinical summary score 
assessed by KCCQ, the planned sample size of 4600 will provide 83% power to detect a 
treatment difference of 2 points at the one-sided significance level of 0.025, assuming a standard 
deviation of 22 (observed in PARADIGM study). This estimation has taken into consideration 
that approximately 10% of patients may be excluded from analysis due to no KCCQ assessment 
done, based on PARADIGM experience.


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13.3.2
Power for NYHA class
From the PARAMOUNT (CLCZ696B2214) study, which is the phase II pilot study with a 
similar HFpEF population, after 9 months of treatment with valsartan, the incidence rates in 
each category distribute as follows in Table 13-2.
Table 13-2
PARAMOUNT NYHA incidence rates
LCZ696
Valsartan
Baseline
Class I
Class II
Class 
III/IV
Baseline
Class I
Class II
Class 
III/IV
Class I
1 ( 0.8)
0 ( 0.0)
1 (100.0)
0 ( 0.0)
1 (0.8)
0 ( 0.0)
1 (100)
0 ( 0.0)
Class II
100 (78.7)
16 (16.0)
80 (80.0)
4 ( 4.0)
102 
(81.6)
9 ( 8.8)
89 (87.3)
4 ( 3.9)
Class III
26 (20.5)
0 ( 0.0)
13 (50.0)
13 (50.0)
22 (17.6)
0 ( 0.0)
8 (36.4)
14 (63.6)
From this table, there are approximately 7% of patients (16/100=16% vs. 9/102=8.8%) within 
class II and 14% of patients (13/26=50% vs. 8/22=36.4%) in class III improved from baseline 
to 9 months endpoint in LCZ696 compared with valsartan. 
Our power evaluation is based on this data and takes the incidence rates in valsartan group as 
the rates in the comparator group. A one-sided alpha of 0.025 is used to control the type I error. 
Table 13-3 shows powers for a sample size of 4600 patients.
Table 13-3
Powers for NYHA class comparisons
Improved from Baseline to endpoint in Class III
Improved from baseline to 
endpoint in Class II
10%
12%
14%
16%
5%
98%
99%
99%
>99%
7%
>99%
>99%
>99%
>99%
9%
>99%
>99%
>99%
>99%
The results in this table are based on simulations with 100000 replicates.
From this table, there are approximately 7% of patients (16/100=16% vs. 9/102=8.8%) within 
class II and 14% of patients (13/26=50% vs. 8/22=36.4%) in class III improved from baseline 
to 9 months endpoint in LCZ696 compared with valsartan.
13.3.3
Power for composite renal endpoint
With an expected hazard reduction of 30% (LCZ696 over valsartan) in composite renal 
endpoint, an annual first occurrence of renal events rate of 0.63% (or 1%), an average follow-
up of 3.375 years, and a one-sided alpha of 0.025, forty-six hundred patients will provide a 
power of 36% (or 52%). When the hazard reduction is about 35%, forty-six hundred patients 
will provide a power of 47% (or 66%) when the annual event rate is 0.63% (or 1%). Note that 
the power provided here is conditional power, when the null hypotheses for the primary 
endpoint, the secondary endpoints of KCCQ change and NYHA class change at month 8 are all 
rejected.


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The power estimations are mainly based on data observed from recently completed 
PARADIGM-HF trial. In that trial, the observed annual event rate for composite renal endpoint 
is 0.63% and the hazard reduction of LCZ696 over enalapril is 37%.
13.3.4
Power for all-cause mortality
With a reduction of 20% in mortality, an annual all-cause mortality rate of 5% (25% increase 
from CV mortality), an average follow-up of 3.375 years, and a one-sided alpha of 0.025, forty-
six hundred patients will provide a power of 81%. When the reduction is about 15%, forty-six
hundred patients will provide a power of 56%.
14
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