Conditions: Heart Failure With Reduced Ejection Fraction
Keywords: Acute decompensated heart failure Reduced ejection fraction Pre-discharge treatment Post-discharge treatment Angiotensin receptor neprilysine inhibitor HFrEF
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1002
Healthy volunteers: no

Brief summary:
To explore two modalities of treatment initiation (Pre-discharge, and Post-discharge) with LCZ696 in HFrEF patients following stabilization after an ADHF episode.

Detailed description:

Arms:
arm 1: Patients received first dose at any point after Randomization but no later than 12 h before discharge. arm 2: Patients received first dose after discharge and up to 14 days thereafter.

Interventions: intervention 1: LCZ696
Intervention descriptions: intervention 1: LCZ696 film-coated tables were supplied to the investigators. Tablets were taken with a glass of water, and were administered with or without food.

The target dose of LCZ696 was 200 mg twice daily. Starting dose of LCZ696 was either 50 or 100 mg, twice daily. The dose of LCZ696 should be doubled every 2-4 weeks to achieve the target dose of 200 mg twice daily, as tolerated by the patient.

Protocol document:
Prot_000.pdf: 
Global Medical Affairs – CardioMetabolic Franchise 
LCZ696 
Clinical Trial Protocol CLCZ696B2401 / NCT02661217
A multicenter, randomized, open label, parallel group study 
comparing pre-discharge and posT-discharge tReatment 
initiation with LCZ696 in heArt failure patieNtS with 
reduced ejectIon-fracTion hospItalized for an acute 
decOmpensation eveNt (ADHF) (the TRANSITION study) 
Authors: 
 
Document type: 
Amended Clinical Trial Protocol - clean 
EUDRACT number: 
2015-003266‐87 
Version number: 
v02 
Development phase: 
IV 
Release date: 
18-Jul -2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0, November, 2013 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 7 
Amendment 2 ............................................................................................................................. 9 
Amendment 1 ............................................................................................................................. 9 
Protocol summary .............................................................................................................. 10 
1 
Introduction ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Purpose .................................................................................................................. 15 
2 
Study objectives ................................................................................................................. 15 
2.1 
Primary objective ................................................................................................... 15 
2.2 
Secondary objectives ............................................................................................. 15 
 
 15 
3 
Investigational plan ........................................................................................................... 16 
3.1 
Study design........................................................................................................... 16 
3.2 
Rationale of study design ....................................................................................... 19 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 20 
3.4 
Rationale for choice of comparator ....................................................................... 21 
3.5 
Purpose and timing of interim analyses ................................................................. 21 
3.6 
Risks and benefits .................................................................................................. 21 
4 
Population .......................................................................................................................... 26 
4.1 
Inclusion criteria .................................................................................................... 26 
4.2 
Exclusion criteria ................................................................................................... 26 
5 
Treatment ........................................................................................................................... 29 
5.1 
Protocol requested treatment ................................................................................. 29 
5.1.1 
Investigational treatment ....................................................................... 29 
5.1.2 
Additional study treatment .................................................................... 29 
5.2 
Treatment groups ................................................................................................... 29 
5.3 
Treatment assignment, randomization ................................................................... 30 
5.4 
Treatment blinding ................................................................................................. 30 
5.5 
Treating the patient ................................................................................................ 30 
5.5.1 
Patient numbering ................................................................................. 30 


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5.5.2 
Dispensing the investigational treatment .............................................. 31 
5.5.3 
Handling of study treatment .................................................................. 31 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 32 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 32 
5.5.6 
Rescue medication ................................................................................ 34 
5.5.7 
Concomitant treatment .......................................................................... 35 
5.5.8 
Prohibited treatment .............................................................................. 36 
5.5.9 
Discontinuation of study treatment ....................................................... 37 
5.5.10 
Withdrawal of consent .......................................................................... 37 
5.5.11 
Loss to follow-up .................................................................................. 38 
5.5.12 
Emergency breaking of assigned treatment code .................................. 38 
5.5.13 
Study completion and post-study treatment .......................................... 38 
5.5.14 
Early study termination ......................................................................... 38 
6 
Visit schedule and assessments ......................................................................................... 39 
6.1 
Information to be collected on screening failures .................................................. 46 
6.2 
Patient demographics/other baseline characteristics ............................................. 46 
6.3 
Treatment exposure and compliance ..................................................................... 46 
6.4 
Efficacy .................................................................................................................. 46 
6.5 
Safety ..................................................................................................................... 46 
6.5.1 
Assessment or primary endpoint ........................................................... 46 
6.5.2 
Assessment of secondary endpoints ...................................................... 46 
6.5.3 
Safety assessments ................................................................................ 47 
6.5.4 
Physical examination ............................................................................ 47 
6.5.5 
Vital signs.............................................................................................. 47 
6.5.6 
Height and weight ................................................................................. 48 
6.5.7 
Laboratory evaluations .......................................................................... 48 
6.5.8 
Electrocardiogram (ECG) ..................................................................... 52 
6.5.9 
HF Signs & Symptoms and New York Heart Association Class.......... 52 
6.5.10 
Pregnancy and assessments of fertility ................................................. 52 
6.5.11 
Appropriateness of safety measurements .............................................. 53 
 
 53 
 
 53 
 
 53 
7 
Safety monitoring .............................................................................................................. 54 
7.1 
Adverse events ....................................................................................................... 54 
7.2 
Angioedema-like events ........................................................................................ 55 


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7.3 
Serious adverse events ........................................................................................... 56 
7.3.1 
Definition of SAE ................................................................................. 56 
7.3.2 
SAE reporting........................................................................................ 57 
7.4 
Liver safety monitoring ......................................................................................... 58 
7.5 
Serum potassium safety monitoring (hyperkalemia) ............................................. 58 
7.6 
Renal safety monitoring ......................................................................................... 58 
7.7 
Pregnancy reporting ............................................................................................... 58 
8 
Data review and database management ............................................................................. 59 
8.1 
Site monitoring ...................................................................................................... 59 
8.2 
Data collection ....................................................................................................... 60 
8.3 
Data Monitoring Committee .................................................................................. 60 
8.4 
Angioedema Adjudication Committee – program-wide ........................................ 61 
9 
Data analysis ...................................................................................................................... 62 
9.1 
Analysis sets .......................................................................................................... 62 
9.2 
Patient demographics and other baseline characteristics ....................................... 62 
9.3 
Treatments ............................................................................................................. 62 
9.4 
Analysis of the primary variable(s) ....................................................................... 63 
9.4.1 
Variable ................................................................................................. 63 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 63 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 63 
9.5 
Analysis of secondary variables ............................................................................ 63 
9.5.1 
Efficacy variables .................................................................................. 63 
9.5.2 
Safety variables ..................................................................................... 63 
 
 65 
9.5.4 
Pharmacokinetics .................................................................................. 65 
 
 65 
9.5.6 
PK/PD ................................................................................................... 65 
9.6 
Sequence of planned analyses ............................................................................... 65 
9.6.1 
Interim analyses .................................................................................... 65 
9.6.2 
Final analyses and reporting.................................................................. 66 
9.7 
Sample size calculation .......................................................................................... 66 
10 Ethical considerations ........................................................................................................ 67 
10.1 
Regulatory and ethical compliance ........................................................................ 67 
10.2 
Informed consent procedures ................................................................................. 67 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 68 
10.4 
Publication of study protocol and results............................................................... 68 


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11 Protocol adherence ............................................................................................................ 68 
11.1 
Protocol Amendments ........................................................................................... 69 
12 References ......................................................................................................................... 69 
13 Appendix 1: Clinically notable laboratory values ............................................................. 71 
14 Appendix 2:  Guidelines for the management of  liver laboratory:  Trigger 
definitions, liver event reporting, and follow-up requirements ......................................... 72 
15 Appendix 3: Guidelines for the management of hyperkalemia (for serum potassium 
greater than 5.4 mmol/L) ................................................................................................... 75 
16 Appendix 4:  Guidelines for the management of blood pressure ...................................... 77 
17 Appendix 5:  Guidelines for the management of renal dysfunction .................................. 78 
 
List of tables 
Table 6-1 
Assessment table ................................................................................... 41 
Table 6-2 
List of laboratory tests ........................................................................... 51 
Table 14-1 
Liver event definitions .......................................................................... 72 
Table 14-2 
Liver event follow up requirements ...................................................... 73 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 18 
 


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List of abbreviations 
ACEI 
Angiotensin Converting Enzyme Inhibitor 
AE 
Adverse Event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ARB 
Angiotensin II Receptor Blocker 
ARNI 
Angiotensin II Receptor Neprilysin Inhibitor 
ADHF 
Acute Decompensated Heart Failure 
b.i.d. 
twice a day 
CCB 
Calcium Channel Blocker 
CFR 
US Code of Federal Regulations  
CRF 
Case Report/Record Form (electronic) 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal Fluid 
CTC 
Common Toxicity Criteria 
CT scan 
Computerized Tomography scan 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
eCRF 
electronic Clinical Report Form 
EDC 
Electronic Data Capture 
FAS  
Full Analysis Set 
GCP 
Good Clinical Practice 
 
 
ICH 
International Conference on Harmonization of technical requirements for 
registration of pharmaceuticals for human use 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LFT 
Liver function test (raised serum transaminases and/or bilirubin levels) 


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LLN 
Lower limit of normal 
MRA 
Mineralocorticoid Receptor Antagonists 
MRI 
Magnetic Resonance Imaging 
MUGA scan 
MUltiGated Acquisition scan 
MedDRA 
Medical dictionary for regulatory activities  
OC/RDC 
Oracle Clinical/Remote Data Capture  
o.d. 
once a day 
p.o. 
oral(ly) 
PARADIGM-HF - Prospective comparison of ARNI with ACEI to Determine Impact on 
Global Mortality and morbidity in Heart Failure – Study CLCZ696B2314 
RAN  
Randomized Population 
SAE 
serious adverse event 
SAF 
Safety Analysis Set 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
ULN 
Upper Limit of Normal 
 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort  
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the drug being tested in the trial 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Epoch 
A portion of the study which serves a specific purpose. Typical Epochs are: 
screening/recruitment, wash-out, treatment, and follow-up 
Investigational 
drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
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 protocol-specified 
concomitant background therapies  when these are standard treatments in 
that indication 


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Medication 
number 
A unique identifier on the label of each investigational/study drug package in 
studies that dispense medication using an IRT system 
Protocol 
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial. 
Part  
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Period 
A subdivision of a cross-over study 
Premature 
subject/patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival 
Randomization 
number 
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment 
Study drug/ 
treatment 
Any single drug or combination of drugs administered to the patient as part of 
the required study procedures; includes investigational drug (s), active drug 
run-ins or background therapy  
Study/investigatio
nal 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 
Subject Number  
A number assigned to each patient who enrolls into the study  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study 
 


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Amendment 2 
Purpose of this amendment is to address the following changes: 
• 
Section 3.1 (Study design) minor wording changes were entered to clarify: 
o the duration of hemodynamic stabilization (i.e., no need for IV diuretics in the 
past 24 hours prior to signing ICF) with respect to the timing of ICF 
administration (first bullet under “ICF should be administered”); 
o a redundant statement on Randomization was deleted on page 18; 
o for patients randomized to Pre-discharge group, with a prolonged hospital stay, 
details on the Discharge visit (Visit 102) assessments are edited on page 20 
(bullet No. 1). 
• Section 4.1 Inclusion criteria number 7:  clarification for the 24-hour duration of 
hemodynamically stable conditions at Screening prior to signing ICF. 
• Section 5.4:  Editorial changes were made to clarify that the sponsor clinical team 
blinding status during the study will not be compromised. 
• Section 6, Assessment table (Table 6-1) a missing check was added under Discharge, 
visit 102, to clarify that IRT should be notified of the visit date. 
• Section 6.5.7.3:  Clarifying text has been added on the parameters of local laboratory 
dipstick assessment to consistently reflect the CRF page. 
• Section 6.5.8:  Clarification on Screening ECG data have been added. 
• Additional minor editorial changes have also been added to address typographical 
errors and inaccuracies. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
Amendment 1 
Amendment rationale 
The purpose of this amendment is to address the inquiry by the Health Authorities from 
Germany.  This change will apply to Germany only. 
• Section 10.2 of the protocol [Informed consent procedure], will indicate an asterisk for the 
first paragraph of the Section.  The modified version of the first paragraph is located at the 
end of the Section.  The text clarifies that the procedure should be limited to patients 
capable to provide written informed consent. 


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Protocol summary 
Protocol number 
CLCZ696B2401 
Title 
A multicenter, randomized, open label, parallel group study comparing pre-
discharge and posT-discharge tReatment initiation with LCZ696 in heArt 
failure patieNtS with reduced ejectIon-fracTion hospItalized for an acute 
decOmpensation eveNt (ADHF) (the TRANSITION study) 
Brief title 
Study to compare Pre-discharge and Post-discharge treatment initiation with 
LCZ696 therapy in heart failure patients with reduced ejection fraction (HF-
rEF) after an acute decompensation event. 
Sponsor and 
Clinical Phase 
Novartis 
Phase IV 
Investigation type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
Purpose of this trial is to explore two modalities of treatment initiation (Pre-
discharge, and Post-discharge) with LCZ696 in HFrEF patients following 
stabilization after an acute decompensated heart failure (ADHF) episode. 
Primary Objective 
Evaluate the proportion of patients in the Pre- and Post-discharge treatment 
initiation groups achieving the target dose of 200 mg LCZ696 twice daily at the 
end of the week-10 after randomization (Treatment Epoch), regardless of 
previous temporary dose interruption or down-titration. 
Secondary 
Objectives 
 
1. Assess the proportion of patients that, regardless of previous dose 
interruption or down-titration during the Treatment Epoch, achieved and 
maintained either the 2 highest doses of LCZ696 bid for at least 2 weeks 
leading to week 10 after randomization. 
2. Assess the proportion of patients that, regardless of previous dose 
interruption or down-titration during the Treatment Epoch, achieved and 
maintained any dose of LCZ696 for at least 2 weeks leading to week 10 
after randomization. 
3. Assess the proportion of patients permanently discontinued from study 
drug, due to Adverse Events, during the 10-week Treatment Epoch. 
Study design 
The TRANSITION study is a Phase IV randomized, multicenter, open-label 
study, testing two treatment-modalities of LCZ696 initiation in 
hemodynamically stabilized HFrEF patients hospitalized due to ADHF 
episode. 
The study consists of three Epochs (phases): the Screening Epoch; the 
Treatment Epoch defined as 10 weeks after Randomization; and 16-week 
Follow-up Epoch. 
Patient will be stratified based on the pre-admission type: 
-  on RAAS-inhibition therapy with ACEI (any dose); 
-  on RAAS-inhibition therapy with ARB (any dose); 
- ACEI/ARB treatment-naïve patients,  
defined as patients either without any previous treatment with ACEI or 
ARBs,or without ACEI/ARB therapy for at least 4 weeks before hospital 


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admission due to ADHF. 
Within each stratum, patients will be randomized 1:1 to start LCZ696 either 
Pre-discharge or Post-discharge, and Randomization should occur no later 
than 48 hours prior to the planned discharge date.  Patients are expected to 
be continuously treated with optimized standard of care therapy, as per HF 
guidelines.  Therapy with LCZ696 is intended to replace the ACEI/ARB-
inhibition therapy:  all ongoing ACEI and ARB treatment will be stopped before 
LCZ696 initiation.  Prior to starting treatment with LCZ696, a mandatory 36 
hours wash-out period between last dose ACEI and first dose of LCZ696 must 
be observed. 
Patients randomized to Pre-discharge treatment initiation could receive first 
dose of LCZ696 at any point after the investigator deemed the patient to be 
stable for at least 24 h, relatively to the ongoing acute HF-therapy. 
Patients randomized to Post-discharge treatment initiation could receive the 
first LCZ696 dose at any point between the day after discharge and up to 14 
days after Discharge. 
Population 
The study population will consist of adult male or female patients (18 years of 
age or older), hospitalized for an episode of acute decompensation of heart 
failure who are diagnosed with CHF NYHA class II-to-IV and reduced ejection 
fraction (LVEF ≤ 40%).  Patients can be either with first HF presentation (de 
novo), or acute decompensation of HF due to deterioration in patients with a 
prior history of chronic HF. 
Inclusion criteria 
1. Patients hospitalized due to acute decompensated HF episode (ADHF) as 
primary diagnosis) and consistent Signs & Symptoms  
2. Diagnosis of HF New York Heart Association class II-to-IV and reduced 
ejection fraction: Left ventricular ejection fraction ≤ 40% at Screening 
3. Patients did not receive any IV vasodilators (except nitrates), and/or any 
IV inotropic therapy from the time of presentation for ADHF to 
Randomization 
4. Stabilized (while in the hospital) for at least 24 hours leading to 
Randomization defined as: 
• 
No need for IV diuretics in the past 24 hours prior to signing ICF 
• 
Systolic blood pressure (SBP) ≥ 110 mm Hg for at least 6 h prior to 
Randomization 
5. Meeting one of the following criteria: 
• 
Patients on any dose of ACEI or ARB at screening  
• 
ACEI/ARB naïve patients and patients not on ACEI or ARB for at least 
4 weeks before screening. 
Exclusion criteria 
1. History of hypersensitivity to the sacubitril, valsartan, or any ARBs, NEP 
inhibitors or to any of the LCZ696 excipients. 
2. Symptomatic hypotension and/or a SBP < 110 mm Hg or SBP > 180 mm 
Hg prior to randomization 
3. End stage renal disease at Screening; or estimated GFR < 30 
mL/min/1.73 m2 as measured by the simplified Modification of Diet in 
Renal Disease (MDRD) formula at Randomization. 


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4. Serum potassium > 5.4 mmol/L at Randomization. 
5. Current hospitalization where patient does not receive treatment for 
decompensated HF. 
6. Known history of hereditary or idiopathic angioedema or angioedema 
related to previous ACE inhibitor or ARB therapy 
7. Severe hepatic impairment, biliary cirrhosis and cholestasis 
Investigational 
therapy 
LCZ696 therapy only (no reference therapy) 
Efficacy 
assessments 
Efficacy variables will not be assessed in this study 
Safety 
assessments 
Adverse events; angioedema; hyperkalemia; hypotension; liver and renal 
dysfunction 
Other 
assessments 
Data analysis 
The primary endpoint will be analyzed using the stratified Cochran-Mantel-
Haenszel method with treatment group and randomization stratification 
variable (ACEI stratum, ARB stratum, or naïve patient stratum) as stratification 
factor.  The risk ratio (of the Pre-discharge initiation of LCZ696 arm versus the 
Post-discharge initiation of LCZ696 arm) will be estimated with a 2-sided 95% 
CI along with the estimated rate and 95% CI for each treatment arm.  The 
above analyses will be performed based on safety analysis set (SAF). 
The secondary variables will be analyzed in an identical fashion to the primary 
variable (using the stratified Cochran-Mantel-Haenszel method  
A sample size of 1000 randomized patients (about 930 patients for ARB and 
ACEI, and about 70 in the naïve group) provides reasonable precision across 
a range of possible outcomes. For instance, when the observed rate 10-weeks 
up-titration, success is 80% in both pre- and post-discharge arms, it will 
provide an estimated risk ratio and 95% CI of 1.00 (0.94, 1.06). 
Key words 
Acute decompensated heart failure, reduced ejection fraction, pre-discharge 
treatment, post-discharge treatment, LCZ696, angiotensin receptor neprilysine 
inhibitor, safety and tolerability. 


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1 
Introduction 
1.1 
Background 
Chronic heart failure (CHF) is a major public health problem characterized by significant 
mortality, frequent hospitalization, and poor quality of life, with an overall prevalence that is 
increasing throughout the world (Hunt SA, 2009; McMurray JJ, 2012). 
Although most patients improve symptomatically during the first 24 hours with current 
medical treatment (Follath F, 2011), their prognosis remains poor with over 15% to 20% 
mortality and 30% to 40% readmission rate in the first year after discharge 
(Maggioni AP, 2013a).  Compared with ambulatory outpatients with heart failure, those 
hospitalized for AHF have >10-fold increase in the risk of dying, and although this risk 
decreases exponentially after discharge, it remains twofold to fourfold higher 12 to 18 months 
later (Gheorghiade M, 2005; Lassus JP, 2013).  These outcomes have not changed in the last 
decade, making AHF one of the most severe clinical conditions leading to hospitalization. 
Despite the changes in treatment during the last decades, where ACE inhibitor therapy 
reduces mortality in patients with HFrEF and has been the standard of care in this disease 
since the 1990s following publications of trials like CONSENSUS in 1987, and SOLV-D in 
1991, although ARBs may be substituted if ACE inhibitors are poorly tolerated.  Beta-
blockers and aldosterone antagonists have further improved survival, but mortality remains 
high. 
LCZ696 exhibits the novel mechanism of action of an Angiotensin Receptor Neprilysin 
Inhibitor (ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via 
LBQ657, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II 
type-1 (AT1) receptor via valsartan.  
The complementary cardiovascular benefits of LCZ696 in heart failure patients are attributed 
to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides 
(NP), by LBQ657 and the simultaneous inhibition of the effects of angiotensin II by valsartan. 
NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, 
resulting in increased concentrations of the second messenger cyclic guanosine 
monophosphate (cGMP), which could result in vasodilation, natriuresis and diuresis, 
increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone 
release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects.  
Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively 
blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. 
This prevents sustained activation of the renin-angiotensin-aldosterone system that would 
result in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and 
proliferation, and subsequent maladaptive cardiovascular remodeling. 
LCZ696 contains a salt complex of the anionic forms of sacubitril and valsartan.  Following 
oral administration, LCZ696 dissociates into the pro-drug sacubitril (also known as AHU377), 
which is further metabolized to the neprilysin inhibitor LBQ657, and valsartan. 


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Dosing in clinical trials was based on the total amount of both components of LCZ696, i.e. 24 
mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg of as sacubitril/valsartan sodium salt complex 
and is referred to as LCZ696 50 mg, 100 mg, and 200 mg respectively. 
The PARADIGM-HF was a multinational, randomized, double-blind study of 8,442 patients 
comparing LCZ696 (200 mg twice daily) to enalapril (10 mg twice daily) in adult patients 
with chronic heart failure, NYHA class II-IV and reduced ejection fraction (left ventricular 
ejection fraction [LVEF] ≤40%, amended later to ≤35%) in addition to other heart failure 
therapy. The primary endpoint was the composite of cardiovascular (CV) death or 
hospitalization for heart failure (HF).  
Prior to study participation, patients were well treated with standard of care therapy which 
included ACE inhibitors/ARBs (>99%), beta blockers (94%), mineralocorticoid antagonists 
(58%) and diuretics (82%). The median follow-up duration was 27 months and patients were 
treated for up to 4.3 years.  In addition, patients were allowed to receive treatment for other 
comorbid conditions (McMurray, JJV, 2014b). 
A total of 8442 patients were randomized and prospectively included in the intention-to-treat 
analysis (4187 to LCZ696 and 4212 to enalapril).  The trial was stopped early, according to 
pre-specified rules, after a median follow-up of 27 months, because the boundary for an 
overwhelming benefit with LCZ696 had been achieved.  The study showed that risk for death 
from cardiovascular causes or hospitalization for heart failure (the composite primary end 
point) was reduced by 20% in the LCZ696 group, compared with the enalapril group.  
LCZ696 was associated with a statistically significant 20% reduction of risk for CV death and 
21% reduction of risk of first hospitalization for heart failure. For the secondary endpoint, the 
risk of death for any reason, had a 16% reduction in the LCZ696 group, compared with the 
enalapril group.  In addition to a benefit in mortality reduction, LCZ696 was also superior to 
enalapril in reducing symptoms and physical limitations of heart failure assessed by Kansas 
City Cardiomyopathy Questionnaire (KCCQ). Fewer patients on LCZ696 (5.4%) had 
worsened NYHA functional class (≥1 class) from baseline to 8 month of treatment compared 
to enalapril (7.0%) (Packer M, 2015). The LCZ696 group had higher proportions of patients 
with hypotension and non-serious angioedema but lower proportions with renal impairment, 
hyperkalemia, and cough than the enalapril group (McMurray JJV, 2014b). 
When compared with enalapril, 16% fewer LCZ696-treated patients required intensification 
of outpatient therapy for worsening of heart failure or 34% fewer patients were evaluated and 
treated in emergency department for worsening heart failure but discharged without hospital 
admission.  The patients in the LCZ696 group had 18% fewer stays in intensive care and were 
31% less likely to receive intravenous positive inotropic agents, and 22% less likely to have 
implantation of a heart failure device or cardiac transplantation.  The reduction in 
HF-hospitalization with LCZ696 was evident within the first 30 days after randomization 
(Packer M, 2015). 
Current acute decompensated HF episode was an exclusion criterion in PARADIGM-HF 
study and only limited evidence is currently available on safety and tolerability of LCZ696 
initiation in recently hospitalized due to acute decompensated HF-rEF episode patients. 


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The simultaneous inhibition of neprilysin and blockade of the AT1 receptors with LCZ696 
was more effective than the ACE inhibitor enalapril in reducing all-cause mortality, 
cardiovascular mortality, and HF hospitalizations.  In addition, treatment with LCZ696 was 
delaying the clinical progression of surviving patients with a reduced ejection fraction 
(Packer M, 2015).  It is expected that starting the LCZ696 therapy closer to the ADHF event 
will be safe and tolerated and may exert favorable effects on the clinical course in stabilized 
HF-rEF patients. 
1.2 
Purpose 
The purpose of this trial is to explore two modalities of treatment initiation (Pre-discharge, 
and Post-discharge) with LCZ696 in HFrEF patients following stabilization after an ADHF 
episode. 
2 
Study objectives 
2.1 
Primary objective 
Evaluate the proportion of patients in the Pre- and Post-discharge treatment initiation groups 
achieving the target dose of 200 mg LCZ696 bid at the end of the week-10 after 
randomization (Treatment Epoch), regardless of previous temporary dose interruption or 
down-titration. 
2.2 
Secondary objectives 
• Assess the proportion of patients that, regardless of previous dose interruption or down-
titration during the Treatment Epoch, achieved and maintained either the dose of 100 mg 
and/or 200 mg LCZ696 bid for at least 2 weeks leading to week 10 after randomization. 
• Assess the proportion of patients that, regardless of previous dose interruption or down-
titration during the Treatment Epoch, achieved and maintained any dose of LCZ696 for at 
least 2 weeks leading to week 10 after randomization. 
• Assess the proportion of patients permanently discontinued from study drug, due to 
Adverse Events, during the 10-week Treatment Epoch. 


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3 
Investigational plan 
3.1 
Study design 
The CLCZ696B2401 study is a Phase IV randomized, multicenter, open-label study, testing 
two treatment-modalities of LCZ696 in the ADHF population.  Data from the study will 
provide information regarding the safety and tolerability of LCZ696 therapy in HF-rEF 
patients when initiated Pre- and Post-discharge following stabilization of patients hospitalized 
due to an ADHF episode. 
Patient will be stratified based on the pre-admission type of RAAS-inhibition therapy:  
• ACEI 
• ARB 
• ACEI/ARB treatment naïve patients  
defined as patients either without any previous treatment with ACEI or ARBs, or 
without ACEI/ARB therapy for at least 4 weeks before hospital admission due to 
ADHF. 
The study consists of three Epochs (phases): the Screening Epoch; the Treatment Epoch 
defined as 10 weeks after Randomization; and 16-week Follow-up Epoch. 
In the attempt to minimize screen failures at the time of Informed Consent Form (ICF) 
administration, patient could be identified/pre-screened at the time of admission for ADHF, 
bearing in mind that patients are severely ill and conditions may changes rapidly.  The 
investigator could conduct a pre-screening assessment based on the patient’s chart 
information compared to the eligibility criteria. 
The Screening Epoch is defined as the time from administration of ICF and up to the time of 
Randomization.  It is expected to range between 1 and 3 days. 
When admitted for acute decompensated HF, conventional therapy is started or continued at 
the discretion of the treating physician and is performed until hemodynamic stability is 
achieved.  
Randomization will occur only after a minimum of 24 h stabilization interval is completed. 
The Treatment Epoch is identified as the initial 10 weeks after Randomization. 
The Follow-up Epoch is identified as the continuation of open-label LCZ696 treatment for 
additional 16 weeks after the Treatment Epoch to further evaluate safety and tolerability. 
All patients must provide written informed consent prior to start any study-related activities.  
Upon signing the ICF, patients give access to the treatment received and medical information 


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starting from the time of admission for ADHF to verify eligibility criteria i.e.,: acute treatment 
received, sign and symptoms consistent with admission for ADHF, local laboratory values, 
conditions confirming achievement of hemodynamic stability. 
ICF should be administered: 
• At least 24 hours after achieving hemodynamic stabilization (i.e., no need for 
intravenous diuretics in the past 24 hours prior to signing ICF, as described in the 
inclusion criteria No. 7, first bullet) following the acute treatment for ADHF. 
• Upon achieving stabilization, but not later than 48 h prior to the planned discharge 
date, to enable the required 36 h wash-out from ACEI therapy if the patient is 
randomized to the Pre-discharge initiation of LCZ696 therapy. 
Patients will be randomized 1:1 to start LCZ696 either Pre-discharge or Post-discharge.  In 
this study the duration of the Treatment Epoch starts from the date of Randomization.  
Patients are expected to be continuously treated with optimized standard of care therapy, as 
per HF guidelines.  The investigator will prescribe to the patient the required HF-medications 
(i.e., locally commercially available ACEI or ARB, beta-blockers, and other HF-guidelines 
recommended treatments) that will be acquired by the patient.  Only LCZ696 will be provided 
through this study to the investigator/patient. 
Therapy with LCZ696 is intended to replace the ACEI/ARB-inhibition therapy:  all ongoing 
ACEI and ARB treatment will be stopped before LCZ696 initiation.  Due to the potential risk 
of angioedema when used concomitantly with an ACE inhibitor, LCZ696 must not be started 
for at least 36 hours after discontinuing ACE inhibitor therapy. 
LCZ696 should not be co-administered with another ARB due to the angiotensin II receptor 
blocking activity of valsartan.  The investigator must train the patient to stop the current ARB 
therapy to ensure the first dose of LCZ696 will replace the routine dose of ARB at the next 
standard time point (usually next day). 


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Figure 3-1 
Study design 
 
OMT = optimized medical treatment 
Total study duration = 26 weeks 
Patients randomized to treatment initiation Pre-discharge initiation could receive first dose of 
LCZ696 at any time during their hospitalization after the investigator deemed the patient to be 
stable for at least 24 h, relatively to the ongoing acute HF-therapy.  The first dose 
administration should occur no later than 12 h before discharge, and no later than 7 days after 
Randomization.  The goals are (1) to administer at least one LCZ696 dose before discharge, 
bearing in mind that, if a patient is receiving ACEI therapy, a 36 h washout is mandatory prior 
to starting LCZ696 therapy; and (2) to initiate LCZ696 treatment adequately close to the 
Randomization event. 
Patients randomized to treatment initiation Post-discharge will continue to be treated with 
optimized standard of care HF-medications (i.e., locally commercially available ACEI or 
ARB, beta-blockers, and other HF-guidelines therapy at the discretion of the treating 
physician).  They could receive the first LCZ696 dose at any point between the day after 
discharge and up to 14 days after Discharge (i.e., Discharge occurred on 01-Oct-2016:  
Post-discharge treatment may start at any time between the day after Discharge and 15-Oct-
2016), implementing the required mandatory 36 hours wash-out if a patient is on current 
ACEI therapy.  
Prolonged hospital stay 
Duration of hospitalization in the various countries may vary broadly.  Across the globe, the 
average length of hospital stay is about 5–10 days (Ponikowski P, 2014).  However, some 
patients may prolong their hospital stay for reasons other than worsening of HF conditions, 


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and the investigator must document the details for the prolongation in the source 
documentation.  To allow for the variability and unplanned lengthening of hospital stay, 
provisions are made to enable initiation of the LCZ696 therapy, as indicated below. 
1. If assigned to Pre-discharge treatment, patients will continue LCZ696 treatment as per 
investigator’s directions. 
The date for the Discharge visit (Visit 102) assessments will be calculated as the date of 
Randomization + 1 week (i.e., Randomization on 07-Mar-2016; Visit 102 will be on 
14-Mar-2016).  All assessment will be completed and entered in the CRF page for Visit 
102. 
Visit 103 (2 weeks after-Randomization) will be calculated as the date of Randomization 
+ 2 weeks (i.e., Randomization on 07-Mar-2016; Visit 103 will be on 21-Mar-2016).    
All subsequent visit dates will be derived from the date of Visit 103 (i.e., visit 104 = Visit 
103 + 2 weeks). 
2. If assigned to Post-discharge AND in the hospital on day 10 AFTER Randomization:  
All the assessments indicated for the Discharge visit (Visit 102) should be carried out 
at least 2 days before starting LCZ696 treatment.  All the results will be reported in the 
Discharge page of the CRFs.  Also, the mandatory 36 h washout for ACEI must be 
completed. 
Patients may start LCZ696 treatment, as early as 12 days but no later than 21 days after 
the RANDOMIZATION date, while remaining in the hospital. 
The date when such patient starts LCZ696 treatment will represents Visit 103 and all 
assessment related to that visit must also be completed.  All subsequent visit dates will be 
derived from the date of Visit 103 (i.e., visit 104 = Visit 103 + 2 weeks). 
If a patient is Randomized but not treated with LCZ696 within the windows provided: 
• For the Pre-discharge group within 7 days after Randomization;  
• For the Post-discharge group either  
a. within 2 weeks after discharge 
b.  or, if due to prolonged hospital stay, between 12 and 21 days after Randomization 
the patient should be withdrawn. 
For more details on study treatment, please refer to Section 5, and refer to the Assessment 
Schedule for the visit frequency during the study. 
To identify early in the course of the study any potential safety or tolerability issues, two 
interim safety analyses will be carried out by an internal independent DMC when 30% and 
60% of the patients have completed the visit at 10-weeks after Randomization (Visit 199) to 
assess if the study should be terminated early. 
3.2 
Rationale of study design 
The study population of hemodynamically stabilized patients, while hospitalized due to 
ADHF episode, was chosen to complement safety and tolerability data from the 
PARADIGM-HF study which investigated chronic HF patients with reduced ejection fraction. 


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The TRANSITION study is designed to provide information whether pre- discharge or post-
discharge initiation of LCZ696 would be effective strategy to support treatment management 
in patients admitted to the hospital due to ADHF, treated and stabilized hemodynamically for 
at least 24-hour. 
Stratification of admitted patients based on their HF therapy prior to admission (i.e., ACEI, 
ARBs, ACEI/ARB naïve treatment) will ensure that within a stratum the distribution between 
Pre- and Post-discharge is similar.  Representation is pre-set only for the patients, who are 
ACEI/ARB-naïve, which are expected to represent at least 7% of the total patient population 
(see Section 5.3 for details).  In the ASTRONAUT trial the patient population was similar to 
that expected to participate in this trial (LVEF<40 and admitted for ADHF), with 15.1% of 
patients not taking ACEI or ARBs at baseline (Gheorghiade M, 2013).  As the use of ACEI 
and ARBs has recently increased, compared to the time when recruitment for the 
ASTRONAUT study occurred (2009-2011), a conservative assessment for the enrollment of 
ACEI/ARB treatment-naïve was taken, leading to the expectation of a minimum of 70 patients 
(7% of total) in this study. 
The open-label treatment is considered to be operationally pragmatic, as the type and number 
of HF treatments are numerous and it would be cumbersome to implement a double-blind 
double dummy treatment plan.  In PARADIGM-HF study fewer patients stopped their study 
medication overall or because of an adverse event in the LCZ696 group than in the enalapril 
group. It is expected that early withdrawal rate due to intolerance or AEs should be the same 
between the Pre- and Post-discharge groups, thus reducing bias. 
Re-hospitalization rates in European countries range from 24% at 12 weeks to 44% at 1 year 
after discharge (Du XJ, 2014; Dar O and Cowie MR, 2008). It is then important for the study 
to capture the totality of hospitalizations for the study duration, given that: 1) hospitalization 
is an independent risk factor for mortality; 2) hospitalization is an independent risk factor for 
future hospitalizations; 3) one of the main goals of treatment of HF is to reduce risk of 
hospitalizations, as per current guidelines. 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
Starting dose, target dose, regimen, titration scheme, and tapering-off scheme for LCZ696 all 
are in accordance with approved product labeling. 
The target dose of 200 mg LCZ696 bid used in this protocol is the dose studied in the 
CLCZ696B2314/PARADIGM-HF trial that demonstrated superiority over enalapril 10 mg 
bid.  A dose of 200 mg LCZ696 bid delivers similar exposures of valsartan (assessed by 
AUC) as valsartan 160 mg bid, the maximal approved valsartan dose for HF and the dose 
recommended in international guidelines for the treatment of HF.  In addition, biomarker 
analysis (increase in levels of ANP and cGMP) indicates that this dose delivers approximately 
90% of its maximal neprilysin inhibition (Gu J, 2010). 
The duration of the Treatment Epoch for 10 weeks after Randomization is deemed adequate to 
enable the assessment of the study endpoints: number of patients in the Pre-discharge 
treatment initiation group and number of patients in the Post-discharge treatment initiation 


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group achieving the target dose of 200 mg LCZ696 twice daily, as well as the safety and 
tolerability of LCZ696 treatment.  The Follow-up Epoch for 16 weeks is deemed adequate to 
evaluate maintenance of either target- or tolerated dose in both treatment groups (Pre- and 
Post-discharge). 
With respect to oral HF treatments, the proportion of patients treated with ACE inhibitors and 
ARBs, beta-blockers, and mineralocorticoid-receptor-antagonists (MRA) significantly 
increases at discharge after the index admission.  This practice is supporting the event of an 
admission for HF as an opportunity to optimize the patient’s background therapy, for a 
relevant number of patients (Maggioni A, 2013b).  Pre-discharge initiation may be one 
approach to optimize evidence-based treatments in this population.  In the IMPACT-HF 
study, Pre-discharge initiation of the beta-blocker carvedilol in stabilized patients hospitalized 
for HF, did not increase side effects or length of stay and was not associated with an increased 
risk of serious adverse events up to 60 days after discharge (Gattis WA, 2004). 
Pre-discharge initiation of LCZ696 is expected to provide patients with the benefits of novel 
therapeutic approach of simultaneous neprilysin inhibition and angiotensin type 1 (AT1) 
receptor blockade as early as possible. 
3.4 
Rationale for choice of comparator 
No comparator is used in this study.  The comparison is carried out between two different 
modalities of treatment with LCZ696, Pre- and Post-discharge treatment initiation. 
3.5 
Purpose and timing of interim analyses 
Two interim analyses of tolerability and safety will be carried out during the study when 30% 
and 60% of the patients have completed the visit at 10-weeks after Randomization (Visit 199). 
Details will be pre-specified in the Charter of the DMC . 
The results of the interim analyses will be reviewed by the internal independent DMC. Apart 
from investigators and pharmacists, all Novartis employees and others, who are involved in 
the conduct of the trial, in the analysis of the final trial results, or who have contact with study 
centers, should remain blinded to the treatment codes as much as possible. The CRF does 
allow accidental systematic unblinding, with treatment assignment only indirectly apparent.  
Interim analysis results should also not be divulged until all monitoring decisions have been 
made and the database has been locked for either of the final analyses. 
3.6 
Risks and benefits 
Risks associated with participation in this study are primarily associated with potential side 
effects of the study drug LCZ696, which are comparable to other proven HF treatments, such 
as ACEI, ARBs, and MRA, including events like hypotension, renal impairment, 
hyperkalemia, angioedema. 
To date, over 15,000 subjects have taken LCZ696 in studies that have been performed in 
healthy subjects and patients with hypertension, heart failure with preserve ejection fraction, 
and heart failure with reduced ejection fraction. 


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In PARADIGM-HF study the overall incidence of adverse drug reactions to LCZ696 in heart 
failure patients was comparable to that seen with enalapril.  During PARADIGM-HF LCZ696 
up-titration run-in phase (median drug exposure 29 days), 10.4% of patients permanently 
discontinued, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), 
hypotension (1.7%) and hyperkalemia (1.3%).  However, discontinuation of therapy due to an 
adverse event in the double-blind period of the PARADIGM-HF study occurred in 10.7% 
LCZ696-treated patients and in 12.2% enalapril-treated patients.  The events most commonly 
associated with dosage adjustment or treatment interruption were hypotension, hyperkalemia 
and renal impairment. 
Risk of hypotension 
Cases of symptomatic hypotension have been reported in patients treated with LCZ696 during 
clinical trials, especially in patients ≥ 65 years old, patients with renal disease and patients 
with low SBP (< 112 mmHg).  Patients with SBP < 100 mmHg were not studied, therefore 
LCZ696 therapy should not be initiated until SBP is ≥ 110 mmHg. 
A higher rate of symptomatic hypotension was observed with LCZ696 than with enalapril in 
the CLCZ696B2314/PARADIGM-HF trial.  However, there was no increase in the rate of 
discontinuation because of possible hypotension-related adverse effects. Other hypotension-
related SAEs, including syncope, dizziness, loss of consciousness, and orthostatic 
hypotension, were infrequent and occurred at a comparable incidence with enalapril.  
Hypotension was reversible and manageable with dose adjustment or temporary treatment 
interruption. 
Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, 
e.g., by diuretic therapy, dietary salt restriction, diarrhea or vomiting. Sodium and/or volume 
depletion should be corrected before starting treatment with LCZ696, however, such 
corrective action must be carefully weighed against the risk of volume overload. 
When initiating therapy or during dose titration with LCZ696, blood pressure should be 
monitored at an appropriate interval, in accordance with normal clinical practice. 
If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and 
treatment of other causes of hypotension (e.g. hypovolemia) should be considered.  If 
hypotension persists despite such measures, the dosage of LCZ696 should be reduced or 
temporarily discontinued. Permanent discontinuation of therapy is usually not required. 
Risk of renal impairment 
As for any drug that acts on the renin-angiotensin-aldosterone system, use of LCZ696 may be 
associated with decreased renal function.  In PARADIGM-HF, the incidence of clinically 
relevant renal impairment was low and associated treatment discontinuation was observed less 
frequently in patients receiving LCZ696 (0.65%) compared to enalapril (1.28%). 
There is very limited clinical experience in patients with severe renal impairment (estimated 
GFR <30 ml/min/1.73 m2), these patients may be at greater risk of hypotension and therefore 
will be excluded from the study participation. There is no experience in patients with end-


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stage renal disease, LCZ696 is not recommended in these patients and should be permanently 
discontinued if such condition should develope during the study. 
Assessments of patient’s renal function will be performed during routine study visits (i.e., 
serum creatinine and eGFR).  
In patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m2), the starting dose 
will be 50 mg twice daily.  Down titration of LCZ696 should be considered in patients who 
develop a clinically significant decrease in renal function 
Concomitant administration of LCZ696 with ACEI, ARBs or direct renin inhibitor aliskiren is 
prohibited.  
In elderly patients, volume-depleted patients (including those on diuretic therapy), which is 
more representative of the TRANSITION-study population, concomitant use of LCZ696 and 
NSAIDs may lead to an increased risk of worsening of renal function.  Monitoring of renal 
function will be carrying out during the study in all study subjects. 
The occurrence of a clinically significant renal dysfunction event must be reported using the 
appropriate CRF pages. 
The risk of renal impairment can be adequately managed by complying with the entry criteria, 
frequent renal function laboratory assessments during the study, as well as following 
Appendix 5 “Guidelines for the management of renal dysfunction”. 
Risk of hyperkalemia 
Similar to other RAAS-blockade agents, the use of LCZ696 may be associated with an 
increased risk of hyperkalemia, although hypokalemia may also occur. 
In PARADIGM-HF, the incidence of hyperkalemia adverse events was 11.6% in the LCZ696 
treated patients compared to 14% in the enalapril treated patients.  Clinically relevant 
hyperkalemia that resulted in treatment discontinuation was observed in 0.26% of LCZ696 
treated patients compared to 0.35% of enalapril treated patients. (McMurray, JJV, 2014b) 
Therapy with LCZ696 should not be initiated if serum potassium level is above 5.4 mmol/L.  
Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium 
supplements) should be used with caution when co-administered with LCZ696, especially in 
patients who have risk factors such as renal impairment, diabetes mellitus, hypoaldosteronism, 
or patients on a high potassium diet or on mineralocorticoid antagonists.  
Monitoring of serum potassium will be performed during all routine study visits. 
If patients experience clinically significant hyperkalemia, adjustment of concomitant 
medications, or temporary down–titration or discontinuation of LCZ696 is recommended.  If 
serum potassium level is above 5.4 mmol/L temporary discontinuation of LCZ696 should be 
considered. 
The risk of hyperkalemia can be adequately managed by the described in Appendix 3 
“Treatment guidelines for hyperkalemia” and frequent laboratory assessments of potassium 
levels starting before LCZ696 initiation and continuing during treatment. An option for 


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stopping potassium supplements or reducing dietary potassium or adjusting the dose of 
concomitant medications, as well as down-titrating and temporary discontinuation of LCZ696 
is also provided. 
Risk of angioedema 
Angioedema has been reported in patients treated with LCZ696.  In PARADIGM-HF, during 
the randomized treatment, angioedema was reported in 19/4187 (0.5%) patients treated with 
LCZ696, 
compared 
with 
10/4212 
(0.2%) 
patients 
treated 
with 
enalapril 
(McMurray JJV, 2014a). 
Black patients have an increased susceptibility to develop angioedema and a higher incidence 
of adjudicated angioedema was observed in Black patients treated with LCZ696 (2.4%) 
compared with enalapril (0.5%).  However, there were no severe cases of angioedema 
involving airway compromise or requiring mechanical support in this study. 
Simultaneous inhibition of the ACE and NEP breakdown pathways of bradykinin is thought 
to significantly increase the risk of occurrence of angioedema (Sulpizio AC, 2002).  Due to 
the potential risk of angioedema when used concomitantly with an ACE inhibitor, the co-
administration of the LCZ696 with ACEI is contraindicated and LCZ696 must not be started 
for at least 36 hours after discontinuing ACE inhibitor therapy. 
Patients with a known history of angioedema were not studied.  As they may be at higher risk 
for angioedema, related exclusion criteria for patients with a history of hereditary or 
idiopathic angioedema or a known history of angioedema related to previous ACE inhibitor or 
ARB therapy is included in this protocol.  
Concomitant use of LCZ696 with ACEIs is contraindicated during the whole duration of the 
study to minimize the risk of angioedema.  A washout period of 36 hours is required between 
taking the last dose of ACEI therapy and initiating LCZ696 to reduce the risk of angioedema 
due to otherwise overlapping ACE/neprilysin inhibition.  The 36-hour washout is 
generalizable for most ACE-inhibitors, which have half-lives comparable to enalapril. For the 
few ACEIs that have longer half-lives than enalapril, those agents will have a 2-4 times 
decrease in plasma levels at 36 hours, which is considered a good compromise between 
avoiding the overlap of simultaneous inhibition of both ACEI and neprilysin inhibition and 
the withdrawal of ACEI therapy.  This 36-hour washout period is expected to present minimal 
risk to patients, especially since all patients will continue using their other background HF 
medications during this period. 
Similarly, a 36 hours washout period will be implemented any time when LCZ696 is 
discontinued and patients resume the use of an ACEI.  This 36-hour ACEI/LCZ696-free 
washout 
period 
is 
consistent 
with 
other 
LCZ696 
studies, 
as 
well 
as 
the 
CLCZ696B2314/PARADIGM-HF study (McMurray JJV, 2014a; Solomon SD, 2012). 
If angioedema occurs, LCZ696 should be immediately discontinued and appropriate therapy 
and monitoring should be provided until complete and sustained resolution of signs and 
symptoms has occurred.  LCZ696 must not be re-administered.  The occurrence of an 
angioedema-like event must be reported using the appropriate CRF pages including the 
narrative of the event. 


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The risk of angioedema is considered to be adequately managed by exclusion criteria, 
warnings and precautions that recommend permanent discontinuation of LCZ696 and 
symptomatic treatment and monitoring in case angioedema occurs. 
Other risks 
Other risks may be associated with general study procedures, such as pain and infection 
potentially associated with needle pricks required for blood draws.  All of these risks are no 
different from ones associated with similar studies. 
Risks to patients in this trial will be minimized by compliance with the entry criteria, close 
clinical monitoring. 
Benefits of LCZ696 
LCZ696 offers an innovative approach to the treatment of patients with heart failure through 
enhancement of the beneficial effects of the endogenous natriuretic peptides (NP) system and 
other vasoactive peptides while simultaneously limiting the detrimental effects of RAAS 
over-activation.  It has been shown that treatment with LCZ696 translated into a clinically 
meaningful benefit over current evidence-based guideline recommended ACEI therapy for 
reduction in CV death, all-cause mortality, HF hospitalization, including first and total 
hospitalization, and improvement in symptoms and patient-reported outcomes in patients with 
NYHA Class II-IV HF with systolic dysfunction (HFrEF) when LCZ696 has been taken for 
an average of 27 months (McMurray JJ, 2014). 
When compared with enalapril, 16% fewer LCZ696-treated patients required intensification 
of outpatient therapy for worsening of HF defined as addition of a new HF drug, intravenous 
therapy, or an increase in the daily dose of diuretic for more than one month.  When all 
(including repeat) emergency department evaluations for heart failure were considered, the 
LCZ696 group had 30% lower rate of such visits than the enalapril group.  The patients in the 
LCZ696 group had 23% fewer hospitalizations for HF (P<0.001).  In addition, the reduction 
in heart failure hospitalization with LCZ696 was evident within the first 30 days after 
randomization (Packer M, 2015).  In this study, treatment is planned for 26 weeks, and there 
are limited information on a short term treatment. 
Benefits associated with participation in the study include receiving a potentially efficacious 
treatment for a currently unmet medical need in the treatment of HF, as suggested by results 
of previous studies.  Also, all medical monitoring/tests associated with the study will be 
provided to closely observe the patients’ health status in a manned that may be stricter than 
the conventional standard of care, and thus eliciting compliance with medical treatments and 
potentially eliciting the feeling to have more control over their condition, which can lead to a 
more positive outlook and better quality of life.  In addition, the contribution to the diseases 
knowledge attained from this study may lead to more effective treatment in the future for HF 
patients. 


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4 
Population 
The study population will consist of patients hospitalized for an episode of acute 
decompensation of heart failure who are diagnosed with CHF NYHA class II-to-IV and 
reduced ejection fraction (LVEF ≤ 40%).  Patients can be either with first presentation (de 
novo), or acute decompensation of HF due to deterioration in patients with a prior history of 
chronic HF. 
The goal is to randomize approximately 1000 patients in approximately 200 centers 
worldwide.  Approximately, 1250 patients will be screened.  Considering that a 20% 
screening failure rate is expected, approximately 1000 patients are expected to be included in 
the primary analysis. 
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. Male or female patients 18 years of age or older 
3. Patients hospitalized due to acute decompensated HF episode (ADHF as primary 
diagnosis), including Signs and Symptoms evaluation at admission. 
4. Diagnosis of HF New York Heart Association class II-to-IV and reduced ejection fraction 
at Screening 
5. Left ventricular ejection fraction ≤ 40% at Screening (if not assessed at Screening, any 
local measurement made within the past 12 months using echocardiography, MUGA, CT 
scanning, MRI, or ventricular angiography is acceptable, provided the latest assessment 
indicates values ≤40% 
6. Patients did not receive any IV vasodilators (except nitrates), and/or any IV inotropic 
therapy from the time of presentation for ADHF to Randomization 
7. Stabilized (while in the hospital) for at least 24 hours leading to Randomization defined 
as: 
• No need for IV diuretics in the past 24 hours prior to signing ICF 
• Systolic blood pressure (SBP) ≥ 110 mm Hg for at least 6 h prior to Randomization 
8. Meeting one of the following criteria: 
• Patients on any dose of ACEI or ARB before admission. 
• ACEI/ARB naïve patients and patients not on ACEI or ARB for at least 4 weeks 
before admission. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. History of hypersensitivity or allergy to the sacubitril, valsartan or any ARBs, or any of 
the LCZ696 excipients.  


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2. Symptomatic hypotension and/or a SBP of (1) < 100 mmHg at Screening, and (2) 
symptomatic hypotension and/or a SBP < 110 mm Hg or SBP > 180 mm Hg prior to 
Randomization. 
3. End-stage renal disease at Screening; or estimated GFR < 30 mL/min/1.73 m2 as 
measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at 
Randomization. 
4. Serum potassium > 5.4 mmol/L at Randomization. 
5. Uses of other investigational drugs within 5 half-lives of enrollment, or within 30 days 
and until the expected pharmacodynamic effects have returned to baseline, whichever is 
longer. 
6. Current hospitalization where patient does not receive treatment for decompensated HF. 
7. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study such as: 
• Concomitant clinically relevant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, symptomatic bradycardia or clinically significant second degree AV 
block, or third degree AV block without a pacemaker; 
• Documented untreated ventricular arrhythmia with syncopal episodes within the 3 
months prior to Screening; 
• History of familial long QT syndrome;  or  
• Known family history of Torsades de Pointes 
8. Known history of hereditary or idiopathic angioedema or angioedema related to previous 
ACE inhibitor or ARB therapy. 
9. Requirement of concomitant treatment with both ACEIs and ARBs, or with aliskiren. 
10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other 
major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty 
within the 3 months prior to Visit 1 (Screening). 
11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 3 months after Visit 1 (Screening). 
12. Implantation of a pacemaker, implantable cardioverter defibrillator (ICD), cardiac 
resynchronization therapy pacemaker / defibrillator (CRT-P/D), or upgrade of an existing 
device or revision of device leads within 1 month of Visit 1 (Screening). 
13. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on 
transplant list) or implant a VAD. 
14. History of severe pulmonary disease (i.e., treatment with oral steroid for their pulmonary 
disease, or with inhaled oxygen on an out-patient basis). 
15. History or evidence of drug or alcohol abuse within the last 12 months. 
16. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months 
prior to Screening. 
17. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral 
regurgitation secondary to left ventricular dilatation. 
18. Presence of other hemodynamically significant obstructive lesions of left ventricular 
outflow tract, including aortic and sub-aortic stenosis. 


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19. 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 at Screening (Visit 1): 
• History of active inflammatory bowel disease during the 12 months before; 
• Current duodenal or gastric ulcers during the 3 months prior to Visit 1; 
• Gastric bypass; 
• Severe hepatic impairment, biliary cirrhosis and cholestasis; 
• History of hepatic encephalopathy, history of esophageal varices, or history of 
portacaval shunt 
OR evidence of hepatic disease as determined by any one of the following: AST or 
ALT values exceeding 5 x ULN or total bilirubin > 3 x ULN at Screening; 
• Active treatment with cholestyramine or colestipol resins; 
20. Presence of any other disease with a life expectancy of < 90 days. 
21. Presence of bilateral or unilateral renal artery stenosis. 
22. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
23. Any surgical or medical condition, which in the opinion of the investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study. 
24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test. 
25. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 7 days after discontinuation of LCZ696 treatment.  
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. 
o Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception; 
• 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): 
a. use of oral, injected or implanted hormonal methods of contraception (combined 
estrogen and progestogen or progestogen only) 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 


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• In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking 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 six months of 
spontaneous amenorrhea with the appropriate hormonal profile, or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to study 
treatment administration.  In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment she is 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 medications: 
• 50 mg LCZ696 film-coated tablet that contains 24 mg sacubitril and 26 mg valsartan (as 
sacubitril valsartan sodium salt complex). 
• 100 mg LCZ696 film-coated tablet that contains 49 mg sacubitril and 51 mg valsartan (as 
sacubitril valsartan sodium salt complex). 
• 200 mg LCZ696 film-coated tablet that contains 97 mg sacubitril and 103 mg valsartan (as 
sacubitril valsartan sodium salt complex). 
Patients will be required to take the study medication twice daily in addition to their daily 
therapies, possibly at 12 hour interval (i.e., at 7:00 in the morning and 19:00 in the evening).  
Tablets should be taken with a glass of water, and may be administered with or without food. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment groups 
Patients will be assigned in a ratio of 1:1 within each stratum to one of the following 
treatment groups 
• Pre-discharge initiation of LCZ696 treatment, where treatment is started prior to 
Discharge (see study design for timing); 
• Post-discharge initiation of LCZ696 treatment, where treatment should be started 
AFTER Discharge but within two (2) weeks after Discharge (see study design for 
timing).  


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5.3 
Treatment assignment, randomization 
Stratification will occur prior to Randomization and it will be based on the patient’s HF-
therapy prior to admission (i.e., ACEI, ARBs, or ‘ACEI/ARB-inhibition-naïve treatment’). 
Stratification will ensure that within a stratum the distribution between Pre- and Post-
discharge is similar.  It is expected that the naïve patients will represent at least 7% of the 
total number of patients (i.e., 70 patients from in total 1000 randomized patients). 
For the samples size of 1000 patients, a maximum of 930 of ACEI or ARB-treated patients 
will be randomized, to ensure achieving the minimum target of 70 ACEI/ARB-naïve patients.  
However, more than 70 RAAS inhibition-naïve treatment patients could be included if during 
the study conduct a higher number is enrolled.  Stratification will be performed at the country 
level. 
Randomization/treatment assignment will be accomplished through the Interactive Response 
Technology (IRT). 
5.4 
Treatment blinding 
This is an open-label study, therefore, after randomization, the investigator, pharmacist and 
subject will be aware of which treatment is administered to the subject.  If the investigator 
interacts with the Novartis clinical team, he/she should not disclose treatment assignment to 
the Novartis team, where avoidable.  The independent statistician, programmer and data 
manager coordinator, who need to be unblinded to review interim analysis reports for the 
DMCs, will not be involved in any other trial activities.  Due to the nature of the CRF, 
accidental systematic unblinding is possible for anyone involved in ongoing data review.  
However, as treatment assignment is not openly apparent, and it would need a combination of 
data from different panels to ascertain, it is assumed that the scientific credibility of the study 
will not be compromised. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number.  The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator.  At each site, the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient number 
2, the third patient is assigned patient number 3).  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. 
For this study using eCRFs, only the assigned patient number should be entered in the field 
labeled “Patient ID” on the EDC data entry screen (e.g. enter ‘1’, ‘2’, etc.).  Once assigned to 
a patient, the patient number will not be reused.  If the patient fails to be randomized for any 
reason, the IRT must be notified within 2 days that the patient was not randomized.  The 


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reason for not being randomized will be enter on Screening phase disposition electronic Case 
report form (eCRF).  
The following eCRF must be completed for subjects who screen fail:  The demography 
eCRF, Informed consent eCRF; Inclusion/ Exclusion eCRF; the adverse event eCRF paper 
serious adverse event (SAE) form should be complete for any SAE that occurred during the 
screening period; Death eCRF (only in case of death during the screening period) and 
Withdrawal of informed consent eCRF (if consent was withdrawn during the screening period 
before the patient was randomized). 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment.  The 
investigational treatment packaging has a 2-part label.  A unique medication number is printed 
on each part of this label which corresponds to one of the two treatment groups 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. 
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. Technical complaints are to be reported to the respective 
Novartis CPO Quality Assurance. 
Medication labels will 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 monitors during site visits or remotely 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. 


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5.5.3.2 
Handling of other study treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
The target dose of LCZ696 is 200 mg twice daily. 
The recommended starting dose of LCZ696 is 100 mg twice daily. 
A starting dose of 50 mg LCZ696 twice daily should be considered for: 
(1) patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or an 
angiotensin II receptor blocker (ARB);  
(2) patients previously taking low doses of these agents; 
(3) patients with moderate hepatic impairment (Child Pugh B classification), or with 
AST/ALT values more than twice the upper limit of the normal range; 
(4) patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m2). 
The dose of LCZ696 should be doubled every 2-4 weeks to achieve the target dose of 200 mg 
twice daily, as tolerated by the patient. 
If a dose of LZC696 is missed, the patient should take the next dose at the scheduled time. 
Investigator judgment will be the basis for up-titration toward the target dose taking into 
consideration tolerability (i.e., incidence of hypotension, renal or hepatic impairment and 
hyperkalemia) based on clinical evaluation and laboratory assessment.  In case of patients 
experiencing tolerability issues, the investigator should consider (a) adjusting concomitant 
medications, or (b) temporary down–titration, or (c) temporary or permanent discontinuation 
of LCZ696. 
All therapy dosages prescribed and dispensed to the patient and all dose changes during the 
study must be recorded on the Dosage Administration Record CRF.  Similarly, if any adverse 
events is reported, the appropriate eCRF page must be completed. 
All kits of investigational treatment assigned by the IRT will be recorded in the IRT system. 
The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the investigator 
if he/she is unable for any reason to take the LCZ696 as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
At the discretion of the investigator, patients could be initiated and may be maintained on 
either 50 or 100 mg LCZ696 bid, if they are unable to tolerate up-titration to higher doses of 
LCZ696 in this open-label study. 
Every attempt should be made to achieve and maintain patients on the target LCZ696 dose 
level of 200 mg bid. 
Study drug dose level adjustments should be based on overall safety and tolerability with 
special focus on: 


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a) hyperkalemia (Appendix 3:  treatment guidelines for hyperkalemia); 
b) symptomatic hypotension (Appendix 4:  guidelines for management of BP); 
c) clinically significant decrease in eGFR/increase in serum creatinine (Appendix 5:  
guidelines for management of renal dysfunction). 
d) worsening hepatic function. (Appendix 2: Liver event and laboratory trigger definitions and 
follow up requirements). 
If, in the opinion of the investigator, the patient does not tolerate the assigned dose level, the 
investigator should consider the following: 
1. Whether non-disease-modifying medication (e.g., diuretics, nitrates, CCBs, α-blockers) 
can be reduced to rectify the situation, before reducing the dose of the study drug to a 
lower dose level (100 mg bid or 50 mg bid LCZ696).  
2. Adjust doses of disease-modifying medications (e.g., β-blockers, aldosterone 
antagonists) if it is believed that they are the most likely cause of the adverse effect. 
3. If adjustment/elimination of concomitant medications is not possible or does not 
alleviate the side effects of concern, the investigator may down-titrate the dose of the 
LCZ696 to: 
a. the next lower level 
The patient should be re-challenged with a higher dose when the investigator feels 
it is appropriate to do so per the directions provided below in this section. 
b. temporary or permanent withdrawal of the study drug 
If the study drug is temporarily discontinued, it should be reintroduced as soon as 
medically justified in the opinion of the investigator. 
Any changes in the LCZ696 dose level must be recorded on the Dosage Administration 
Record eCRF and registered in the IRT system.  Similarly, if any adverse events is reported, 
the appropriate (AEV) eCRF page must be completed. 
Adjustment of LCZ696 dose level 
If, adjustment of concomitant medications as per the guidance provided above does not rectify 
the situation, the investigator may consider adjusting the dose of LCZ696 according to the 
following instructions. 
If down-titration is necessary, the patient should be down-titrated to the next lower dose level. 
The patient may continue to receive the lower dose level for a recommended period of 1 to 4 
weeks, or longer based on the investigator’s judgment, before re-challenging the patient with 
the next higher dose level.  For example, a patient who encounters tolerability problems at the 
target dose of 200 mg LCZ696 bid could be down-titrated to the dose of 100 mg LCZ696 bid 
for 1 to 4 weeks. 
If the tolerability issues are not alleviated despite down-titration by one dose level, the 
investigator may lower the study drug dose further to the next lower level for 1 to 4 weeks, if 
feasible, or to temporary discontinue the study drug (see next paragraph for details). 
In some instances, according to the safety and tolerability criteria and the investigator’s 
judgment, LCZ696 dose level of 50 or 100 mg bid can be maintained if he/she considers that 


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the patient’s condition would not allow any further up-titration to the target dose of 200 mg 
LCZ696 bid.  In this case it would be acceptable to maintain the patient at the highest 
tolerated dose level. 
At each up- or down-titration, IRT should be contacted to register any changes in the patient’s 
LCZ696 dose level, including cases of temporary and permanent withdrawal of the study 
drug, and to obtain the medication numbers of the LCZ696 supplies required for the new dose 
level. 
Study drug restart after temporary treatment interruption 
Once the investigator considers the patient’s condition appropriate for receiving LCZ696, the 
investigator should re-start the patient on the study drug at the most appropriate and allowable 
dose level per his/her medical judgment. If tolerated, the dose of LCZ696 should be doubled 
every 2 to 4 weeks to the target dose of 200 mg twice daily, as tolerated by the patient and as 
per the investigator’s judgment.  
Should the patient not tolerate the re-started study drug at a particular dose level, he/she may 
be down-titrated again (if appropriate) or the study medication temporary discontinued again 
and a new attempt to up-titrate or reintroduce the study drug could be considered by the 
investigator if justified in his/her medical judgment. 
Study visits should occur as close as possible to the time points indicated in the Assessment 
Schedule. The time interval between the regular visits should be maintained as scheduled, 
irrespective of the number of unscheduled visits that may be performed in between, according 
to the visit and time schedule described in the Assessment Table. 
In case of pregnancy discovered during the study, the patient should be instructed to 
stop taking the study drug immediately.  See Section 7.7 for further details on pregnancies 
and reporting guidelines. 
Upon permanent discontinuation of LCZ696 treatment, a minimum of 36 h between last 
dose LCZ696 and first dose of ACEI should be completed.  Any changes in the study drug 
dose level, including temporary/permanent withdrawal or re-start of the study drug, must be 
recorded on the Dosage Administration Record eCRF and registered in the IRT system. 
5.5.6 
Rescue medication 
Guidance on handling liver event, hyperkalemia, hypotension, and renal dysfunction are 
provided to investigators in Appendix 2, 3, 4, and 5, respectively.  Based on reported 
tolerability events, changes/lowering in LCZ696 dose levels or temporary discontinuation are 
allowed during the study and must be recorded in the eCRF page. 
In case of concomitant medication administration, please record them in the appropriate eCRF 
page, and in the occurrence of an adverse event refer to the safety section of this protocol for 
reporting procedures. 
ONLY if LCZ696 has been permanently discontinued, patients may resume the ACEIs and/or 
ARBs treatment.  Se Section 5.5.9 for discontinuation of study treatment. 


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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 (i.e., after signing ICF) into the study must be 
recorded in the CRFs. 
Medication to be recorded in the CRFs: 
• Prior medications:  Medications taken BEFORE hospital admission will be reported in 
the CRFs (also needed for stratification). 
• Treatment administered after signing ICF will be recorded in the CRFs. 
Medications administered during the acute treatments of the decompensated heart failure 
event (from admission to the time of signing ICF) will NOT be included in the CRFs but will 
remain as source documentation. 
5.5.7.1 
Heart failure medications for chronic therapy and other cardiovascular 
medications  
Patients should be on an optimal medical regimen of HF medications except ACE inhibitors 
and ARBs during the whole study duration. The use of an MRA and a β-blocker (if tolerated) 
should be considered in all patients eligible for this study. In self-identified black patients, the 
use of isosorbide dinitrate/hydralazine hydrochloride (e.g., BiDil®) should be considered. 
Every effort should be made to keep the dose level of these background HF medications 
stable throughout the entire study. However, if the patient’s condition warrants a change in 
any of these medications (for example, if the investigator believes a medication is causing an 
adverse event), it is allowed at the discretion of the study investigator. 
Diuretics may be used and may be adjusted throughout the length of the study at the discretion 
of the investigator. 
5.5.7.2 
Medications known to raise potassium levels 
Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid 
antagonists (e.g. spironolactone, eplerenone), potassium supplements, and salt substitutes 
containing potassium or other agents (such as heparin) may lead to increases in serum 
potassium, and to increases in serum creatinine. 
Medications known to raise potassium levels should be used with caution while the patient is 
receiving the study medication due to the increased possibility of occurrence of hyperkalemia. 
The investigator is encouraged to assess patients’ potassium levels regularly, especially if 
LCZ696 is co-administered with these agents.  
5.5.7.3 
Phosphodiesterase-5 (PDE-5) inhibitors  
PDE-5 inhibitors (e.g., sildenafil, vardenafil and tadalafil) should be used with caution while 
the patient is receiving LCZ696 due to the increased possibility of occurrence of hypotension. 


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5.5.7.4 
Intravenous neseritide, nitroprusside and nitrates 
The concomitant administration of LCZ696 with intravenous (i.v.) nitrates/nitroglycerin has 
been studied in healthy volunteers.  There was no significant difference in the magnitude, 
dose or time-course of the decrease in systolic and diastolic blood pressure when nitroglycerin 
was given alone compared to the co-administration of nitroglycerin and LCZ696. 
The concomitant administration of LCZ696 with i.v. neseritide or nitroprusside has not 
been studied. In the event a study patient requires the concomitant administration of neseritide 
and/or nitroprusside with LCZ696, the investigator should consider starting them at a lower 
dose or a slower infusion rate while monitoring the patient’s blood pressure carefully. 
5.5.7.5 
Atorvastatin and other statins 
In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters.  LCZ696 
may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as 
statins. 
In vivo, at steady state, the levels of atorvastatin increased when co-administered with 
LCZ696.  Co-administration of LCZ696 increased the Cmax of atorvastatin and its 
metabolites by up to 2-fold and AUC by up to 1.3-fold.  Therefore, caution should be 
exercised upon co-administration of LCZ696 with statins. 
However, steady state pharmacokinetics of LBQ657 (neprilysin component of LCZ696) were 
not changed, valsartan levels decreased slightly when administered with atorvastatin. The 
effect of LCZ696 on other statins has not been examined. 
Based on these results, caution is recommended when LCZ696 is co-administered with 
atorvastatin or other statins that are substrates of the organic anion transporters, OATP1B1 
and OATP1B3. 
5.5.8 
Prohibited treatment 
ACEIs, ARBs and direct renin inhibitors such as aliskiren 
In this clinical trial, patients’ pre-study ACEIs/ARBs will be replaced with LCZ696. 
Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, 
LCZ696 must not be started for at least 36 hours after discontinuing ACE inhibitor therapy. 
LCZ696 should not be co-administered with an ARB due to the angiotensin II receptor 
blocking activity of valsartan. 
The concomitant use of any ACEIs or ARBs is strictly prohibited while the patient is 
receiving LCZ696. If the investigator believes that addition of an ACEI or ARB is necessary, 
then LCZ696 must be discontinued. If treatment with LCZ696 is stopped, ACE inhibitor 
therapy must not be initiated until 36 hours after the last dose of LCZ696. 
Concomitant administration of direct renin inhibitors, such as aliskiren is also prohibited in 
this study. 


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Other medications 
Bile acid sequestering agents, such as cholestyramine and colestipol are prohibited to avoid 
interference with study drug absorption. 
5.5.9 
Discontinuation of study treatment 
During the Treatment Epoch (up to 10 weeks after Randomization), permanent 
discontinuation of LCZ696 treatment should NOT be considered withdrawn from the study.  
The patient should return for the assessments indicated for Visit 199 (10-weeks after 
Randomization), if discontinued before that visit, and Visit 199 will be also the End of Study 
visit for that patient.  If they fail to return for these assessments for unknown reasons, every 
effort (e.g. telephone, e-mail, letter) should be made to contact them as specified in Section 
5.5.11. 
During the Follow-up Epoch, permanent discontinuation of LCZ696 constitutes withdrawal 
from the study.  Under these circumstances, the patient should be evaluated at a final study 
visit but will not undergo assessments thereafter unless additional follow-up is required due to 
prior occurrence of an adverse event. 
The investigator must also notify the IRT of the patient’s permanent discontinuation of 
LCZ696 and record it on the Drug Administration Record of the eCRFs.  
The emergence of the following circumstances will require LCZ696 discontinuation: 
• Withdrawal of informed consent 
• Failure to follow study-related instructions 
• Pregnancy (Section 7.7) 
• Use of prohibited treatment 
• Investigator thinks that continuation would be detrimental to the patient’s well-being  
LCZ696 may be permanently discontinued at the investigator’s discretion if any of the 
following occurs: 
• Any severe suspected drug-related AE 
• Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator and constitute a 
reason for discontinuation of study medication. 
Depending on the serum potassium, blood pressure, or eGFR, patients may need to have their 
LCZ696 dose or the dose of another concomitant medication reduced or discontinued, or, if 
appropriate, have potentially contributing agents adjusted.  Please refer to Appendices 3, 4, 
and 5 for treatment guidelines for hyperkalemia, hypotension, or renal dysfunction, 
respectively. 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  


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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 (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information.  
Treatment with LCZ696 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. 
5.5.11 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show “due diligence” by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred. 
5.5.12 
Emergency breaking of assigned treatment code 
This is an open-label study therefore emergency breaking of treatment assignment is not 
applicable. 
5.5.13 
Study completion and post-study treatment 
Patients who reach Visit 299/EoS while taking study medication will be considered 
completers.  Patients already in screening at the time planned enrollment is met will be 
allowed to continue in the study based only on approval from Novartis.  Otherwise, these 
patients will be screen-failed. 
The investigator must provide follow-up medical care for all study completers and all patients 
who are prematurely withdrawn from the study, or must refer them for appropriate ongoing 
care.  This care may include continuation of treatment with commercially available LCZ696 
treatment or, if this will be not feasible, switching patients to ACEI/ARBs in addition to other 
guidelines recommended HF medications. Due to the potential risk of angioedema when 
LCZ696 used concomitantly with an ACE inhibitor, ACE inhibitor therapy must not be re-
started until 36 hours after discontinuing of LCZ696.  The type of treatment administered 
after End of study with regard to HF treatment (i.e., ACEI, ARBs, LCZ696) will be also 
included in the Concomitant Medication page. 
5.5.14 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 


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Ethics Committee (IRBs/IECs) of the early termination of the trial. The trial could also be 
terminated prematurely at the recommendation of the DMC if they decide any safety issues 
require trial termination. 
6 
Visit schedule and assessments 
The assessment table (Table 6-1) lists the assessments schedule by study visit.  All data 
obtained from the assessments listed, and described in detail in the subsections below, must be 
supported in the patient’s source documentation (e.g., medical charts or patient notes).  In the 
table it is and indicates with an “X” when the visits are performed, and identified which data 
remain in source documents only (S), or are entered into the database from separate source 
documents, i.e. outside vendors (D).  
The investigator should remember to implement the mandatory 36 hours washout for ACEI 
prior to starting treatment with LCZ696, although it is not clearly indicated in the table of 
assessment. 
Patients should take their scheduled dose of LCZ696 in the morning of their study visits. 
Patients are not required to fast overnight on the day prior to or the day of the study visit.  
 
 
Since this study will compare two initiation regimens for LCZ696 that may differ in 
their duration, it will be important for patient visits to be maintained within the visit 
windows specified in the protocol. 
Up to the time of 10 weeks after Randomization (Visit 199), if one visit is changed with either 
an earlier or later date outside of the range provided, that should not result in a rescheduling of 
the next visit.  In fact, the next visit, if at all possible, should adhere to the original time 
schedule. 
Visits occurring after discharge but before 10 weeks after Randomization (Visit 199) should 
occur within a window of +/- 3 days of the designated calendar day according to 
Table 6-1.  Visits occurring during the Follow-up Epoch should occur within a window of +/- 
7 days of the designated calendar day 
Specific circumstances surrounding missed or rescheduled visits must be discussed with the 
study monitor.  Missed or rescheduled visits SHOULD NOT LEAD automatically to patient 
discontinuation. 
For patients who permanently discontinue LCZ696 during the Treatment Epoch (up to visit 
199), irrespective of the treatment assignment group, the last date of LCZ696 administration 
will be entered in the drug administration records (DAR) page of the CRFs.  However, the 
patient will be followed-up and should return to the site for all remaining visits up to Visit 199 
(10 weeks after Randomization) but will not return for the Follow-up epoch. 
Enrolled patients withdrawing from the study for any reasons during the Follow-up Epoch 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 


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for End of Study visit (EoS, Visit 299) will be performed.  At this final visit all dispensed 
medication supplies should be reconciled and the Adverse Events and Concomitant 
Medications updated on their respective CRFs. 
Documentation of attempts to contact the patient who do not report for the EoS visit, and are 
lost to follow-up, should be recorded in the source documentation.  


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Table 6-1 
Assessment table 
Epoch 
Screen-
ing 
Treatment 
Follow-up 
Visit 
1 
101 
Random
-ization 
Start date 
of Pre-
discharge 
treatment
102 
Discharge 
 
Start date 
of Post-
discharge 
103 
104 
105 
106 
199 
& TD 
and/or 
PPW 
201 
202 
203 
End of Study 
Visit 
299  
& TD and/or 
PPW 
Day 
-3-to-1 
1 
 
 
 
14§ 
28§ 
 
 
 
 
 
 
 
Weeks AFTER 
Randomization 
 
 
 
 
 
2§ 
4§ 
6§ 
8§ 
10§ 
14 Φ 
18 Φ 
22 Φ 
26 Φ 
Weeks of follow-up 
 
 
 
 
 
 
 
 
 
 
4 
8 
12 
16 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and smoking 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
S 
X  
 
X 
 
 
 
 
 
X 
 
 
 
X 
Signs & Symptoms 
S 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
NYHA class 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Prior & Concomitant 
HF Medications 
X  
X  
 
XΔ 
 
XΔ 
XΔ 
XΔ 
XΔ 
XΔ 
XΔ 
XΔ 
XΔ 
XΔ 
Physical Exam 
S 
 
 
 
 
 
 
 
 
 
 
 
 
S 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Epoch 
Screen-
ing 
Treatment 
Follow-up 
Visit 
1 
101 
Random
-ization 
Start date 
of Pre-
discharge 
treatment
102 
Discharge 
 
Start date 
of Post-
discharge 
103 
104 
105 
106 
199 
& TD 
and/or 
PPW 
201 
202 
203 
End of Study 
Visit 
299  
& TD and/or 
PPW 
Day 
-3-to-1 
1 
 
 
 
14§ 
28§ 
 
 
 
 
 
 
 
Weeks AFTER 
Randomization 
 
 
 
 
 
2§ 
4§ 
6§ 
8§ 
10§ 
14 Φ 
18 Φ 
22 Φ 
26 Φ 
Weeks of follow-up 
 
 
 
 
 
 
 
 
 
 
4 
8 
12 
16 
Weight 
S 
X 
 
S 
 
 
 
 
 
S 
 
 
 
S 
Vital signs 
X 
X ₪ 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood hematology 
L, S 
C 
 
 
 
 
 
 
 
C 
 
 
 
C 
Blood biochemistry, 
Local Laboratory 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biochemistry 
Central laboratory 
 
C 
 
C 
 
 
C 
 
 
C 
 
 
 
C 
Serum creatinine, 
potassium, ALT, AST, 
total bilirubin -  
Local Laboratory 
Ł 
L 
 
L 
 
L 
L 
L 
L 
L 
L 
L 
L 
L 
Serum creatinine, 
potassium, ALT, AST, 
total bilirubin - 
Central laboratory 
 
 
 
 
 
C 
 
C 
C 
 
C 
C 
C 
 
Urine dipstick 
 
L 
 
 
 
L 
L 
L 
L 
L 
L 
L 
L 
L 
Urine albumin & 
 
C 
 
C 
 
C 
C 
C 
C 
C 
C 
C 
C 
C 


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Epoch 
Screen-
ing 
Treatment 
Follow-up 
Visit 
1 
101 
Random
-ization 
Start date 
of Pre-
discharge 
treatment
102 
Discharge 
 
Start date 
of Post-
discharge 
103 
104 
105 
106 
199 
& TD 
and/or 
PPW 
201 
202 
203 
End of Study 
Visit 
299  
& TD and/or 
PPW 
Day 
-3-to-1 
1 
 
 
 
14§ 
28§ 
 
 
 
 
 
 
 
Weeks AFTER 
Randomization 
 
 
 
 
 
2§ 
4§ 
6§ 
8§ 
10§ 
14 Φ 
18 Φ 
22 Φ 
26 Φ 
Weeks of follow-up 
 
 
 
 
 
 
 
 
 
 
4 
8 
12 
16 
creatinine- 
Central laboratory 
Pregnancy test * 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Contact IRT 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
x 
X 
Dispense Study 
Medication / DAR 
 
 
A 
 
B 
X** 
X** 
X** 
X** 
X** 
X** 
X** 
X** 
 
Drug accountability 
 
 
 
 
 
D 
D 
D 
D 
D 
D 
D 
D 
D 
Adverse events 
X 
Study Completion 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 TD = study discontinuation 
 PPW = Premature patient withdrawal 
 X = assessment to be recorded on clinical data base 


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Epoch 
Screen-
ing 
Treatment 
Follow-up 
Visit 
1 
101 
Random
-ization 
Start date 
of Pre-
discharge 
treatment
102 
Discharge 
 
Start date 
of Post-
discharge 
103 
104 
105 
106 
199 
& TD 
and/or 
PPW 
201 
202 
203 
End of Study 
Visit 
299  
& TD and/or 
PPW 
Day 
-3-to-1 
1 
 
 
 
14§ 
28§ 
 
 
 
 
 
 
 
Weeks AFTER 
Randomization 
 
 
 
 
 
2§ 
4§ 
6§ 
8§ 
10§ 
14 Φ 
18 Φ 
22 Φ 
26 Φ 
Weeks of follow-up 
 
 
 
 
 
 
 
 
 
 
4 
8 
12 
16 
 S = assessment to be recorded on source documentation only 
 L = assessment carried out through the Local laboratory (and entered manually in the data base) 
 D = These assessments are source documentation only and will not be entered into the CRF, but collected and transferred to the database 
 *   Please, see Section 6.5.7 for details. 
 **  dispensing study medication depending upon change of dose level, or refilling the same dose 
 
 §  Visit should occur  within a window of +/- 3 days of the designated calendar day 
 Φ  Visit should occur  within a window of +/- 7 days of the designated calendar day 
   For patients with ‘prolonged hospital stay’ (see Section 3.1 Study design) the assessments assigned to the Discharge visit should be carried out 
BEFORE starting LCZ696 treatment 
₪ Values of BP over the preceding 24 h leading to confirmation of hemodynamic stabilization and leading to Randomization must be entered in the 
CRFs. 
 A start of LCZ696 treatment if assigned to the PRE-discharge treatment initiation 
 B start of LCZ696 treatment if assigned to the POST-discharge treatment initiation, and no later than 2 weeks after Discharge, or the date of 
stabilization as indicated by the physician. 
Ł  Values for [Serum creatinine, potassium, ALT, AST, total bilirubin] obtained from the local full biochemistry assessment should be entered in the 
CRFs. 


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Epoch 
Screen-
ing 
Treatment 
Follow-up 
Visit 
1 
101 
Random
-ization 
Start date 
of Pre-
discharge 
treatment
102 
Discharge 
 
Start date 
of Post-
discharge 
103 
104 
105 
106 
199 
& TD 
and/or 
PPW 
201 
202 
203 
End of Study 
Visit 
299  
& TD and/or 
PPW 
Day 
-3-to-1 
1 
 
 
 
14§ 
28§ 
 
 
 
 
 
 
 
Weeks AFTER 
Randomization 
 
 
 
 
 
2§ 
4§ 
6§ 
8§ 
10§ 
14 Φ 
18 Φ 
22 Φ 
26 Φ 
Weeks of follow-up 
 
 
 
 
 
 
 
 
 
 
4 
8 
12 
16 
  
 
 
 Δ Review and update ConMeds as therapies may change/be optimized or titrated 
   Concomitant medications taken BEFORE admission, to enable stratification 
    Concomitant medications/therapy provided at the time of achieving hemodynamic stability (24 h prior to Randomization) 
  
 


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6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the Treatment Epoch will 
have the study completion page for the screening epoch, demographics, inclusion/exclusion, 
reason for failing screening, and serious adverse event (SAE) data collected.  Adverse events 
that are not SAEs will be followed by the investigator and collected only in the source data. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
year of birth, age, sex, race, ethnicity, smoking habit and alcohol use, relevant medical 
history/current medical condition present before signing informed consent, where diagnoses 
and not symptoms will be recorded. 
Concomitant medication prior to admission will be collected at Screening to enable allocation 
of stratum.  No acute therapy to treat ADHF will be collected up to the time of stabilization.  
Records of concomitant medications/therapy will resume (entered in the CRFs) at the time of 
achieving hemodynamic stability (24 h prior to Randomization), when concomitant 
medications are expected to be stable after the acute event treatment.  Concomitant 
medications provided to treat AEs will be entered all the time when administered. 
6.3 
Treatment exposure and compliance 
Duration of study drug exposure will be calculated based upon the start and stop dates 
recorded in the eCRF. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the care giver, where feasible.  Study drug accountability 
will also be determined by the site monitor while performing routine site visits and at the 
completion of the study. 
6.4 
Efficacy 
Efficacy variables will not be assessed in this study. 
6.5 
Safety 
6.5.1 
Assessment or primary endpoint 
The primary endpoint for this trial will be assessing the proportion of patients who achieve 10 
weeks up-titration success, which is defined as achieving the target dose of LCZ696 200 mg 
bid at 10 weeks after randomization (Visit 199) regardless of previous dose interruption or 
down-titration  (Yes/no). 
6.5.2 
Assessment of secondary endpoints 
One of the secondary endpoints for this trial will be assessing the proportion of patients 
achieving and maintaining either the dose of 100 mg and/or 200 mg LCZ696 bid for at least 2 


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weeks leading to week 10 after randomization (Visit 199), regardless of previous dose 
interruption or down-titration during the 10-week after Randomization (Yes/no) 
A further secondary endpoint for this trial will be assessing the proportion of patients 
achieving and maintaining any dose of LCZ696 for at least 2 weeks leading to week 10 after 
randomization (Visit 199), regardless of previous dose interruption or down-titration during 
the 10-week after Randomization (Yes/no) 
The other secondary endpoints for this trial will be assessing the proportion of patients 
permanently discontinuation from study drug, at any time between randomization and week 
10 (Visit 199), as well as during Follow-up Epoch, due to either AEs or any reasons (Yes/no). 
6.5.3 
Safety assessments 
The following safety assessments will be collected throughout the study in all patients: 
• Physical examinations 
• Vital signs 
• Height, weight 
• Laboratory evaluations 
• Electrocardiogram (ECG) 
• All adverse events 
For specific adverse events of interest (Angioedema, Hyperkalemia, Renal Impairment, 
Hypotension, Pregnancy), relevant data will be collected as described in the safety section 
and/or the appendices.  
A Data Monitoring Committee (DMC) will perform interim analyses of tolerability and safety 
with a pre-specified charter in place that outlines potential stopping rules that will be agreed 
upon in advance by the sponsor. 
6.5.4 
Physical examination  
A complete physical examination will be conducted at Screening and at End of Study visit 
(Visits 1, and 299) and 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. 
Information for all physical examinations must be included in the source documentation at the 
study site.  Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF.  Significant findings made after the start of study drug which meet the definition of an 
Adverse Event must be recorded on the Adverse Event screen of the patient’s eCRF. 
6.5.5 
Vital signs 
Vital signs will be assessed at every visit. This will include SBP/DBP and pulse 
measurements. SBP/DBP will be measured by using either a standard sphygmomanometer, or 
an automated blood pressure device, with an appropriate size cuff and the non-dominant arm 
in the sitting/semirecumbent position after 5 minutes of rest. 


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At Screening the values of SBP must be ≥ 100 mm Hg. 
During the 24 hours stabilization interval leading to Randomization, the values of BP must be 
documented.  At least 6 BP measurements should be made, where the initial and last 
measurement should cover the interval of about 24 h (± 1 h).  In particular, during the last 6 
hours prior to Randomization, 3 BP measurements should be made and SBP must be equal or 
above 110 mm Hg for all of them.  For example, if the first measurement is done at 18:00 on 
Tue. 02-Feb-2016, the last measurement should be around 18:00 on Wed. 03-Feb-2016 (± 1 
h).  During the last 6 hours (between 12:00 noon and 18:00 on Wed. 3 measurements must be 
recorded and all should be equal or above 110 mm Hg. 
During the out-patient visits (e.g., after discharge), vital signs include BP and pulse 
measurements assessed after the patient has been sitting for five minutes, with back supported 
and both feet placed on the floor.  If a repeat sitting measurements is deemed appropriate, as 
the patient may display a ‘white coat effect’, the measurement should be taken after 10-15 
minute after the preceding one. 
Clinically notable vital signs requiring review of ongoing therapeutic management are defined 
in Appendix 4. 
6.5.6 
Height and weight  
Height in centimeters (cm) will be measured at Screening (Visit 1) if feasible, otherwise it 
could be assessed at any time before Discharge (Visit 102). 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing without shoes) will be 
measured at Screening (Visit 1, source documentation), at Randomization (Visit 101, to be 
entered in the CRF).  All subsequent assessments at Discharge (Visit 102), at the Visit at 10 
weeks after Randomization (Visit 199), and End of Study visit (Visit 299) will be part of 
source documentation. 
6.5.7 
Laboratory evaluations  
Laboratory samples will be analyzed at the central and local laboratories.  Local laboratory 
results will allow investigators to proceed with study visit procedures without the need to wait 
for central laboratory results, which may take several days to arrive. 
Central and local laboratory results need not agree in order for the investigator to qualify a 
patient for the trial or make a dose titration decision.  Local laboratory assessments will be 
done in addition to central laboratory assessments, not instead of them. 
It is the responsibility of the investigator to review all laboratory results and make an 
assessment of whether an abnormal or notable value is clinically significant, whether 
additional evaluations should be performed as judged appropriate, and whether the patient 
may continue in the trial. Sample collection should be conducted according to the standards 
and requirements of the local laboratory. 
• Laboratory values that exceed the boundaries of a notable laboratory abnormality of 
interest (refer to Appendix 1) must be commented on by the investigator and additional 
laboratory evaluations should be performed, as judged appropriate by the investigator.  


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• If the laboratory abnormality induces clinical signs or symptoms, or requires therapeutic 
intervention, and satisfies the criteria defined in Section 7.1, then the diagnosis or medical 
condition must be entered on the AEs page of the patient's eCRF and any treatment 
necessary should be documented. If the laboratory abnormality is the primary reason for 
an unforeseen prolongation of hospitalization, or unforeseen hospitalization during the 
out-patient period, or otherwise fulfills the seriousness category of an AE, then the 
procedure for rapid notification of SAEs must be followed. 
• Likewise, if the laboratory abnormality leads to LCZ696 dose changes or discontinuation 
of LCZ696 , the patient must be followed until the abnormality resolves or until it is 
judged to be permanent.  Any dose changes must be recorded in the DAR eCRF page.  
This investigation may include continued monitoring by repeat laboratory testing or by 
performing additional laboratory tests as deemed necessary by the investigator or the 
Sponsor’s medical monitor. 
If laboratory assessments must be repeated to confirm laboratory values or due to spoiled 
samples, such repeat assessments must occur within two days from the original 
assessment/study visit.  If the dose of study medication was changed, IRT should be 
contacted, and an update to the Drug Administration Record page of the eCRFs should be 
entered indicating the end of the previous dose level and the start date and new dose level. 
6.5.7.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be reported as per Table 6-2. 
6.5.7.2 
Clinical chemistry 
A full biochemistry laboratory assessment is provided in the table below.  Assessments will 
be carried out at Central and local laboratory as indicated in Table 6-2.  Central laboratory 
assessments are carried out in addition to local laboratory assessment to provide a consistent 
platform and enable comparisons between different centers where different laboratories may 
use different methodologies for the analysis. 
Local laboratory facilities may be used for screening and for safety monitoring supporting the 
evaluation of any dose changes (increase or decrease in the LCZ696 dose). Local laboratory 
results will allow investigators to proceed with study visit procedures, instead of waiting for 
central laboratory results, which may take several days to deliver the results.  In addition, 
there will be no reconciliation of data between central and local laboratory results, and the 
investigator will base the decision to qualify a patient for the next step in the trial based on 
local laboratory data. 
If a patient experiences liver function test (i.e. ALT, AST, ALP, TBL) values upper limit of 
normal during the study, please refer to Appendix 2 for the reporting of liver dysfunction 
events. 
The assessment of eGFR, is based on levels of serum creatinine and should be provided by 
the laboratory of analysis and should be carried out using the simplified MDRD formula 
(Stenens LA, 2006). 


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Please, refer to Table 6-2 for the laboratory (central and/or local) and timing of collection. 


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Table 6-2 
List of laboratory tests 
Hematology * 
Biochemistry ** 
Urine assessments 
Hematocrit 
Hemoglobin 
Platelet Count 
Red Blood Cells count 
WBC Differential 
White Blood Cells count 
 
Alanine amino-transferase (ALT) *** 
Albumin 
Alkaline phosphatase 
Aspartate amino-transferase (AST) *** 
Blood urea nitrogen (BUN)   (OR urea ONLY for 
local laboratory unable to assess BUN) 
Calcium 
Chloride  
Creatinine *** 
eGFR *** 
Fractionated bilirubin (if total bilirubin > 2x ULN) 
Glucose 
Lipid profile (total cholesterol, LDL, HDL, and 
triglycerides) 
Potassium *** 
Sodium  
Total Bilirubin*** 
Total protein 
Uric Acid 
Albumin ¥ 
Creatinine ¥ 
Urine dipstick § 
 
  * Timepoints of hematology assessments performed at  
LOCAL laboratory 
Visit No. 
1, S 
S   to be kept as source documentation 
CENTRAL laboratory 
Visit No. 
101 
199 
299 EoS 
 
 **  Timepoints of complete list blood biochemistry assessments including those marked with ***, 
performed at  
LOCAL laboratory 
Visit No. 
1, S 
S   to be kept as source documentation, with only ‘selected’ values to be entered in the CRFs (see below “Ł”) 
CENTRAL laboratory 
Visit No. 
101 
102 
104 
199 
299 EoS 
 
***  Timepoints of ‘selected’ blood biochemistry, to be entered in the CRFs, performed at  
LOCAL laboratory 
Visit No. 
1 Ł 
101 
102 
103 
104 
105 
106 
199 
201 
202 
203 
299 EoS 
Ł values obtained at Screening for ‘selected’ assessments from the Local full biochemistry should be entered 
in the CRFs 
CENTRAL laboratory 
Visit No. 
103 
105 
106 
201 
202 
203 
 
  §   Urine dipstick performed at 
LOCAL 
laboratory 
Visit No. 
101 
103 
104 
105 
106 
199 
201 
202 
203 
299 EoS 
 
  ¥   Urine albumin and creatinine (spot urine sample) to be assessed at  
CENTRAL 
laboratory 
Visit No. 
101 
102 
103 
104 
105 
106 
199 
201 
202 
203 
299 EoS 


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6.5.7.3 
Urinalysis 
First morning void urine samples should be collected from patients for the dipstick 
assessment.  Dipstick measurements for specific gravity, pH, protein, glucose, bilirubin, 
ketones, WBC, and blood will be performed. WBC sediments will also be measured in case of 
an abnormal dipstick test. 
A spot urine sample could be collected for the assessment of albumin and creatinine to be sent 
to the Central laboratory. 
Please, refer to Table 6-2 for the laboratory (central or local) and timing of collection. 
6.5.8 
Electrocardiogram (ECG)  
ECGs must be recorded after 10 minutes rest to ensure a stable baseline. The preferred 
sequence of CV data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. 
Standard 12 lead ECG will be performed at Screening (Visits 1), at Randomization 
(Visit 101)if more than 48 h after Screening, Discharge (Visit 102), at 10-weeks after 
Randomization (Visit 199), and End of Study visit (Visit 299).  
The original ECGs should be on non-heat sensitive paper and appropriately signed.  The 
assessment at Screening (Visit 1) will be archived at the study site as part of the Source 
documentation.  If Randomization (Visit 101) occurs within 48 hours from Screening, and a 
new ECG is not performed, the ECG data from Visit 1 may be entered in the Randomization 
CRF set, to be used as baseline. All subsequent ECG assessments will be performed on the 
visit date and entered into the CRFs. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings prior to dosing with investigational treatment must be discussed with 
the sponsor. 
6.5.9 
HF Signs & Symptoms and New York Heart Association Class 
Heart failure signs and symptoms and NYHA functional class score will be collected at 
Screening (visit 1, but kept at source) to verify admission for ADHF conditions, 
Randomization (Visit 101), Discharge (Visit 102), at 10-weeks after Randomization (visit 
199), and End of Study (Visit 299). 
6.5.10 
Pregnancy and assessments of fertility  
All pre-menopausal women who are not surgically sterile, as well as women of childbearing 
potential will have pregnancy tests performed locally as serum test at Screening (Visits 1), 
and End of Study visit (Visit 299).  A pregnancy urine test will be performed at 10-weeks 
after Randomization (Visit 199), and monthly during the Follow-up Epoch (Visits 201, 202, 
203).  Se see assessment schedule for visit number reference. 


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A positive pregnancy test at Visit 1 constitutes a screen failure unless the serum β-hCG test is 
performed and found to be negative.  In case of pregnancy discovered at any time during the 
treatment with LZC696, the patient should be instructed to stop taking LCZ696 immediately.  
A follow-up serum pregnancy test can be perform at the discretion of the patient and 
investigator but restarting LCZ696 treatment can be considered only if the test is negative. 
6.5.11 
Appropriateness of safety measurements  
The safety assessments selected are appropriate for this indication/patient population, as well 
as assessing safety for a treatment with the mechanism of action of LCZ696 (angiotensin 
receptor antagonist and neprilysin inhibitor).  For further details, see appendices 1-through 4 
in this document. 


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7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (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. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy.  
Clinically significant abnormal laboratory values or test results 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 adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information. 
• the severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• 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 a serious adverse event (SAE - See section 7.2 for definition of 
SAE) 


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• action taken regarding study treatment 
All adverse events should be treated appropriately.  Treatment may include one or more of the 
following:  
• no action taken (i.e. further observation only) 
• study treatment dosage adjusted/temporarily interrupted  
• study treatment permanently discontinued due to this adverse event  
• concomitant medication given 
• non-drug therapy given 
• patient hospitalized/patient’s hospitalization prolonged 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event 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. 
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 adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information 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 
Angioedema-like events 
Angioedema 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway 
compromise. Although, the mechanism is not fully understood, bradykinin has been 
implicated as the putative mediator. Therefore, medications that raise the levels of 
endogenous bradykinin by inhibiting the enzymes responsible for its breakdown, such as 
ACE, aminopeptidase P, and NEP, may result in this potentially dangerous side effect.  
If angioedema occurs, LCZ696 should be immediately discontinued and appropriate therapy 
and monitoring should be provided until complete and sustained resolution of signs and 
symptoms has occurred. LCZ696 must not be re-administered.  The procedure for reporting 
angioedema-like events is outlined in Section 8.4 of this document. 


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In the event of angioedema reporting, the treatment with LCZ696 must be immediately and 
permanently interrupted (i.e., do not wait for the adjudication outcome). 
 
7.3 
Serious adverse events 
7.3.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 


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All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per section 7.2.2. 
7.3.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any 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 
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. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study treatment, complete the SAE 
Report Form in English, and send the completed, signed form by fax within 24 hours after 
awareness of the SAE to the local Novartis Drug Safety and Epidemiology Department. The 
telephone and fax number of the contact persons in the local department of Drug Safety and 
Epidemiology, specific to the site, are listed in the investigator folder provided to each site. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the case report form documentation at the study site. Follow-up information should be 
provided using a new paper SAE Report Form stating that this is a follow-up to a previously 
reported SAE 
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 or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries. 


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7.4 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of 
LCZ696, a standardized process for identification, monitoring and evaluation of liver events 
has to be followed. 
Liver events are divided into two categories: 
• Liver events of special interest (AESI) which consist of LFTs elevations 
• Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events. 
Please refer to the table in Appendix 2 for complete definitions of liver events.  In case of a 
Liver Event reporting is needed, please remember to fill out the appropriate CRF pages 
(Liver-Events CRF). 
Any liver event which meets the criteria for “medically significant” event as outlined in the 
table of Appendix 2 should follow the standard procedures for SAE reporting as described 
in Section 7.3 of this protocol.  
Every liver event as defined in the table of Appendix 2 should be followed up by the 
investigator or designated personal at the trial site as summarized below.  
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of LCZ696 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 the 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 
Serum potassium safety monitoring (hyperkalemia) 
To ensure patient safety, a standardized process for identifying, monitoring, and managing 
hyperkalemia is summarized in Appendix 3. 
7.6 
Renal safety monitoring 
To ensure patient safety, a standardized process for identifying, monitoring, and managing 
renal dysfunction is summarized in Appendix 5. 
7.7 
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, 


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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 the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to LCZ696 treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization.  
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file.  The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the 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. 


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8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
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.  
Novartis staff [or 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. 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 adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
In addition, for laboratory samples are analyzed centrally, laboratory samples will be 
processed centrally and the results will be sent electronically to Novartis. 
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). 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked.  Any changes to the database after that time can only be made after written agreement 
by Novartis Development management. 
8.3 
Data Monitoring Committee 
An internal and independent data monitoring committee (DMC) will be formed for this trial to 
monitor the study conduct, to review the results from the interim analyses, and to determine if 
it is safe to continue the study according to the protocol.  If applicable, the recommendation 
may include any new relevant safety issues(s) identified by the DMC during the evaluation or 
recommendation to stop the trial for safety or tolerability. 


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The DMC will include experts in cardiovascular disease, nephrology, clinical trials, and 
statistics; the members will review the results confidentially and will have no other roles in 
the study.  
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 the data flow, purpose, 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. 
8.4 
Angioedema Adjudication Committee – program-wide 
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis in the 
study eCRF). Details on the process of reporting angioedema and angioedema like events are 
outlined in a manual provided to investigators. 
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.  
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document (entitled ”Data Monitoring Committee Charter”).  The DMC Charter 
will include information about data flow, purpose and timing of DMC meetings, guidance in 
the decision making process, communication strategy, procedures for ensuring confidentiality, 
procedures to address conflicts of interest and statistical monitoring guidelines.  The DMC is 
not specific to this study, but reviews all angioedema events in the LCZ696 program. 
The procedure for reporting angioedema-like events 
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema that may be reported by patients.  
If swelling or edema that resembles angioedema occurs, the investigator will complete a 
Questionnaire for an Angioedema Event form (provided by the Sponsor in the eCRFs) to 
summarize the event, its treatment, and its ultimate outcome and communicate this report to 
the Sponsor as soon as possible.  An angioedema AE will be recorded in the Adverse Event 
eCRFs if the criteria described in Section 7.1 are fulfilled.  All angioedema reports will be 
forwarded to an angioedema adjudication committee for assessment. 
If such an event occurs, the investigator will complete a Questionnaire for an Angioedema 
Event form (provided by the Sponsor in the eCRFs) to summarize the event, its treatment, 
and its ultimate outcome and communicate this report to the Sponsor as soon as possible. 
Follow up reports must be communicated to the Sponsor as soon as new information 
regarding the event becomes available. All hospital records related to the event must be 
communicated to the Sponsor. 
All Angioedema Questionnaire for an Angioedema Event will be forwarded to an 
angioedema adjudication committee by the Sponsor for assessment. 


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If an angioedema event satisfies the definition of an SAE, the investigator must also submit 
an SAE report, as outlined in the next section.  Submission of an angioedema questionnaire 
report is not a substitution for the submission of an SAE report. 
9 
Data analysis 
9.1 
Analysis sets 
The following populations will be used for the statistical analyses: 
Randomized Population (RAN) will consist of all patients randomized. 
The full analysis set (FAS) will consist of all randomized patients with the exception of those 
patients who 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. 
The Safety Population (SAF) will consist of all randomized patients who received at least one 
dose of study drug. Patients will be analyzed according to treatment actually received. The 
safety population will be used for the analyses of safety variables. 
9.2 
Patient demographics and other baseline characteristics 
The baseline value for any analysis variable in general is defined as the value measured at 
Visit 101 for all analyses except that a specific definition or reason is provided. For 
information which is not collected at Visit 101, e.g. NYHA class, physical exam, 
demography, local laboratory assessment, etc., the information collected at Visit 1 will be 
used for baseline evaluations.  
Summary statistics for demographics and baseline characteristics will be provided by 
treatment group. The summary will be provided in mean, standard deviation, median, 
minimum and maximum for continuous variables or in frequency and percentage for 
categorical variables. 
Treatment group comparability at baseline will be examined using a chi-squared test for the 
categorical variables and using a t-test for the continuous variables as appropriate. These p-
values are provided for descriptive purposes, and are not to be considered to define any formal 
basis for determining factors that should be included in statistical models.  
In addition, the patient relevant medical history and/or continuing medical conditions 
recorded at Visit 1 or Visit 101 will be summarized by primary system organ class, preferred 
term and treatment group. 
The FAS will be the patient population for the above analyses. 
9.3 
Treatments 
The duration on the treatment period will be summarized by treatment group (i.e., n, mean, 
standard deviation, median, minimum, and maximum). 


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Prior concomitant medications and concomitant medications used during the double-blind 
treatment period will be summarized by therapeutic class, preferred term and treatment group. 
The SAF population will be used for the above analyses. 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Variable 
The primary variable is 10 weeks up-titration success, and is defined as: “achieving the target 
dose of LCZ696 200 mg bid at 10 weeks after randomization (Visit 199) regardless of 
previous dose interruption or down-titration (Yes/no)”. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary endpoint will be analyzed using the stratified Cochran-Mantel-Haenszel method 
with treatment group and randomization stratification variable (ACEI stratum, ARB stratum, 
or naïve patient stratum) as stratification factor; although randomization is stratified at the 
country level, country will not be used here as an additional stratification factor due to the 
expected small cell counts in some countries, in particular in the naïve patient stratum.  The 
risk ratio (of the Pre-discharge initiation of LCZ696 arm versus the Post-discharge initiation 
of LCZ696 arm) will be estimated with a 2-sided 95% CI along with the estimated rate and 
95% CI for each treatment arm.  The above analyses will be performed based on SAF. 
In addition, a supplementary analysis will be carried out, based on evaluable patients where 
patients with administrative discontinuations (non-AE or non-death reasons) will be 
considered as non-evaluable, and thus excluded.  
9.4.3 
Handling of missing values/censoring/discontinuations 
In the primary analysis, no imputation will be used for any patients, who discontinue study 
therapy due to adverse events or abnormal laboratory values.  All patients who prematurely 
discontinue, and do not achieve and maintain the target dose of LCZ696 200 mg bid at 
10 weeks after randomization will be regarded as 10 week up-titration failures.  Information 
of patients discontinuing study drug or participation in trial visits will be collected whenever 
possible and will be used in the analysis.  In patients who could not be followed up for the 
primary endpoint, it is aimed to at least determine the vital status of the patients at the final 
visit. For the supplementary analysis, patients who prematurely discontinue due to 
administrative reasons (non-AE or non-death) will defined as non-evaluable, and thus be 
excluded from the analysis. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Efficacy variables will not be assessed in this study 
9.5.2 
Safety variables 
The following secondary variables will be used in the analyses: 


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• Achieving and maintaining either the dose of 100 mg and/or 200 mg LCZ696 bid for at 
least 2 weeks leading to week 10 after randomization, regardless of previous dose 
interruption or down-titration during the 10-week after Randomization (Yes/no) 
• Achieving and maintaining any dose of LCZ696 for at least 2 weeks leading to week 10 
after randomization, regardless of previous dose interruption or down-titration during 
the 10-week after Randomization (Yes/no) 
• Permanently discontinuation from study drug (Yes/no),  
1. at any time between Randomization and week-10 after randomization, and  
2. during Follow-up Epoch, due to  
i. either AEs and  
ii. any reasons 
These secondary variables will be analysed in an identical fashion to the primary variable 
(using the stratified Cochran-Mantel-Haenszel method – see 9.4.2 for details). Further safety 
and tolerability assessments are listed below: 
• AEs and SAEs 
• Angioedema 
• Laboratory values  
• Liver safety 
• Vital signs: Systolic and diastolic blood pressure, pulse, heart rate, and body weight 
• ECG changes 
• Physical examination 
• Pregnancy and assessments of fertility 
The assessment of safety will be based primarily on the frequency of adverse events, SAEs, 
and laboratory abnormalities. Other safety data will be summarized as appropriate.  
The incidence of adverse events (new or worsened) will be summarized by primary system 
organ class, preferred term, severity, and relationship to study drug. In addition, the incidence 
of death, SAEs, and AEs leading to discontinuation will be summarized separately by primary 
system organ class and preferred term. 
The characteristics of angioedema will be summarized as appropriate, using relative 
frequencies. 
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. 
Liver safety analyses include frequencies of treatment-emergent elevations, a shift table of 
baseline and worst post-baseline values, respective narrow and broad "Possible drug related 
hepatic disorders - comprehensive search" SMQ and preferred term frequencies, eDISH plots, 
and narratives for any patients discontinued due to liver function abnormalities. 


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Data from vital signs including body weight will be summarized as appropriate, , using both 
descriptive summary statistics, and various threshold flags; incidences of notable values will 
be presented in the tables and notable values will be flagged in the listings. 
The following ECG variables will be summarized as appropriate, using both descriptive 
summary statistics and qualitative changes will be described. 
Safety analyses will be performed based on the safety population. There will be no formal 
statistical inference analysis. 
 
9.5.4 
Pharmacokinetics 
Not applicable 
9.5.6 
PK/PD 
Not Applicable 
9.6 
Sequence of planned analyses 
9.6.1 
Interim analyses 
Two interim analyses are planned to be conducted when 30% and 60% of the patients have 
completed the visit at 10-weeks after Randomization (Visit 199) to detect early safety signals.  
The review will include the following analyses: 
• AEs leading to permanent discontinuation of LCZ696 
• AEs reported leading to down-titration of LCZ696 or temporary discontinuation 
• Incidence of AEs of interest  
• Concomitant medication changes when down-titration was implemented 
• Compliance with the washout from ACEi or discontinuation of ARBs 


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The unblinded interim analysis results will be reviewed with other   safety data by an 
unblinded DMC. At their discretion, the DMC will make a recommendation regarding trial 
continuation/amendment/termination. No stringent stopping boundaries are pre-specified. The 
details of the interim analyses will be defined in the DMC Charter. 
9.6.2 
Final analyses and reporting 
The clinical database will be locked twice. The first database lock will occur when all subjects 
have completed 10 weeks after Randomization evaluation period of the study (Visit 199) and 
all data has been monitored, is query-clean and final. All follow-up data between 10 weeks 
after Randomization (Visit 199) and 26 weeks after Randomization (End of study Visit 299) 
will be included in the 26 weeks database. All planned analyses summarizing results by 
treatment group will be performed after the last subject has completed the 10 weeks after 
Randomization evaluation period of the study. For this analysis, group summaries will be 
presented. Individual subject treatment assignments (e.g. listing) will be provided prior to the 
26 weeks after Randomization lock only if the required for regulatory submission(s); if 
required, these will be provided only to personnel identified by the Sponsor, who have no 
direct role in study operations. These results will be shared with a limited group of people to 
be identified by the Sponsor. 
A second database lock will occur after all subjects have reached 26 weeks after 
Randomization of the study. Analyses of subject accountability and length of following, and 
subject status will be updated. Listings of individual subject data, and other information 
regarding individual subjects’ treatment assignments, will be provided only after the 26 weeks 
after Randomization database is locked, unless required for regulatory submission(s). 
9.7 
Sample size calculation 
The purpose of this study is to explore two modalities (Pre-discharge, and Post-discharge) of 
treatment initiation with LCZ696 in HFrEF patients following stabilization after an ADHF 
episode. 
A sample size of about 1000 patients provides reasonable precision across a range of possible 
outcomes. When the observed rate of 10-weeks up-titration treatment success is 80% in both 
pre- and post-discharge, it will provide estimated risk-ratio and 95% CI of 1.00 (0.94, 1.06). 
 


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Observed rate 
of uptitration success 
at week 10 after 
Randomization 
Risk ratio 
(Pre-discharge / 
Post-discharge) 
2-sided 95% CI 
Total sample size 
without adjustment 
Late 
initiation 
Early 
initiation 
75% 
70% 
0.93 
0.87, 1.01 
1000 
75% 
75% 
1.00 
0.93, 1.07 
1000 
75% 
80% 
1.07 
1.00, 1.14 
1000 
80% 
75% 
0.94 
0.88, 1.00 
1000 
80% 
80% 
1.00 
0.94, 1.06 
1000 
80% 
85% 
1.06 
1.00, 1.13 
1000 
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 CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki. 
10.2 
Informed consent procedures  
[*] Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient 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 
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 treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 


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[*] For Germany only, the first paragraph will read as follows: 
 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent.  He/she should indicate 
assent by personally signing and dating the written informed consent document.  Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. 
 
10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis  Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results 
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. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR. 


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11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in section 7 Safety Monitoring should be followed. 
12 
References 
Du XJ, Hewitson TD, NguyenM-N, et al. (2014) Therapeutic Effects of Serelaxin in Acute 
Heart Failure Circ J. 78:542-552 
Dar O and Cowie MR (2008) Acute heart failure in the intensive care unit: epidemiology.  
Crit. Care Med. 36:S3-8 
Follath F, Yilmaz MB, Delgado JF, et al. (2011) A. Clinical presentation, management and 
outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). 
Intensive Care Med 37:619-626 
Gheorghiade M, Bohm M, Gree SJ, et al. (2013) Effect of aliskiren on postdischarge mortality 
and heart failure readmissions among patients hospitalized for heart failure The 
ASTRONAUT randomized trial.  JAMA 309:1125-1135 
Gattis WA, O’Connor CM, Gallup DS, et al. (2004) Predischarge initiation of carvedilol in 
patients hospitalized for decompensated heart failure: Results of the initiation management 
predischarge: process for assessment of carvedilol therapy in heart failure (IMPACT-HF) 
trial. J Am Coll Cardiol 43:1534–41 
Gu J, Noe A, Chandra P, et al. (2010) LCZ696, a novel dual-acting angiotensin 
receptor−neprilysin inhibitor (ARNi).  J Clin Pharmacol 50:401-414 
Hunt SA, Abraham WT, Chin MH, et al. (2009) Focused update incorporated into the 
ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a 
report of the American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. Circulation;119:e391– e479 
Lassus JP, Siirila-Waris K, et al. (2013)  Long-term survival after hospitalization for acute 
heart failure differences in prognosis of acutely decompensated chronic and new-onset acute 
heart failure. Int J Cardiol 168:458-462 
Maggioni AP, Dahlstrom U, Filippatos G, et al. (2013a) . EURObservational Research 
Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot 
Survey (ESC-HF Pilot). Eur J Heart Fail;15: 808-817 
Maggioni AP, Anker SD., Dahlstrom U, Filippatos G, et al. (2013b) Are hospitalized or 
ambulatory patients with heart failure treated in accordance with European Society of 


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Cardiology guidelines? Evidence from 12 440 patients of the ESC Heart Failure Long-Term 
Registry. European Journal of Heart Failure 15:1173–1184 
McMurray JJ, Adamopoulos S, Anker SD, et al (2012) ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure (2012): The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. 
Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J; 
33(14):1787-847 
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, et al. (2013) Dual angiotensin 
receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme 
inhibition in patients with chronic systolic heart failure: rationale for and design of the 
Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and 
morbidity in Heart Failure trial (PARADIGM-HF).  Eur J Heart Fail 15:1062–1073 
McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, et al. (2014a) Angiotensin-
neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004 
McMurray JJV, Packer M, Desai AS, et al (2014b) Baseline characteristics and treatment of 
patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global 
Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 16:817-825  
Ponikowski P, Anker SD, AlHabib KF, et al. (2014) Heart failure: preventing disease and 
death worldwide.  ESC Heart Failure 1:4–25 
Packer M; McMurray JJ; Desai AS, Gong J, et al. (2015) Angiotensin receptor neprilysin 
inhibition compared with enalapril on the risk of clinical progression in surviving patients 
with heart failure.  Circulation 131:54-61 
Solomon SD, Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor 
LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized 
controlled trial. Lancet; 380:1387-95 
Stevens LA, Coresh J, Greene T, Levey AS (2006) Assessing kidney function – measured and 
estimated glomerular filtration rate. N Engl J Med; 354:2473-2483 
Sulpizio AC, Pullen MA, Edwards RM, Brooks DP (2005) The effect of acute angiotensin-
converting enzyme and neutral endopeptidase 24.11 inhibition on plasma extravasation in the 
rat. J Pharmacol Exp Ther; 309:1141-1147 
 


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13 
Appendix 1: 
Clinically notable laboratory values  
Guidelines for the treating physician on clinically notable laboratory abnormalities for 
selected tests based on a percent change from either Screening or Randomization: 
Hematology 
RBC count 
 
>50% increase, >20% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit 
 
>50% increase, >20% decrease 
WBC count 
 
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Blood Chemistry 
ALT (SGPT)  
>150% increase 
AST (SGOT)  
>150% increase 
BUN  
 
>50% increase 
Creatinine 
 
>50% increase 
Total bilirubin  
>100% increase 
CPK  
 
>300% increase 
Alkaline phosphatase >100% increase 
Sodium 
 
>5% decrease 
Potassium 
 
>20% increase, >20% decrease 
Uric acid 
 
>50% increase 
 


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14 
Appendix 2:  Guidelines for the management of 
 
liver laboratory:  Trigger definitions, liver event reporting, 
and follow-up requirements 
General principles 
Guidance is provided, based on the changes of liver function tests, to adequately and monitor 
report the changes in case of the occurrence during the study. 
Therapy with LCZ696 should be immediately interrupted if severe hepatic impairment is 
developed during the study. 
A special set of CRF pages should be completed at the time of reporting, to account medical 
history potential contributing to liver dysfunction, details on the event(s) reported, and 
laboratory tests. 
Table 14-1 
Liver event definitions 
 
Definition/ threshold (leading to adverse event reporting) 
Laboratory values 
ALT or AST > 3 x ULN 
 
ALP > 2 x ULN 
 
TBL > 1.5 x ULN 
Medically significant event (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 
 


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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  
(patient is 
asymptomatic) 
AESI 
• Laboratory to report to 
Investigator and Investigator 
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 
≤ 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 


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Criteria 
Event type 
Actions required 
Follow-up monitoring 
> 2 to ≤5 x ULN  
(patient is 
asymptomatic) 
AESI 
• Laboratory to report to 
Investigator and Investigator 
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 
≤ 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 
• Laboratory to report to 
Investigator and Investigator 
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 
disorders - severe 
events only” SMQ 
AE 
Medically 
significant 
• Discontinue the study drug  
• Hospitalization if clinically 
appropriate 
• Report to Novartis as an SAE 
• Establish causality 
Investigator discretion 
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. 


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15 
Appendix 3: 
Guidelines for the management of hyperkalemia 
(for serum potassium greater than 5.4 mmol/L) 
General principles 
Use of LCZ696 may be associated with an increased risk of hyperkalemia, although 
hypokalemia may also occur.  
Therapy with LCZ696 should not be initiated if serum potassium level is above 5.4 mmol/L.  
Monitoring of serum potassium will be performed during all routine study visits by both local 
and central laboratories. 
If patients experience clinically significant hyperkalemia adjustment of concomitant 
medications, temporary down–titration or discontinuation of LCZ696 is recommended.  If 
serum potassium persists at levels above 5.4 mmol/L temporary discontinuation of LCZ696 
should be considered. 
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken. 
Any patient with a serum potassium above 5.4 mmol/L after enrollment into the study 
requires regular, repeated checks of potassium concentration (beyond that prescribed in the 
protocol) until it is clear that the potassium concentration is stable and not rising into the 
range of concern (≥ 5.5 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L).  
Patients with an elevated potassium value will be managed according to the corrective actions 
outlined below.  Hyperkalemia must be followed until resolution. 
Corrective action for management of hyperkalemia 
Serum potassium above 5.4 and less than or equal to 5.5 mmol/L 
• Confirm potassium concentration in a non-hemolyzed sample 
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.)  
• Review medical regimen (including dietary supplements and over-the-counter 
medications) for agents known to cause hyperkalemia. Consider reduction in dose or 
discontinuation of these agents: 
• Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 
• Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics  
• Potassium supplements, e.g., potassium chloride 
• Salt substitutes  
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors 


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• Trimethoprim and trimethoprim-containing combination products, such as Bactrim® 
and Septra® (trimethoprim/sulfamethoxazole fixed combination) 
• Herbal Supplements:  
• For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily 
of the valley, Siberian ginseng, hawthorn berries 
• Repeat serum potassium measurement within 3 to 5 days 
• If serum potassium remains above 5.4 and equal or less than 5.5 mmol/L, regularly 
monitor serum potassium levels to ensure stability  
• Consider down-titration of LCZ696, according to investigator’s medical judgment. 
Serum potassium above 5.5 and less than 6.0 mmol/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 > 5.4 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 
• Immediately discontinue LCZ696 
• Confirm potassium concentration in a non-hemolyzed sample 
• Urgently evaluate patient and treat hyperkalemia as clinically indicated  
• Apply all measures outlined for serum potassium > 5.4 and < 6.0 mmol/L 
Notification to the sponsor of a potassium level equal to- or above 6 mmol/L should be done 
within 48 h.  No resumption of LCZ696 without individualized case discussion with and 
permission from the Sponsor’s Medical Monitor or his/her designee. 


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16 
Appendix 4:  Guidelines for the management of blood 
pressure 
Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, 
e.g., by diuretic therapy, dietary salt restriction, diarrhea or vomiting.  Sodium and/or volume 
depletion should be corrected before starting treatment with LCZ696, however, such 
corrective action must be carefully weighed against the risk of volume overload. 
If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and 
treatment of other causes of hypotension (e.g. hypovolemia) should be considered. 
If hypotension persists despite such measures, the dosage of LCZ696 should be reduced or 
temporarily discontinued.  
Permanent discontinuation of therapy is usually not required. 
The dose re-challenge and medication adjustment guidelines described in Section 5.5.5 should 
be adhered to as much as possible. 
 


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17 
Appendix 5:  
Guidelines for the management of renal dysfunction 
General principles: 
The recommendations that follow have been developed to guide investigators in managing 
patients with renal dysfunction during the course of the study. 
If patients experience clinically significant decrease in renal function, adjustment of 
concomitant medications, temporary down–titration or discontinuation of LCZ696 is 
recommended. 
In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients 
with compromised renal function, concomitant use of LCZ696 and NSAIDs may lead to an 
increased risk of worsening of renal function. 
The use of LCZ696 in end-stage renal disease patients is not recommended and LCZ696 
should be immediately discontinued if patient develops this condition during the study. 
If a clinically significant renal event is reported during the study, the investigator must ensure 
completion of the CRF pages for ‘Renal events reporting’. 
Two types of response to serum creatinine increase are described: 
Surveillance situation  
If, at any time after enrollment, eGFR decreases by ≥ 25% from baseline (Visit 1) (or if serum 
creatinine concentration increases 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 serum creatinine levels 
• Volume decrease, including that resulting from excessive dosing of diuretics 
• Urinary infection 
• Urinary tract obstruction 
• Study medication 
Action situation  
If a patient eGFR decreases by ≥ 40% from baseline (Visit 1) (or if serum creatinine 
concentration rises above 3 mg/dL (265 µmol/L), the investigator will check for potentially 
reversible causes of renal dysfunction (see above). 
If the investigator judges that study medication has to be stopped, he/she should do so and 
also  notify the Sponsor’s Medical Monitor or his/her designee.  
Thereafter, serum creatinine assessments will have to be repeated at least each week until 
levels return to acceptable values.  If able to resume study drug treatment, renal function must 
be periodically monitored to ensure stability of eGFR. 

SAP_001.pdf: 
Clinical Development 
LCZ696 
Clinical Trial Protocol CLCZ696B2401 / NCT02661217
A multicenter, randomized, open label, parallel group study 
comparing pre-discharge and posT-discharge tReatment 
initiation with LCZ696 in heArt failure patieNtS with 
reduced ejectIon-fracTion hospItalized for an acute 
decOmpensation eveNt (ADHF) (the TRANSITION study) 
Statistical Analysis Plan (SAP) 
Amendment 4 
Author: 
Trial Statistician, 
Document type: 
SAP Documentation 
Document status: 
Final; Amendment 4 
Release date: 
18-Oct-2018
Number of pages: 
34 
Property of Novartis 
For business use only 


Novartis 
 
Page 2 
SAP 
 
CLCZ696B2401 
 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Section and 
title impacted 
(Current) 
04-MAR-
2016 
Prior to 
DB lock 
Creation of final version 
First version 
NA 
10-Nov-
2017 
Prior to 
DB lock 
Add SCR set 
Update the 
rehospitalization not-HF 
cause 
Update concomitant 
medication selection and 
imputation rules on dates 
Update the exposure cutoff 
to be consistent with 
protocol visit window  
Add liver toxicity criteria 
table and notable vital sign 
criteria 
Update PDs that excluded 
from populations 
Detail liver and renal 
events 
Amendment 1 
NA 
16-Mar-
2018 
Prior to 
DB lock 
Typology updates 
FAS/SAF definitions 
Update compliance 
information 
Update prior/concomitant 
definitions 
Update TEAE definition  
Update concomitant 
medication start date 
imputation rules on date 
Amendment 2 
NA 
17-Apr-
2018 
Prior to 
DB lock 
Add Protocol deviation 
OTH13: Patient not starting 
Amendment 3 
NA 


Novartis 
 
Page 3 
SAP 
 
CLCZ696B2401 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Section and 
title impacted 
(Current) 
treatment within protocol 
specified windows. Patients 
with this PD to be excluded 
from FAS and included in 
SAF.  
Definition 
of 
FAS 
is 
updated accordingly due to 
this additional exclusion. 
18-Oct-
2018 
Prior to 
Final 
DBL 
Definition of adverse 
events of special interest 
updated for hyperkalemia 
and renal dysfunction. 
Updates in notable vital 
signs. 
Medical 
history 
date 
imputation added. 
Precision added for CM end 
date imputation. 
Clarification 
for 
 
the 
medications collected after 
end of study visit. 
Updates in wording terms 
used for the duration of 
treatment and the total 
exposure to study drug. 
Updates 
in 
clinically 
notable 
laboratory 
parameter definition and 
adding of imputation rule. 
Updated ‘Change to 
protocol specified analyses’ 
section. 
Precision added for the 
analysis of patients 
permanently discontinued 
from study drug, due to any 
reasons, at any time during 
the study. 
Amendment 4 
2.8.8.1 
 
 
 
2.8.4.2 
 
 
4.1.4 
 
5.1.3.1 
 
2.4.2 
 
 
 
2.4.1 
 
 
2.8.3 
 
 
 
4 
 
1.2.5 


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Table of contents 
Table of contents ................................................................................................................. 4 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 8 
1.2.1 
Primary objective .................................................................................... 8 
1.2.2 
Secondary objectives ............................................................................... 9 
 
 9 
1.2.4 
Assessment of primary endpoint ............................................................. 9 
1.2.5 
Assessment of secondary endpoints ........................................................ 9 
 
 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 15 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 15 
2.4.1 
Study treatment / compliance ................................................................ 15 
2.4.2 
Prior, concomitant and post therapies ................................................... 16 
2.5 
Analysis of the primary objective .......................................................................... 18 
2.5.1 
Primary endpoint ................................................................................... 18 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 18 
2.5.4 
Supportive analyses ............................................................................... 18 
2.6 
Analysis of the key secondary objective ............................................................... 18 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 18 
2.8 
Safety analyses ....................................................................................................... 19 
2.8.1 
Adverse events (AEs) ............................................................................ 19 
2.8.2 
Deaths .................................................................................................... 21 
2.8.3 
Laboratory data ..................................................................................... 21 
2.8.4 
Other safety data ................................................................................... 23 
 
 25 
 
 25 


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2.11 
Interim analysis ...................................................................................................... 26 
3 
Sample size calculation ..................................................................................................... 27 
4 
Change to protocol specified analyses .............................................................................. 27 
5 
Appendix ........................................................................................................................... 28 
5.1 
Imputation rules ..................................................................................................... 28 
5.1.1 
Study drug ............................................................................................. 28 
5.1.2 
AE date imputation ............................................................................... 28 
5.1.3 
Concomitant medication date imputation ............................................. 29 
5.1.4 
Medical history date imputation............................................................ 31 
5.2 
The imputed medical history date cannot be later than the screening date.AEs 
coding/grading ....................................................................................................... 31 
5.3 
Laboratory parameters derivations ........................................................................ 32 
5.4 
Statistical models ................................................................................................... 32 
5.4.1 
Primary analysis .................................................................................... 32 
5.4.2 
Key secondary analysis ......................................................................... 32 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 32 
6 
Reference ........................................................................................................................... 34 
 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular accident 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
ICD  
Implantable cardioverter defibrillator 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse event 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
 
The TRANSITION study is a multicenter, randomized, open label, parallel group study 
comparing pre-discharge and post-discharge treatment initiation with LCZ696 in heart failure 
patients with reduced ejection-fraction hospitalized for an acute decompensation event 
(ADHF). 
This document outlines the Statistical Analysis Plan for TRANSITION. This detailed statistical 
analysis plan includes details of 
 table shells and 
data set specifications. 
The two Interim Analysis Reports for the DMC, the First Interpretable Results (FIR), and the 
Clinical Study Report (CSR) will result from the analysis described in this SAP. 
1.1 
Study design 
The CLCZ696B2401 study is a Phase IV randomized, multicenter, open-label study, testing 
two treatment-modalities of LCZ696 in the ADHF population. Data from the study will provide 
information regarding the safety and tolerability of LCZ696 therapy in HF-rEF patients when 
initiated Pre- and Post-discharge following stabilization of patients hospitalized due to an 
ADHF episode. 
Patient will be stratified based on the pre-admission type of RAAS-inhibition therapy: ACEI, 
ARB, or ACEI/ARB treatment naïve patients.  
The study consists of three Epochs (phases): the Screening Epoch; the Treatment Epoch defined 
as 10 weeks after Randomization; and 16-week Follow-up Epoch. 
The Screening Epoch is defined as the time from administration of ICF and up to the time of 
Randomization. It is expected to range between 1 and 3 days. When admitted for acute 
decompensated HF, conventional therapy is started or continued at the discretion of the treating 
physician and is performed until hemodynamic stability is achieved. Randomization will occur 
only after the 24 h stabilization interval is completed. The Treatment Epoch is identified as the 
initial 10 weeks after Randomization. The Follow-up Epoch is identified as the continuation of 
open-label LCZ696 treatment for additional 16 weeks after the Treatment Epoch to further 
evaluate safety and tolerability. 
All patients must provide written informed consent prior to start any study-related activities. 
Upon signing the ICF, patients are given access to the treatment received and medical 
information starting from the time of admission for ADHF to verify eligibility criteria i.e.,: 
acute treatment received, sign and symptoms consistent with admission for ADHF, local 
laboratory values, conditions confirming achievement of hemodynamic stability. ICF should be 
administered, either at least 24 hours after achieving hemodynamic stabilization following the 
acute treatment for ADHF, or upon achieving stabilization, but not later than 48 h prior to the 
planned discharge date, to enable the required 36 h wash-out from ACEI therapy if the patient 
is randomized to the Pre-discharge initiation of LCZ696 therapy.  
Patients will be randomized 1:1 to start LCZ696 either Pre-discharge or Post-discharge, and 
Pre-discharge treatment should start no later than 48 h prior to the planned discharge date.  


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A sample size of approximately 1000 randomized patients (about 930 patients for ARB and 
ACEI, and about 70 in the naïve group) provides reasonable precision across a range of possible 
outcomes.  
Stratification will occur prior to Randomization and it will be based on the patient’s HF therapy 
prior to admission (i.e., ACEI, ARBs, or ‘ACEI/ARB-inhibition-naïve treatment’). 
Stratification will ensure that within a stratum the distribution between Pre- and Post-discharge 
is similar. It is expected that the naïve patients will represent at least 7% of the total number of 
patients (i.e., 70 patients from in total 1000 randomized patients). For the samples size of 1000 
patients, a maximum of 930 of ACEI or ARB-treated patients will be randomized, to ensure 
achieving the minimum target of 70 ACEI/ARB-naïve patients. However, more than 70 RAAS 
inhibition-naïve treatment patients could be included if during the study conduct a higher 
number is enrolled. Stratification will be performed at the country level. 
Randomization/treatment assignment will be accomplished through the Interactive Response 
Technology (IRT). 
The primary analysis time point is Week 10 after randomization. In the primary analysis, no 
imputation will be used for any patients who discontinue study therapy due to adverse events 
or abnormal laboratory values prematurely. 
Two interim analyses of tolerability and safety will be carried out during the study when 30% 
and 60% of the patients have completed the visit at 10-weeks after Randomization (Visit 199). 
Details will be pre-specified in the Charter of the DMC. 
The clinical database will be locked twice. The first database lock will occur when all subjects 
have completed 10 weeks after Randomization evaluation period of the study (Visit 199) and 
all data has been monitored, query-clean and final. All follow-up data between 10 weeks after 
Randomization (Visit 199) and 26 weeks after Randomization (End of study Visit 299) will be 
included in the 26 weeks database lock. All planned analyses summarizing results by treatment 
group will be performed after the last subject has completed the 10 weeks after Randomization 
evaluation period of the study. For this analysis, group summaries will be presented. Individual 
subject treatment assignments (e.g. listing) will be provided prior to the 26 weeks after 
Randomization lock only if the required for regulatory submission(s); if required, these will be 
provided only to personnel identified by the Sponsor, who have no direct role in study 
operations. These results will be shared with a limited group of people to be identified by the 
Sponsor. A second database lock will occur after all subjects have reached 26 weeks after 
Randomization of the study. Analyses of subject accountability and length of following, and 
subject status will be updated. Listings of individual subject data, and other information 
regarding individual subjects’ treatment assignments, will be provided only after the 26 weeks 
after Randomization database is locked, unless required for regulatory submission(s). 
1.2 
Study objectives and endpoints 
1.2.1 
Primary objective 
Evaluate the proportion of patients in the Pre- and Post-discharge treatment initiation groups 
achieving the target dose of 200 mg LCZ696 bid at the end of the week-10 after 


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randomization (Treatment Epoch), regardless of previous temporary dose interruption or 
down-titration. 
1.2.2 
Secondary objectives 
• Assess the proportion of patients that, regardless of previous dose interruption or down-
titration during the Treatment Epoch, achieved and maintained either the dose of 100 mg 
and/or 200 mg LCZ696 bid for at least 2 weeks leading to week 10 after randomization. 
• Assess the proportion of patients that, regardless of previous dose interruption or down-
titration during the Treatment Epoch, achieved and maintained any dose of LCZ696 for at 
least 2 weeks leading to week 10 after randomization. 
• Assess the proportion of patients permanently discontinued from study drug, due to 
Adverse Events, during the 10-week Treatment Epoch. 
1.2.4 
Assessment of primary endpoint 
The primary endpoint for this trial will be assessing the proportion of patients who achieve 10 
weeks up-titration success, which is defined as achieving the target dose of LCZ696 200 mg 
bid at 10 weeks after randomization (Visit 199) regardless of previous dose interruption or 
down-titration (Yes/no). 
1.2.5 
Assessment of secondary endpoints 
There are three secondary objectives for this trial. 
One endpoint will be the proportion of patients achieving and maintaining either the dose of 
100 mg and/or 200 mg LCZ696 bid for at least 2 weeks leading to week 10 after randomization 
(Visit 199), regardless of previous dose interruption or down-titration during the 10-week after 
Randomization (Yes/no). 


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One endpoint will be the proportion of patients achieving and maintaining any dose of LCZ696 
for at least 2 weeks leading to week 10 after randomization (Visit 199), regardless of previous 
dose interruption or down-titration during the 10-week after Randomization (Yes/no). 
And the last endpoint will be the proportion of patients permanently discontinued from study 
drug, at any time between randomization and week 10 (Visit 199), as well as during Follow-up 
Epoch, due to either AEs or any reasons (Yes/no). To analyze the proportion of patients who 
permanently discontinued from study drug, due to any reasons, at any time during the study, 
only the patients who stopped the study drug at least 7 days prior to the end of study will be 
considered as permanently discontinued. 


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2 
Statistical methods 
2.1 
Data analysis general information 
An external vendor (CRO), to which the statistical analysis  is outsourced, will perfom the 
primary/final analysis. Data will be analyzed using SAS® version 9.4 (or higher). 
Descriptive summary statistics for continuous variables include mean, median, standard 
deviation, Q1 (25th percentile), Q3 (75th percentile), minimum and maximum, and geometric 
mean (where appropriate), while for categorical variables frequencies and relative percentages 
will be reported. 
Two interim analyses are planned, after 30% and 60% of the patients have completed the visit 
at 10-weeks after Randomization (Visit 199). These will be carried out by an independent 
statistician and independent programmer at the third-party vendor (details can be found in 
section 2.11) who will not be otherwise involved in the trial. Cut-off dates will need to be 
determined empirically; these will allow for all necessary activities (data cleaning, raising and 
resolution of all queries to the clinical sites, etc.) to be concluded. Details of the interim analyses 
are outlined in this document and in the DMC Charter 
Specific descriptive analyses will be stratified by the randomization stratification factor HF 
therapy prior to admission (i.e. ACEI, ARBs, ACEI/ARB naïve treatment) and/or regions, 
countries, or centers, where deemed appropriate. The randomization stratification factor will be 
included in the primary endpoint analysis. 


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2.1.1 
General definitions  
In this study, patients are randomized to two Treatment groups: 
• Pre-discharge initiation of LCZ696 treatment  
• Post-discharge initiation of LCZ696 treatment 
Thus study treatment in this document will refer to Pre-discharge and Post-discharge. Study 
drug will refer to LCZ696 film-coated tablets at doses of 50 mg, 100 mg, and 200 mg. Treatment 
actually received will refer to the actual treatment group, rather than the randomized treatment 
group. 
The terms date of first administration of study drug/treatment and date of last administration 
of study drug/treatment are the first and last reported dates of administration of LCZ696 
reported in the  Drug Administration Record page of the eCRF. 
The term Study Day in this document relates to the Analysis Relative Day, Relative Start Day 
or Relative End Day as applicable. Study Day is defined relative to the analysis reference date, 
which is the date of randomization; it is the number of days from the reference date to the 
analysis date. For all dates on or after the analysis reference date, the study day is the difference 
to the analysis reference date plus one day (ie for date ≥ reference date, study day = date - 
reference date + 1); for any dates prior to the analysis reference date, the study day is simply 
the difference to the reference date (ie for date < reference date, study day = date - reference 
date). Thus the Subject Reference Start Date is designated as Study Day 1, while the date 
directly prior to the reference date is defined as Study Day -1 (there is no Study Day 0). 
The baseline value for any analysis variable in general is defined as the value measured at Visit 
101 (Randomization) for all analyses except when a specific definition or reason is provided. 
For information which is not collected at Visit 101, e.g. physical exam, demography, medical 
history, local laboratory assessment, etc., the information collected at Visit 1 will be used for 
baseline evaluations.  
The study consists of three Epochs (phases): the Screening Epoch, the Treatment Epoch, and 
the Follow-up Epoch. The Screening Epoch is defined as the time from administration of ICF 
and up to the time of Randomization, which is expected to range between 1 and 3 days. When 
admitted for acute decompensated HF, conventional therapy is started or continued at the 
discretion of the treating physician and is performed until hemodynamic stability is achieved. 
Randomization will occur only after the 24h stabilization interval is completed. The Treatment 
Epoch is identified as the initial 10 weeks after Randomization. The Follow-up Epoch is 
identified as the continuation of open-label LCZ696 treatment for additional 16 weeks after the 
Treatment Epoch to further evaluate safety and tolerability.  
In this study, last contact with the subject will be the end of study visit, unless an SAE occurs 
(see below). However, to ensure patient safety, every SAE must be reported to Novartis: 
• occurring until 30 days after the last study visit, regardless of causality 
• occurring after the 30 days period, if a causal relationship to study treatment is suspected 
The on-treatment period exposure is defined as: 


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• Date of last study drug intake – first study drug intake  + 1 
In general, treatment emergent AEs are defined as events starting after the first dose of study 
treatment that were absent pre-treatment, or events present prior to the first dose but increased 
in severity after the first dose. This assumes the same AE with increased severity is properly 
entered as a separate record in the database with start date being the date when severity increases 
and that a second AE with same severity won’t be entered before the same AE is resolved.  
For any other safety analyses based on abnormalities post-baseline compared to baseline (i.e. 
ECGs, vital signs, etc.), where either of the results is not available, the missing category will be 
included to avoid any abnormalities being overlooked.  
The following regions will be defined: 
Table 2-1 Region definition 
Region 
Country 
North America  Canada 
Latin America  
Argentina 
Western 
Europe  
Belgium, France, Germany, Italy, Norway, Portugal, Spain, Sweden, 
Switzerland, United Kingdom 
Eastern 
Europe  
Czech Republic, Poland, Russia, Slovakia 
Asia  
Lebanon, Saudi Arabia, Turkey 
2.2 
Analysis sets 
The following populations will be used for the statistical analyses: 
• Screened set (SCR) – All patients who signed the informed consent. The SCR includes only 
unique screened patients. 
• Randomized Population (RAN) will consist of all patients randomized. 
• The full analysis set (FAS) will consist of all randomized patients with the exception of 
those patients who have inadvertently been randomized into the study. In addition, patients 
not starting treatment within protocol specified windows will be excluded from FAS. 
Following the intent-to-treat principle, patients will be analyzed according to the treatment 
to which they were assigned at randomization.  
• The Safety Population (SAF) will consist of all randomized patients who received at least 
one dose of study drug with the exception of those patients who have inadvertently been 
randomized into the study. Patients will be analyzed according to treatment actually 
received. The safety population will be used for the analyses of safety variables. 
The protocol deviation codes leading to exclusion from the analysis sets defined above are 
presented in the section 4.5 Rule of exclusion criteria of analysis sets.  
 


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2.2.1 
Subgroup of interest 
Here is a list of subgroups to be used in the analysis. They will be summarized descriptively. 
They will also be used to stratify the primary and secondary endpoint analyses both in 
descriptive tables, as well as graphically in forest plots. 
Table 2-2 Subgroups to be used in the statistical analysis 
 
Subgroup  
1 
Age groups: (<65, ≥65; <75, ≥75 years) 
2 
Gender  
3 
Race (Caucasian, Black,  Asian, Other)   
4 
eGFR (≥ 30 - <60 mL/min/1.73m2, >= 60 mL/min/1.73m2) 
5 
Patients on Beta-blocker before admission (yes, no) 
6 
Patients on MRA (aldosterone antagonist) before admission (yes, no) 
7 
Patients on diuretics at baseline (before admission) (yes, no) 
8 
ACEI or ARBs or Naïve prior to admission (ACEi, ARB, naive) 
10 Diabetes (yes, no) 
11 History of implantable device (CRT or ICD) (yes, no) 
12 Heart failure due to ischemic heart disease (yes, no) 
13 Previous hospitalization within 12 months  (yes, no) 
14 Atrial Fibrillation  (present, absent) 
15 Systolic BP at baseline (<100, ≥100 - <120, ≥120 mmHg) 
16 Region * 
*Region is defined as outlined in Table 2-1 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The baseline value for any analysis variable in general is defined as the value measured at Visit 
101 for all analyses except that a specific definition or reason is provided. For information 
which is not collected at Visit 101, e.g. NYHA class, physical exam, demography, local 
laboratory assessment, ECG, etc., the information collected at Visit 1 will be used for baseline 
evaluations. 
Summary statistics for demographics (age, sex, child bearing potential, race, ethnicity, weight, 
height and BMI), baseline characteristics, and enrolment, will be provided by treatment group. 
The summary will be provided in mean, standard deviation, Q1, median, Q3, minimum, and 
maximum for continuous variables or in frequency and percentage for categorical variables. 
Treatment group comparability at baseline will be examined using a chi-squared test for the 
categorical variables and using a t-test for the continuous variables as appropriate. These values 
are provided for descriptive purposes, and are not to be considered to define any formal basis 
for determining factors that should be included in statistical models. In addition, the patient 


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relevant medical history and/or continuing medical conditions recorded at Visit 1 or Visit 101 
will be summarized by primary system organ class, preferred term and treatment group. 
The RAN will be the patient population for the above analyses. If the SAF differs from the RAN 
population by more than 10 patients, summary statistics for demographics, baseline 
characteristics, and enrolment, will carried out on the SAF patient population additionally.  
2.3.1 
Patient disposition 
The number and percentage of patients who completed, discontinued from the study, and the 
reason for discontinuation will be summarized by both epoch and treatment group.  The SCR 
and RAN will be the patient population for the above analyses; additionally, relative frequencies 
for both SAF and FAS populations will also be reported. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Analysis will be performed for duration of treatment with interruptions and total exposure  to 
study drug separately. The analysis will be based on the SAF. The following definitions will be 
computed in days:  
Duration of treatment with interruptions is defined as: 
• Date of last study drug intake – first study drug intake + 1 
Duration of treatment with interruptions will be summarized by treatment group for the 
descriptively (i.e. n, mean, standard deviation, minimum, Q1, median, Q3, and maximum) and 
the number (percentage) of patients will be summarized by exposure category: 
• <4 weeks 
• 4 to < 10 weeks 
• 10 to < 14 weeks 
• 14 to < 18 weeks 
• 18 to <22 weeks 
• 22 to <26 weeks 
• ≥26 weeks 
The overall patient-years on-treatment and average patient years on-treatment will be computed 
based on the duration of the treatment exposure as follows:  
Overall patient-years = ∑
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑖𝑖𝑜𝑜𝑜𝑜 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖/365.25
𝑛𝑛
𝑖𝑖=1
 
where n is the total number of patients in 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 of each dose level, 
and time from first dose level to final top dose will be summarized by treatment group. 


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Total exposure to study drug (excluding interruptions) will be computed as: 
• date of last study drug intake – first study drug date + 1 – number of days of treatment 
interruption. 
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. 
• <4 weeks 
• 4 to < 10 weeks 
• 10 to < 14 weeks 
• 14 to < 18 weeks 
• 18 to < 22 weeks 
• 22 to <26 weeks 
• ≥26 weeks 
Percentage exposure for each patient is defined as the ratio of the total exposure to study drug 
divided by the duration of treatment with interruptions x 100. The percentage exposure to study 
drug will be summarized by treatment group (mean, standard deviation, median, minimum and 
maximum). Treatment compliance for the on-treatment period will also be presented. The 
compliance is reported in the eCRF page as assessed by the investigator at each visit. No overall 
compliance is collected.  
For each patient overall compliance will be assessed by averaging over all visits with 
compliance data available.  
 
2.4.2 
Prior, concomitant and post therapies 
Prior or concomitant medications will be summarized for the safety set in separate tabulations 
based on the coding dictionary used. Prior and concomitant medications used during the 
randomized phase will be summarized by therapeutic class, preferred term and treatment group. 
The SAF population will be used for the above analyses. 
Prior medications are defined as drugs taken prior to index hospital admission. Concomitant 
medication is any medication given at least once post-admission and the last day of the study, 
including those which were started pre-admission and continued post-admission. Prior or 
concomitant medication will be identified based on recorded or imputed start and end dates of 
medication taking. Medications administered during the acute treatments of the decompensated 
heart failure event (from admission to the time of signing ICF) will NOT be included in the 
CRFs. Concomitant medication at discharge will be summarized separately. 
Per protocol, HF-related therapy starting after the End of Study (to ensure adequate chronic 
treatment after conclusion of study participation) is also reported. This therapy is HF-specific 
and may start either on the same day of EoS or as late as 10 days later due to availablity in the 
country of the commercial product, and also considering the needed 36-h washout that may be 


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needed to resume ACEI treatment after ending study medication administration. A separate 
table will be compiled indicating the treatment started after End of study Visit. 
Prior and concomitant heart failure and cardiovascular-related medications will be summarized 
separately at separate time points. To be consistent with LCZ696B2314, here are the 
medications that will be summarized: 
• ACEi* 
• ARBs* 
• Beta-blocking agents* 
• Diuretic* 
• Loop diuretics 
• Thiazide 
• Other Potassium sparing diuretics 
• Mineralocorticoid receptor antagonists (MRAs)* 
• Digoxin 
• Cardiac glycosides* 
• Calcium Channel Blockers (CCB)/Calcium antagonist* 
• Nitrates* 
• Other vasodilators* 
• Oral anticoagulant* 
• Other antiplatelet agents* 
• Aspirin* 
• Antiarrhythmic agent* 
• Statins* 
• Other lipid lowering agents* 
• Simvastatin 
• Inotropic agents 
Note: those with an asterisk will be included additionally in a figure 
The classes of medications will be defined in a separate file with ATC preferred term and WHO 
drug code. 
The compliance with 36-hour washout from ACEi strata will also be summarized.  


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2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary variable is 10 weeks up-titration success, and is defined as: “achieving the target 
dose of LCZ696 200 mg bid at 10 weeks after randomization (Visit 199) regardless of previous 
dose interruption or down-titration (Yes/no)”. There is no primary efficacy analysis. The Safety 
Population (SAF) will be used for the primary endpoint analysis. The primary endpoint will 
also be investigated for its robustness across subgroups defined in section 2.2.1. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary endpoint will be analyzed using the stratified Cochran-Mantel-Haenszel method 
with treatment group and randomization stratification variable (ACEI stratum, ARB stratum, or 
naïve patient stratum) as stratification factor; although randomization is stratified at the country 
level, country will not be used here as an additional stratification factor due to the expected 
small cell counts in some countries, in particular in the naïve patient stratum. The risk ratio (of 
the Pre-discharge initiation of LCZ696 arm versus the Post-discharge initiation of LCZ696 arm) 
will be estimated with a 2-sided 95% CI along with the estimated rate and 95% CI for each 
treatment arm. The above analyses will be performed based on SAF; patients will be analyzed 
according to treatment actually received, as well as the actual stratum (rather than randomized 
stratum). 
2.5.3 
Handling of missing values/censoring/discontinuations 
In the primary analysis, no imputation will be used for any patients, who discontinue study 
therapy due to adverse events or abnormal laboratory values. All patients who prematurely 
discontinue, and do not achieve and maintain the target dose of LCZ696 200 mg bid at 10 weeks 
after randomization will be regarded as 10 week up-titration failures. Information of patients 
discontinuing study drug or participation in trial visits will be collected whenever possible and 
will be used in the analysis. In patients who could not be followed up for the primary endpoint, 
it is aimed to at least determine the vital status of the patients at the final visit.  
2.5.4 
Supportive analyses 
In addition to the primary analysis, a supportive analysis will be carried out, based on evaluable 
patients in the SAF population where patients with administrative discontinuations (non-AE or 
non-death reasons) will be considered as non-evaluable, and thus excluded. 
As a further supportive analysis, the primary analysis, will be repeated using the FAS population 
instead of the SAF population,  
2.6 
Analysis of the key secondary objective 
There is no key secondary objective. 
2.7 
Analysis of secondary efficacy objective(s) 
There are no other secondary efficacy objectives to be analyzed. 


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2.8 
Safety analyses 
The following secondary variables will be used in the analyses: 
• Achieving and maintaining either the dose of 100 mg and/or 200 mg LCZ696 bid for at least 
2 weeks leading to week 10 after randomization, regardless of previous dose interruption or 
down-titration during the 10-week after Randomization (Yes/no) 
• Achieving and maintaining any dose of LCZ696 for at least 2 weeks leading to week 10 
after randomization, regardless of previous dose interruption or down-titration during the 
10-week after Randomization (Yes/no) 
• Permanently discontinuation from study drug (Yes/no) at any time between Randomization 
and week-10 after randomization due to Adverse Events  
These secondary variables will be analyzed in an identical fashion to the primary variable (using 
the stratified Cochran-Mantel-Haenszel method; see 2.5.2 for details). 
2.8.1 
Adverse events (AEs) 
The incidence of treatment emergent adverse events (events occurred between the first dose and 
the last dose of study medication, including those occurred on the first dose date or last dose 
date of study medication) will be summarized by primary system organ class and preferred 
term. Additional summaries will be provided by severity and relationship to study medication. 
As the analysis of treatment emergent AEs will most likely lead to a higher frequency in the 
pre-discharge group, due to the longer exposure duration as well as the early exposure in a well-
monitored hospital setting, an additional analysis of AEs since randomization will be carried 
out in the FAS population; for this analysis, AEs are defined as events occurred between the 
randomization date and the last dose of study medication that were absent pre-randomization, 
or events present prior to randomization but increased in severity after randomization. 
Adverse events occurring after the last dose of study medication will be summarized by primary 
system organ class and preferred term. 
Adverse events will be reported by primary system organ class and preferred term and 
separately by SMQ according to the Medical Dictionary for Regulatory Activities (MedDRA). 
The MedDRA version used for reporting the study will be described in a footnote. 
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.  
The number and percentage of subjects reporting any adverse event and adverse events adjusted 
for exposure during the double-blind period of the study will be summarized by primary system 
organ class, preferred term and treatment and also by SMQ and treatment. The most common 
adverse events reported ( 1 % in any group for each preferred term in the SOC-PT table or 1% 
in any group for each SMQ table) will be presented in descending frequency according to its 
incidence in <treatment group xxx > starting from the most common event.  


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse event, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment. 
Three periods will be considered for the AEs analysis: 
- 
10 weeks of treatment epoch which is defined as the initial 10 weeks after 
randomization: all AEs started during the 10 weeks of treatment epoch will be 
included; 
- 
16-weeks follow-up epoch which is defined as the additional 16 weeks after the 
treatment epoch: all AEs started during the follow-up epoch will be included; 
- 
26 weeks duration which is defined as the whole study from the randomization 
date up to the end of study date. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
The characteristics of the following adverse events of special interest will be summarized as 
appropriate, using relative frequencies.  
Table 2-3 Adverse events of special interest  
 
AE of special interest 
Definition: MedDRA preferred term / eCRF form 
Hypotension events 
Hypotension 
 
Orthostatic hypotension 
 
Presyncope 
 
Dizziness 
 
Dizziness postural 
 
Syncope 
 
Blood pressure decreased 
 
Syncope vasovagal 
 
Vertigo 
 
Vertigo positional 
Hyperkalemia events 
Hyperkalaemia 
Serum potassium increased 
 
Blood potassium increased 
Renal dysfunction events 
All events captured in the renal questionnaire event pages 
of the CRF 
Only the adjudicated angioedema (as adjudicated by the adjudication Committee) reported 
during treatment and follow-up periods will be presented.   
The information is derived from the first page of the Angioedema questionaire, after the 
Adjudication committee has completed and the adjudication is = Yes. 
For all events, please refer to the table for specific angioedema questionnaires details. 


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2.8.2 
Deaths 
Separate summaries will be provided for deaths, including flags for on-treatment or post-
treatment follow-up. 
2.8.3 
Laboratory data 
Central 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 
absolute data and change from baseline values (mean, medians, standard deviations, ranges) at 
each visit for which assessments are available for the parameters as in Table 2-4, and by the 
flagging of notable values in data listings by the criteria defined in Table 2-5. Listings will be 
provided for local laboratory evaluations for hematology and biochemistry parameters, as 
available. 
Any values below the limit of quantification will be analysed as 0.5* the lower limit.  Any 
values above the limit of quantification will be analysed as 1.5*the upper limit.   
Liver safety analyses include frequencies of treatment-emergent elevations, a shift table of 
baseline and worst post-baseline values, respective narrow and broad "Possible drug related 
hepatic disorders - comprehensive search" SMQ and preferred term frequencies, eDISH plots, 
and narratives for any patients discontinued due to liver function abnormalities. 
Table 2-4 List of laboratory tests 
Hematology  
Biochemistry  
Urine assessments 
Hematocrit 
Alanine amino-transferase (ALT)  
Albumin 
Hemoglobin 
Albumin 
Creatinine 
Platelet Count 
Alkaline phosphatase 
Urine dipstick 
Red Blood Cells count 
Aspartate amino-transferase (AST)  
 
WBC Differential 
Blood urea nitrogen (BUN) (OR urea 
ONLY for local laboratory unable to 
assess BUN) 
 
White Blood Cells count Calcium 
 
 
Chloride 
 
 
Creatinine  
 
 
eGFR  
 
 
Fractionated bilirubin (if total bilirubin > 
2x ULN) 
 
 
Glucose 
 
 
Lipid profile (total cholesterol, LDL, 
HDL, and triglycerides) 
 
 
Potassium  
 
 
Sodium 
 
 
Total Bilirubin 
 
 
Total protein 
 


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Uric Acid 
 
Table 2-5 Clinically notable laboratory values 
These laboratory abnormalities are based on a percent change from either Screening or 
Randomization: 
 
Hematology 
 
RBC count  
>50% increase, >20% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit  
>50% increase, >20% decrease 
WBC count  
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Blood Chemistry 
 
ALT (SGPT)  
>150% increase 
AST (SGOT)  
>150% increase 
Alkaline phosphatase  
>100% increase 
Total bilirubin  
>100% increase 
BUN  
>50% increase 
Creatinine  
>50% increase 
Sodium  
>5% decrease 
Potassium  
>20% increase, >20% decrease 
Uric acid  
>50% increase 
To evaluate potential drug-induced liver injury, newly occurring liver enzyme abnormalities at 
any time post-baseline will also be summarized based on the event criteria in below table.  
Table 2-6 Criteria for evaluating liver toxicity 
Parameter 
Criteria 
ALT 
ALT > 3x ULN                                    
 
ALT > 5x ULN                                    
 
ALT > 8x ULN                                    
 
ALT > 10x ULN                                   
 
ALT > 20x ULN                                   
 
 
AST 
AST > 3x ULN                                    
 
AST > 5x ULN                                    
 
AST > 8x ULN                                    
 
AST > 10x ULN                                   
 
AST > 20x ULN                                   
 
 
ALT or AST 
ALT or AST > 3x ULN                             
 
ALT or AST > 5x ULN                             


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ALT or AST > 8x ULN                             
 
ALT or AST > 10x ULN                            
 
ALT or AST > 20x ULN                            
 
 
ALT/AST & TBL 
ALT or AST > 3x ULN & TBL > 1.5x ULN            
 
ALT or AST > 3x ULN & TBL > 2x ULN              
 
ALT or AST > 5x ULN & TBL > 2x ULN              
 
ALT or AST > 8x ULN & TBL > 2x ULN              
 
ALT or AST > 10x ULN & TBL > 2x ULN             
 
ALT or AST > 20x ULN & TBL > 2x ULN             
 
 
ALP 
ALP > 1.5x ULN                                  
 
ALP > 2x ULN                                    
 
ALP > 3x ULN                                    
 
ALP > 5x ULN                                    
 
 
TBL 
TBL > 1.5x ULN                                  
 
TBL > 2x ULN                                    
 
TBL > 3x ULN                                    
 
 
ALP & TBL 
ALP > 3x ULN & TBL > 2x ULN                     
 
ALP > 5x ULN & TBL > 2x ULN                     
 
 
ALT/AST & TBL & ALP 
ALT or AST > 3x ULN & TBL > 2x ULN & ALP ≤ 2x ULN     
 
(ALT or AST > 3x ULN & TBL > 2x ULN & ALP ≤ 2x ULN) 
or reported Hy’s Law case   
 
 
ALT or AST & AEs  
ALT or AST > 3x ULN & (nausea or vomiting or fatigue or 
general malaise or abdominal pain or (rash and eosinophilia) 
 ULN: upper limit of normal  
In addition, laboratory results meeting criteria (ALT/AST > 5x upper limit, Biliruin > 2x upper 
limit, Creatinine > 265 umol, eGFR decrease >=25%, 40% from baseline,  potassium > 5.5 but 
<6.0 mmol/L or >=6 mmol/L)  specified in protocol appendix will be summarized. 
2.8.4 
Other safety data 
2.8.4.1 
ECG data 
The ECG variables (Heart rate, QRS duration) will be summarized by reporting actual and 
change from baseline values using descriptive summary statistics and qualitative changes as 
shift from baseline will be described. Additionally, data will be listed, and any other information 
collected will be listed as appropriate. 


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2.8.4.2 
Vital signs 
Data from vital signs will be summarized by reporting descriptive summary statistics for both 
actual and change from baseline at each available visit with visit 101 as baseline; furthermore, 
various threshold flags will also be used to determine incidences of notable values, which will 
be presented in tables and notable values will be flagged in the listings. 
Patients with notable vital signs as defined below will be summarized: 
• Pulse rate: 
o Low: <= 50 bpm and decrease from baseline higher or equal to 15 bpm 
o High: >= 120 bpm and increase from baseline higher or equal to 15 bpm 
• Systolic blood pressure (SBP): 
o Low: <= 90 mmHg and a decrease from baseline higher or equal to 20 mmHg  
o High: >= 180 mmHg and increase from baseline higher or equal to 20 mmHg 
• Diastolic blood pressure: 
o Low: <= 50 mmHg and a decrease from baseline higher or equal to 15 mmHg  
o High: >= 105 mmHg and increase from baseline higher or equal to 15 mmHg. 
2.8.4.3 
Liver and renal events 
Detailed information of liver and renal event is collected only if patients report any.  
The following eCRF pages will be collected for the reported liver event. 
• Acetaminophen/Paracetamol 
• Liver event overview: details of clinical signs and symptoms, event related to study 
drug, other alternative diagnoses etc. 
• Local laboratory liver function test 
• Autoimmune 
• Viral serology 
• Medical history possibly contributing to liver dysfunction. 
• Pathology 
• Drugs of abuse history 
• History of alcohol use 
• Imaging 
The following eCRF pages will be collected for renal events include: 
• Diagnosis page 
• Follow up pages: details of clinical signs and symptoms 
• Overview: other alternative diagnoses 
• Renal function tests 
• Local lab results 
• Pathology 
• Imaging 


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2.11 
Interim analysis 
Two interim analyses of tolerability and safety will be carried out during the study when 30% 
and 60% of the patients have completed the visit at 10-weeks after Randomization (Visit 199). 
Details will be pre-specified in the Charter of the DMC. 
The review will include the following analyses: 
• AEs leading to permanent discontinuation of LCZ696 
• AEs reported leading to down-titration of LCZ696 or temporary discontinuation 
• Incidence of AEs of interest 
• Concomitant medication changes when down-titration was implemented 
• Compliance with the washout from ACEi or discontinuation of ARBs 
The DMC will also monitor all adverse outcomes during the trial and weigh them against the 
potential benefits of treatment. The DMC will in particular monitor: 
• Angioedema 
• Hyperkalemia 
• Liver and Renal Dysfunction 
• Hypotension 
• Pregnancy 
When considering whether to stop any active treatment arm of LCZ696 for safety concerns 
the following points should be considered  
• whether observed adverse trends are compelling in terms of the amount of evidence 
• whether observed adverse trends outweigh the potential benefits of treatment. 
If the study is terminated, all ongoing patients will be brought in for the end of study visits. 
Those incomplete patients which do not get to Week 10 (Visit 199) as a result of DMC study 
termination by the DMC, will be excluded from both the primary analysis and the 
supplementary primary analysis. 


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To ensure the DMC is provided all required information and to ensure the proper execution of 
the interim analysis an interim analysis plan will be prepared. This analysis plan will include a 
description of all statistical analyses to be conducted, specifications for the analysis data sets 
and the layout of tables, figures and listings. Analyses will be planned and conducted as 
specified in the Clinical Trial Protocol, unless specific monitoring requirements of the DMC 
necessitate a different approach. The Novartis trial team will be given the opportunity to provide 
comments and recommendations and the Novartis list of mandatory tables for a DMC safety 
report will be included. 
The interim analysis will not bias the course of the trial. Firstly, the independent statisticians 
and programmer, as well as all DMC members, are not involved in the conduct of or decisions 
about the study. Secondly, the DMC deliberations remain confidential to members of the 
clinical trial team, as well as investigators and their staff. And finally, only the recommendation 
to terminate the trial, if at all, will be reported to the clinical trial team.  
3 
Sample size calculation 
The purpose of this study is to explore two modalities (Pre-discharge, and Post-discharge) of 
treatment initiation with LCZ696 in HFrEF patients following stabilization after an ADHF 
episode. 
A sample size of about 1000 patients provides reasonable precision across a range of possible 
outcomes. When the observed rate of 10-weeks up-titration treatment success is 80% in both 
pre- and post-discharge, it will provide estimated risk-ratio and 95% CI of 1.00 (0.94, 1.06). 
Observed rate of up-titration 
success at week 10 after 
Randomization 
Risk ratio   
(Pre-discharge / 
Post-discharge) 
2-sided 95% CI 
Total sample 
size without 
adjustment 
Late initiation 
Early initiation 
75% 
70% 
0.93 
0.87, 1.01 
1000 
75% 
75% 
1.00 
0.93, 1.07 
1000 
75% 
80% 
1.07 
1.00, 1.14 
1000 
80% 
75% 
0.94 
0.88, 1.00 
1000 
80% 
80% 
1.00 
0.94, 1.06 
1000 
80% 
85% 
1.06 
1.00, 1.13 
1000 
4 
Change to protocol specified analyses 
• The definition of the full analysis set (FAS) was updated to exclude patients who have 
inadvertently been randomized, regardless the study medication intake. 
• The definition of the safety analysis set (SAF) was updated to exclude patients who 
have inadvertently been randomized, regardless the study medication intake. 
• Creatinine kinase parameter is not analyzed as the data have not been collected. 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Start date and end date of study drug on the respective CRF panel are mandatory; thus no date 
imputation will be applied. 
5.1.2 
AE date imputation 
5.1.2.1 
Adverse Event End Date Imputation  
Rules for imputing the AE end date 
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (treatment follow-up period end date, 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow-up period end date, last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
5.1.2.2 
Adverse Event Start Date Imputation  
Rules for imputing the AE start date 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date  
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation.  
 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
YYYY < TRTY 
 
( 2.a ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
YYYY = TRTY 
 
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment 
Start 
( 4.c ) 
Uncertain 
( 4.c ) 
After Treatment Start 
YYYY > TRTY 
 
( 3.a ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
Before imputing AE start date, find the AE start reference date.  


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1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min (informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
Impute AE start date -  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment. Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.3 
Concomitant medication date imputation 
5.1.3.1 
Concomitant medication end date imputation 
Rules for imputing the CM end date: 
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the earliest of treatment follow-up period end date, last day of the month, date of death. 


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2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the earliest of treatment follow-up period end date, 31DECYYYY, date of death. 
3. If CM day/month/year is missing then use the treatment follow-up period end date as 
the imputed CM end date. No imputation is performed when the concomitant 
medication start date is on or after the end of study visit. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 
 
5.1.3.2 
Concomitant medication start date imputation 
Rules for imputing the CM start date:  
The following table explains the notation used in the logic matrix. Please note that missing start dates 
will not be imputed. 
 
 
 
 
Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Index Admission Date 
Not used 
ZHSTM 
ZHSTY 
 
Where ZHSTM and ZHSTY is the corresponding Month and Year part of Index Admission Date.  
The following matrix explains the logic behind the imputation. 
 
 
MON 
MISSING 
MON < ZHSTM 
MON = ZHSTM 
MON > ZHSTM 
YYYY 
MISSING 
 ( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY < ZHSTY 
 
( 2.a )  
Before Admission Date 
( 2.b ) 
Before Admission Date 
( 2.b ) 
Before Admission Date 
( 2.b ) 
Before Admission Date 
YYYY = ZHSTY 
 
( 4.a ) 
Uncertain 
( 4.b ) 
Before Admission Date 
( 4.a ) 
Uncertain 
( 4.c ) 
After Admission Date 
YYYY > ZHSTY 
 
( 3.a ) 
After Admission Date 
( 3.b ) 
After Admission Date 
( 3.b ) 
After Admission Date 
( 3.b ) 
After Admission Date 
 
1. If the CM start date year value is missing and month/day is not missing, the imputed 
CM start date is set to one day prior to index admission date.  
2. If the CM start date year value is less than the index admission date year value, the CM 
started before index admission. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the index admission date year value, the 
CM started after index admission. Therefore: 


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a. If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY). 
4. If the CM start date year value is equal to the index admission date year value: 
a. And the CM month is missing or the CM month is equal to the index admission 
date month, then the imputed CM start date is set to one day prior to index 
admission date. 
b. Else if the CM month is less than the index admission date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the index admission date month, the 
imputed CM start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
5.1.3.3 
Prior therapies date imputation 
See above 
5.1.3.4 
Post therapies date imputation 
See above 
5.1.3.5 
Other imputations 
There are currently no other imputation rules. 
5.1.4 
Medical history date imputation 
If the date is not known or is incomplete, the imputation rules are: 
1. If only the day is unknown, then the 01th day of this month will be imputed for a missing 
day; 
2. If only the month is unknown, then July will be used for imputation of the missing; 
3. If only the year is known, then the 1st of Jan. will be imputed for a missing day and month 
4. If AE year is missing or AE is ongoing, the end date will not be imputed. 
5.2 
The imputed medical history date cannot be later than the 
screening date.AEs coding/grading 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version available at database lock. 


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5.3 
Laboratory parameters derivations 
See section 2.8.3.  
5.4 
Statistical models 
5.4.1 
Primary analysis 
The primary endpoint will be analyzed using the stratified Cochran-Mantel-Haenszel method 
with treatment group and randomization stratification variable (ACEI stratum, ARB stratum, or 
naïve patient stratum) as stratification factor; although randomization is stratified at the country 
level, country will not be used here as an additional stratification factor due to the expected 
small cell counts in some countries, in particular in the naïve patient stratum. The risk ratio (of 
the Pre-discharge initiation of LCZ696 arm versus the Post-discharge initiation of LCZ696 arm) 
will be estimated with a 2-sided 95% CI along with the estimated rate and 95% CI for each 
treatment arm; no statistical test will be performed. The above analyses will be performed based 
on SAF. 
For a single 2 x 2 table within each stratum, the layout is 
 
Treatment 
Outcome present 
Outcome Absent 
Total 
Post-discharge 
A 
b 
a+b 
Pre-discharge 
C 
d 
c+d 
Total 
a+c 
b+d 
n 
 
The risk ratio 𝑅𝑅𝑅𝑅
෢post vs pre  = (a/(a + b))/(c/(c + d)) 
 
The Cochran-Mantel-Haenzel (CMH) test is for a series of two-by-two tables, one for each 
stratum, and the risk ratio estimate is 
𝑅𝑅𝑅𝑅
෢𝐶𝐶𝐶𝐶𝐶𝐶= 
∑𝑎𝑎𝑖𝑖 (𝑐𝑐𝑖𝑖+ 𝑑𝑑𝑖𝑖)
𝑛𝑛𝑖𝑖
∑𝑐𝑐𝑖𝑖 (𝑎𝑎𝑖𝑖+ 𝑏𝑏𝑖𝑖)
𝑛𝑛𝑖𝑖
 
PROC FREQ is used to calculate the relative risk estimate and the 95% confidence interval, 
using the RELRISK option (Dmitrienko et al, 2005). 
5.4.2 
Key secondary analysis 
The three secondary endpoints are analyzed in identical fashion to the primary analysis, defined 
in section 5.4.1. 
5.5 
Rule of exclusion criteria of analysis sets  
Table 5-1 
Protocol deviations that cause subjects to be excluded 
The table below shows the selected PDs leading to exclusion of the subject from analysis: 


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Check condition 
Protocol 
Deviation ID 
(DVSPID) 
Description used to 
Report PDs to 
HA/IRBs (DVTERM) 
PD category - text 
description (DVDECOD) 
Exclusion form 
analysis 
No informed 
consent signature. 
INCL01 
No informed consent 
signature. 
SELECTION CRITERIA 
NOT MET 
Exclude from all 
analysis 
Patient randomized 
but no study 
medication taken. 
TRT04 
Patient randomized 
(who have completed 
Randomization Visit) 
but no study medication 
taken. 
TREATMENT 
DEVIATION 
Exclude from 
SAF analysis 
Patient was 
randomized in error 
but did NOT receive 
any study 
medication. 
*OTH10 
Patient was 
randomized in error but 
did NOT receive any 
study medication. 
OTHER 
Exclude from 
FAS and SAF 
analysis 
Not Hospitalized 
due to acute 
decompensated HF 
episode (ADHF 
primary diagnosis), 
including signs and 
symptoms 
evaluation at 
admission. 
*INCL03 
Not Hospitalized due to 
acute decompensated 
HF episode (ADHF 
primary diagnosis), 
including signs and 
symptoms evaluation at 
admission. 
SELECTION CRITERIA 
NOT MET 
Exclude from 
FAS and SAF 
analysis 
Patient not starting 
treatment within 
protocol specified 
windows. 
OTH13 
Patient not starting 
treatment within 
protocol specified 
windows 
OTHER 
Exclude from 
FAS analysis 
*Subjects with PDs INCL03 and/or OTH10 are considered to have been inadvertently 
randomized into the study. 
Table 5-2 
Subject classification 
Analysis 
Set 
PD ID that cause subjects to be 
excluded 
Non-PD criteria that cause subjects to be 
excluded 
RAN 
INCL01 
Patients that did not sign ICF 
FAS 
INCL01, OTH10, INCL03, OTH13 
Patients that did not sign ICF 
Patient was randomized in error but did NOT receive 
any study medication. 
Patients not hospitalized for acute decompensated 
heart failure as primary diagnosis (not the same 
population) 
Patient not starting treatment within protocol specified 
windows. 
SAF 
INCL01, TRT04, OTH10, INCL03 
Patients that did not sign ICF 
Patient randomized but no study medication taken  
Patient was randomized in error but did NOT receive 
any study medication. 
Patients not hospitalized for acute decompensated 
heart failure as primary diagnosis (not the same 
population) 


Novartis 
 
Page 34 
SAP 
 
CLCZ696B2401 
 
6 
Reference 
Dmitrienko, A, Molenberghs, G, Chuang-Stein, C, Offen, W (2005 ) Analysis of Clinical Trials 
Using SAS® A Practical Guide. SAS Institute Inc., Cary, NC, USA.