Clinical trial NCT02468232
Conditions: Heart Failure With Reduced Ejection Fraction (HF-rEF)
Keywords: chronic heart failure cardiovascular death hospitalization outcome study worsening heart failure NT-proBNP NYHA KCCQ HF-rEF
Sponsor: Novartis Pharmaceuticals
Start date: 2015-06-15; Completion date: 2021-02-18
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. compared to enalapril 10 mg b.i.d., in addition to the background heart failure (HF) treatment, on delaying time to first occurrence of either cardiovascular (CV) death or HF hospitalization events in Japanese patients with stable chronic heart failure (CHF), New York Heart Association (NYHA) classes II-IV and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 35%).

Detailed description:
The study consisted of two parts: the core part and the Open label extension (OLE) epoch.

The core part of this study was a multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled study to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. and enalapril 10 mg b.i.d. on CV mortality and morbidity reduction in Japanese HF patients with reduced ejection fraction. Patients who met the eligibility criteria at screening entered a 2 week, single-blind, active treatment run-in epoch in which they received LCZ696 50 mg b.i.d. Patients who tolerated LCZ696 50 mg b.i.d. for 2 weeks were randomized in a 1:1 ratio to receive LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. for 4 weeks during the double-blind treatment epoch. The patient randomization was stratified by using NT-proBNP measured at the screening visit as a stratification factor. The patients were then titrated up to the target dose of LCZ696 200 mg b.i.d. or enalapril 10 mg b.i.d. if they tolerated 4 weeks treatment of LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. Dose adjustment (LCZ696 50-100 mg b.i.d. \& enalapril 2.5-5 mg b.i.d.) was permitted if not tolerated at the target dose of study drugs during the double-blind treatment epoch.

This was an event-driven study in which subjects remained on the study (regardless of whether receiving investigational medications) until the projected number of patients with primary events (approximately 57 events) had been reached.

The Open label extension (OLE) epoch was conducted following the completion of the core part, with the aim to provide access to LCZ696 for eligible subjects until the marketed product was available in Japan or 2 years from the date of the first subject enrolled in the OLE epoch, whichever occurred first, and also to obtain the safety and tolerability data of long-term treatment with LCZ696.

Upon completion of the core part, the eligibility of the subjects to enter the OLE epoch was assessed by the investigator at OLE baseline (Visit 301), which occurred on the same day as the end of study (EOS) visit of the core part (Visit 299). At this visit, subjects were switched to open-label LCZ696.

At Visit 302 (2 to 4 weeks after Visit 301), subjects who tolerated the open-label LCZ696 and met the safety monitoring criteria were up-titrated to the next higher level of daily dose. Thereafter, subject visits occurred at 8 weeks, and then every 4 months until EOS visit for OLE epoch.

Arms: arm 1: Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months. arm 2: Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.
Interventions: intervention 1: LCZ696 intervention 2: Enalapril intervention 3: Placebo to LCZ696 intervention 4: Placebo to Enalapril
Intervention descriptions: intervention 1: The target dose during the study was LCZ696 200 mg bid given orally. LCZ696 was supplied as 50 mg, 100 mg and 200 mg film-coated tablets. intervention 2: The target dose during the study was enalapril 10 mg bid given orally. Enalapril was provided as 2.5 mg, 5 mg, and 10 mg tablets. intervention 3: LCZ696 Placebo 50 mg, 100 mg and 200 mg film-coated tablets intervention 4: Enalapril Placebo 2.5 mg, 5 mg and 10 mg tablets

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
LCZ696 
Clinical Trial Protocol CLCZ696B1301 / NCT02468232 
A multicenter, randomized, double-blind, parallel group, 
active-controlled study to evaluate the efficacy and safety 
of LCZ696 compared to enalapril on morbidity and 
mortality in Japanese patients with chronic heart failure 
and reduced ejection fraction 
Authors: 
 
 
Document type: 
Amended Protocol Version 
EUDRACT number: 
Not Applicable 
Version number: 
v04 Clean 
Development phase: 
III 
Release date: 
19-Nov-2018
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 


Novartis 
Confidential 
Page 2 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 04 .................................................................................................................. 12 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 21 
1.1 
Background ............................................................................................................ 21 
1.2 
Purpose .................................................................................................................. 22 
2 
Study objectives ................................................................................................................. 22 
2.1 
Primary objective(s) ............................................................................................... 22 
2.2 
Secondary objectives ............................................................................................. 23 
2.2.1 
Key secondary objectives ...................................................................... 23 
2.2.2 
Other secondary objectives ................................................................... 23 
2.2.3 
Objectives during the open-label extension .......................................... 23 
 
 24 
3 
Investigational plan ........................................................................................................... 24 
3.1 
Study design........................................................................................................... 24 
3.1.1 
Study visits ............................................................................................ 26 
3.2 
Rationale of study design ....................................................................................... 33 
3.2.1 
Rationale for primary endpoint ............................................................. 34 
3.2.2 
Rationale for treatment run-in epoch .................................................... 34 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 35 
3.4 
Rationale for choice of comparator ....................................................................... 36 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 36 
3.6 
Risks and benefits .................................................................................................. 36 
4 
Population .......................................................................................................................... 37 
4.1 
Inclusion criteria .................................................................................................... 37 
4.2 
Exclusion criteria ................................................................................................... 38 
5 
Treatment ........................................................................................................................... 41 
5.1 
Protocol requested treatment ................................................................................. 41 
5.1.1 
Investigational treatment ....................................................................... 41 
5.1.2 
Additional study treatment .................................................................... 43 
5.2 
Treatment arms ...................................................................................................... 43 


Novartis 
Confidential 
Page 3 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.3 
Treatment assignment, randomization ................................................................... 43 
5.4 
Treatment blinding ................................................................................................. 44 
5.5 
Treating the patient ................................................................................................ 44 
5.5.1 
Patient numbering ................................................................................. 44 
5.5.2 
Dispensing the investigational treatment .............................................. 44 
5.5.3 
Handling of study treatment .................................................................. 45 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 45 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 47 
5.5.6 
Rescue medication ................................................................................ 49 
5.5.7 
Concomitant treatment .......................................................................... 49 
5.5.8 
Prohibited Treatment ............................................................................. 50 
5.5.9 
Discontinuation of study treatment ....................................................... 51 
5.5.10 
Withdrawal of consent .......................................................................... 52 
5.5.11 
Loss to follow-up .................................................................................. 52 
5.5.12 
Emergency breaking of assigned treatment code .................................. 52 
5.5.13 
Study completion and post-study treatment .......................................... 53 
5.5.14 
Early study termination ......................................................................... 53 
6 
Visit schedule and assessments ......................................................................................... 53 
6.1 
Information to be collected on screening failures .................................................. 61 
6.2 
Patient demographics/other baseline characteristics ............................................. 61 
6.3 
Treatment exposure and compliance ..................................................................... 62 
6.4 
Efficacy .................................................................................................................. 62 
6.4.1 
Primary and secondary efficacy endpoints ........................................... 62 
6.4.2 
Endpoint committee .............................................................................. 63 
6.4.3 
Heart failure symptoms reduction and reduction in physical 
limitation ............................................................................................... 63 
6.4.4 
Biomarkers ............................................................................................ 63 
6.4.5 
Clinical composite score ....................................................................... 64 
6.4.6 
Echocardiogram .................................................................................... 65 
6.4.7 
Appropriateness of efficacy assessments .............................................. 65 
6.5 
Safety ..................................................................................................................... 65 
6.5.1 
Physical examination ............................................................................ 65 
6.5.2 
Vital signs.............................................................................................. 66 
6.5.3 
Height and weight ................................................................................. 66 
6.5.4 
Laboratory evaluations .......................................................................... 66 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 69 
6.5.6 
Pregnancy and assessments of fertility ................................................. 69 


Novartis 
Confidential 
Page 4 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
6.5.7 
Angioedema .......................................................................................... 70 
6.5.8 
Appropriateness of safety measurements .............................................. 70 
6.6 
Other assessments .................................................................................................. 70 
6.6.1 
Resource utilization ............................................................................... 70 
 
 71 
6.6.3 
Other biomarkers ................................................................................... 71 
7 
Safety monitoring .............................................................................................................. 72 
7.1 
Adverse events ....................................................................................................... 72 
7.2 
Serious adverse events ........................................................................................... 73 
7.2.1 
Definition of SAE ................................................................................. 73 
7.2.2 
SAE reporting........................................................................................ 74 
7.2.3 
Protocol specific unblinding rules for SUSARs that are also 
efficacy endpoints ................................................................................. 75 
7.3 
Liver safety monitoring ......................................................................................... 76 
7.4 
Pregnancy reporting ............................................................................................... 77 
8 
Data review and database management ............................................................................. 78 
8.1 
Site monitoring ...................................................................................................... 78 
8.2 
Data collection ....................................................................................................... 78 
8.3 
Database management and quality control ............................................................ 78 
8.4 
Data Monitoring Committee .................................................................................. 79 
8.5 
Adjudication Committee ........................................................................................ 80 
8.5.1 
Clinical Endpoint Committee ................................................................ 80 
8.5.2 
Angioedema Adjudication Committee .................................................. 80 
9 
Data analysis ...................................................................................................................... 81 
9.1 
Analysis sets .......................................................................................................... 81 
9.2 
Patient demographics and other baseline characteristics ....................................... 81 
9.3 
Treatments ............................................................................................................. 82 
9.4 
Analysis of the primary variable ............................................................................ 82 
9.4.1 
Variable ................................................................................................. 82 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 82 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 83 
9.4.4 
Supportive analyses ............................................................................... 83 
9.5 
Analysis of secondary variables ............................................................................ 83 
9.5.1 
Efficacy variables .................................................................................. 83 
9.5.2 
Safety variables ..................................................................................... 86 
9.5.3 
Resource utilization ............................................................................... 87 
9.5.4 
Health-related Quality of Life ............................................................... 88 


Novartis 
Confidential 
Page 5 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 
 88 
9.5.6 
Biomarkers ............................................................................................ 88 
9.5.7 
PD ................................................................................................... 88 
9.6 
Interim analyses ..................................................................................................... 88 
9.7 
Sample size calculation .......................................................................................... 88 
10 Ethical considerations ........................................................................................................ 89 
10.1 
Regulatory and ethical compliance ........................................................................ 89 
10.2 
Informed consent procedures ................................................................................. 89 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 90 
10.4 
Publication of study protocol and results............................................................... 90 
11 Protocol adherence ............................................................................................................ 90 
11.1 
Protocol Amendments ........................................................................................... 90 
12 References ......................................................................................................................... 92 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 94 
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 95 
15 Appendix 3: Treatment guidelines for hyperkalemia (serum potassium greater than 
5.3 mmol/L[mEq/L]) ......................................................................................................... 98 
16 Appendix 4: Guidelines for the management of blood pressure ..................................... 100 
17 Appendix 5: Guidelines for the management of renal dysfunction ................................. 101 
 
103 
 


Novartis 
Confidential 
Page 6 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
List of tables 
Table 3-1 
Safety monitoring criteria that must be met at Visit 1 (screening) 
and Visit 199 ......................................................................................... 28 
Table 3-2 
Starting dose levels of open-label LCZ696 at the start of the OLE 
epoch ..................................................................................................... 31 
Table 3-3 
Safety monitoring criteria for up-titration at Visit 302 (Week 2 to 4)
 ............................................................................................................... 31 
Table 5-1 
Study drug dispensed during the randomized treatment epoch ............ 46 
Table 5-2 
Study drug dispensed during the OLE epoch ........................................ 46 
Table 6-1 
Assessment schedule (Core part) .......................................................... 56 
Table 6-2 
Assessment schedule (OLE epoch) ....................................................... 59 
Table 6-3 
Routine laboratory examinations .......................................................... 67 
Table 7-1 
Adverse events commonly seen in study population ............................ 76 
Table 9-1 
Primary composite endpoint of PARADIGM-HF study ....................... 89 
Table 14-1 
Liver Event and Laboratory Trigger Definitions .................................. 95 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 96 
 
 103 
 
List of figures 
Figure 3-1 
Study design (Core)............................................................................... 25 
Figure 3-2 
Study design (OLE)............................................................................... 26 
 


Novartis 
Confidential 
Page 7 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
List of abbreviations 
ACE 
angiotensin converting enzyme 
ACEI 
angiotensin converting enzyme inhibitor 
AE 
adverse event 
AF 
atrial fibrillation 
Alb 
albumin 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ARB 
angiotensin receptor blocker 
ARNI 
angiotensin receptor neprilysin inhibitor 
AST 
aspartate aminotransferase 
AT1 
angiotensin II type 1 
AUEC 
area under the effect curve 
b.i.d. 
twice a day 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CCB 
calcium channel blocker 
CEC 
Clinical Endpoint Committee 
cGMP 
cyclic guanosine monophosphate 
CHF 
chronic heart failure 
CI 
confidence interval 
Cmin 
minimum drug plasma (serum/blood) concentration 
COPD 
chronic obstructive pulmonary disease 
COX-2 
cyclo-oxygenase-2 
CPO 
Country Pharma Organization 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRT-D 
cardiac resynchronization therapy defibrillator 
CRT-P 
cardiac resynchronization therapy pacemaker 


Novartis 
Confidential 
Page 8 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
CSR 
clinical study report 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DICOM 
Digital Imaging and Communication in Medicine 
DMC 
Data Monitoring Committee 
DS 
assessment to be recorded in clinical database 
DS&E 
Drug Safety and Epidemiology 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FMV 
first morning void 
GCP 
good clinical practice 
hCG 
human chorionic gonadotropin 
HDL 
high density lipoprotein 
HDPE 
high density polyethylene 
HF 
heart failure 
HF-pEF 
heart failure with preserved left ventricular ejection fraction 
HF-rEF 
heart failure with reduced left ventricular ejection fraction 
IA 
interim analysis 
IB 
Investigator Brochure 
ICD 
implantable cardioverter defibrillator 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
international normalized ratio 


Novartis 
Confidential 
Page 9 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
left atrial 
LDL 
low density lipoprotein 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical dictionary for regulatory activities 
MRA 
mineralocorticoid antagonist 
MRI 
magnetic resonance imaging 
MUGA 
multiple gate acquisition scan 
NEP 
neutral endopeptidase 
NSAID 
non-steroidal anti-inflammatory drug 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OC/RDC 
Oracle Clinical/Remote Data Capture 
OLE 
open-label extension 
PCI 
percutaneous coronary intervention 
PD 
Pharmacodynamics 
PDE-5 
phosphodiesterase-5 
 
 
PP 
per protocol 
PT/INR 
international normalized ratio of prothrombin time 
PINP 
amino-terminal propeptide of type I procollagen  
PIIINP 
amino-terminal propeptide of type III procollagen 
QOL 
quality of life 
RAS 
renin angiotensin system 
RBC 
red blood cell 
SAE 
serious adverse event 


Novartis 
Confidential 
Page 10 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
SAF 
safety 
SBP 
systolic blood pressure 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
ULN 
upper limit of normal 
UNS 
Unscheduled visit 
US 
United States 
VAD 
ventricular assistance device 
WBC 
white blood cell 
WHO 
World Health Organization 
γGT 
gamma-glutamyltransferase 


Novartis 
Confidential 
Page 11 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
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 
Medication number 
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system 
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in subjects with established 
disease and in those with newly-diagnosed disease. 
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. 
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/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of 
premature patient withdrawal 
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 


Novartis 
Confidential 
Page 12 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Amendment 04 
Amendment rationale 
This is the fourth amendment to the protocol. This amendment serves the following purpose;  
Local laboratory assessments for serum potassium and eGFR at Visits 301 and 302 in the 
open-label extension (OLE) epoch are added to ascertain if patient meets safety monitoring 
criteria and ensure patient safety. 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy 
of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities. The changes described in this amended 
protocol require IRB/IEC approval prior to implementation. 
 


Novartis 
Confidential 
Page 13 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Summary of previous amendments 
The first amendment of protocol CLCZ696B1301 (v01 of the protocol) was dated 
27-Mar-2015. The main purpose of this amendment was to clarify study drug dose 
adjustments during the double-blind randomized treatment epoch and change some laboratory 
measurements.  
The second amendment (v02) was dated 05-Nov-2015. The main purpose of this amendment 
was to correct the definition of ‘worsening heart failure’ events involved in the key secondary 
objectives, clarify the exclusion criteria related to heart block, change the action on the study 
treatment when emergency treatment code broken, and update the list of adverse events that 
are commonly seen in study population. 
The third amendment (v03) was dated 11-Jun-2018. The main purpose of this amendment was 
to add the open-label extension epoch in the study design and provides details and the related 
changes in relevant sections of this protocol. 
 


Novartis 
Confidential 
Page 14 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Protocol summary 
Protocol number 
CLCZ696B1301 
Title 
A multicenter, randomized, double-blind, parallel group, active-controlled 
study to evaluate the efficacy and safety of LCZ696 compared to enalapril 
on morbidity and mortality in Japanese patients with chronic heart failure 
and reduced ejection fraction 
Brief title 
Study of efficacy and safety of LCZ696 in Japanese patients with chronic 
heart failure and reduced ejection fraction 
Sponsor 
and 
Clinical 
Phase 
Novartis, Phase 3 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of the core part of this study is to assess the effect of LCZ696 
compared to enalapril, in addition to the background HF treatment, on 
delaying time to first occurrence of either CV death or HF hospitalization 
events in Japanese patients with stable CHF, NYHA classes II-IV and 
reduced ejection fraction (LVEF ≤ 35%). Data from this core part are 
intended to be used to support registration of LCZ696 for treatment of HF 
patients in Japan. 
This study is designed to align with the guideline requirement for drug 
approval, to observe a similar trend of LCZ696 better than enalapril in 
reducing morbidity and mortality in Japanese HF patients and capture data 
of the efficacy variables of PARADIGM-HF so that the efficacy of LCZ696 
over enalaprill in Japanese HF patients can be assessed in aspects 
comparing with PARADIGM-HF study outcomes. 
An open-label extension (OLE) to the study will be conducted following the 
completion of the core part. The purpose of this OLE is to provide access 
to LCZ696 for the eligible patients until marketed product is available in 
Japan or approximately 2 years from the date of the first patient enrolled in 
the OLE epoch, whichever occurs first, and also to assess the safety, 
tolerability and efficacy of the treatment with LCZ696. 
Primary Objective(s) 
To assess the effect of LCZ696 and enalapril on delaying time to first 
occurrence of the composite endpoint, which is defined as either CV death 
or HF hospitalization in patients with HF and reduced ejection fraction. 
Secondary Objectives 
Key secondary objectives 
 
To assess the effect of LCZ696 on changes in NT-proBNP from 
baseline at predefined time points (Weeks 4, 8 and Month 6) 
 
To assess the effect of LCZ696, compared to enalapril, on 
delaying the time to first occurrence of CV death, HF 
hospitalization, or intensification of treatments due to documented 
episode(s) of worsening HF defined as: worsening signs and 
symptoms of HF requiring addition of a new drug for HF 
treatment, initiation of IV treatment, increase of diuretic dose for 
persistent use for ≥ 4 consecutive weeks, or institution of 
mechanical or circulatory support such as mechanical ventilation, 
ultrafiltration, hemodialysis, intra-aortic balloon pump or 
ventricular assist device 


Novartis 
Confidential 
Page 15 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 
To assess the effect of LCZ696, compared to enalapril, on 
changes in NYHA classification from baseline at predefined time 
points (Weeks 4, 8 and Month 6) 
 
To assess the effect of LCZ696, compared to enalapril, on 
improving the clinical summary score for HF symptoms and 
physical limitations, as assessed by the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) at predefined time points 
(Week 8 and Month 6) 
 
To assess safety and tolerability of LCZ696 compared to enalapril 
Other secondary objectives 
 
To assess the effect of LCZ696, compared to enalapril, on 
reducing the rate of the composite endpoint of CV death and total 
(first and recurrent) HF hospitalizations 
 
To assess the effect of LCZ696, compared to enalapril, on the 
clinical composite score (as assessed by NYHA classification and 
patient global assessment) at predefined time point (Month 6) 
 
To assess the effect of LCZ696, compared to enalapril, on 
delaying the time to all-cause mortality 
 
To assess the effects of LCZ696, compared to enalapril, on 
reducing the number of patients hospitalized and number of 
hospital admission (all-cause and cause-specific) 
 
To assess the effects of LCZ696, compared to enalapril, on 
reducing healthcare resource utilization, e.g., number of 
days/stays in ICU, number of rehospitalizations, and number of 
ER visits for HF 
 
To assess the effects of LCZ696 and enalapril on changes in pre-
specified and/or other relevant biomarkers (e.g., cardiac, 
vascular, renal, collagen, metabolism, and inflammatory 
biomarkers) from baseline to predefined timepoints (Weeks 2, 4, 
8, Month 6 and 18) 
Objectives during the open-label extension 
 
To evaluate the safety and tolerability of LCZ696 treatment during 
the OLE epoch 
 
To assess the proportion of patients reaching target dose level 3 
of LCZ696 at Week 8 and maintained at Month 4 
 
To assess the effect of LCZ696 on change in NYHA classification 
from OLE baseline (Visit 301) at Month 12 
 
To assess the effects of LCZ696 on change in cardiac 
measurements by echocardiography (LV end systolic and 
diastolic volume indices, LVEF, and LA volume index, etc.) from 
OLE baseline (Visit 301) at Month 12 
 
To assess the effects of LCZ696 on changes in pre-specified 
biomarkers from OLE baseline (Visit 301) to predefined 
timepoints (Weeks 2-4, 8, Month 4 and 12) 
 
To assess the association between change in concentration of 
NT-proBNP and change in structural cardiac measurements (LV 
end systolic and diastolic volume indices, LVEF, and LA volume 
index) from OLE baseline (Visit 301) at Month 12 
 
To assess the effects of long-term treatment with LCZ696 on the 
safety and tolerability throughout the study period 


Novartis 
Confidential 
Page 16 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Study design 
This study is a multicenter, randomized, double-blind, double-dummy, 
parallel-group, active-controlled study to assess the effect of LCZ696 and 
enalapril on CV mortality and morbidity reduction in Japanese HF patients 
with reduced ejection fraction. 
The core part above is followed by the optional OLE in which patients are 
treated with open-label LCZ696 to assess the long-term safety and 
tolerability of LCZ696 treatment. 
Population 
Male or female patients with CHF (NYHA class II-IV), aged 20 years or 
older with LVEF ≤ 35%. Approximately 220 patients (110 patients in each 
arm) will be randomized. 
All participants of the core part who are eligible to receive study drug will 
be offered the option to enter the OLE. It is anticipated that approximately 
180 patients will complete the core part of the study and that the majority 
of them will be enrolled into the OLE. 
Key Inclusion criteria 
Core part: Patients eligible for inclusion in the core part have to fulfill all of 
the following criteria: 
 
Written informed consent must be obtained before any 
assessment is performed. 
 
Outpatients ≥ 20 years of age (at the time of signing informed 
consent), male or female. 
 
Patients with a diagnosis of CHF NYHA class II-IV and reduced 
ejection fraction: 
- 
LVEF ≤ 35% at Visit 1 (any local measurement, made within 
the past 6 months using echocardiography, MUGA, CT 
scanning, MRI or ventricular angiography is also acceptable, 
provided no subsequent measurement above 35%) 
- 
NT-proBNP ≥ 600 pg/ml at Visit 1 OR NT-proBNP ≥ 400 pg/ml 
at Visit 1 and a hospitalization for HF within the last 12 months 
(according to central laboratory measurements) 
 
Patients must be on an ACEI or an ARB at a stable dose for at 
least 4 weeks before Visit 1. 
 
Patients must be treated with a β-blocker, unless contraindicated 
or not tolerated, at a stable dose for at least 4 weeks prior to Visit 
1 (reason should be documented if patients reported 
contraindications or intolerance). 
 
An aldosterone antagonist should also be considered in all 
patients, taking account of renal function, serum potassium and 
tolerability. If given, the dose of aldosterone antagonist should be 
optimized according to guideline recommendations and patient 
tolerability, and should be stable for at least 4 weeks prior to Visit 
1. Other evidence-based therapy for HF should also be 
considered e.g. cardiac resynchronization therapy and an 
implantable cardioverter-defibrillator in selected patients, as 
recommended by guidelines. 
Open-label extension (OLE) epoch: Patients eligible for inclusion into the 
open-label extension must fulfill the following criteria: 
 
Written informed consent for the open-label extension must be 
obtained before any assessment is performed. 
 
Patients who have completed the double-blind treatment epoch 
and are able to be safely enrolled into the OLE as judged by the 


Novartis 
Confidential 
Page 17 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
investigator. 
Key Exclusion criteria 
Core part: Patients fulfilling any of the following criteria are not eligible for 
inclusion in the core part. 
 
History of hypersensitivity to any of the study drugs or to drugs of 
similar chemical classes, ACEIs, ARBs, NEP inhibitors as well as 
known or suspected contraindications to the study drugs. 
 
Previous documented history of intolerance to ACEIs or ARBs. 
 
Known history of angioedema. 
 
Requirement of treatment with both ACEIs and ARBs. 
 
Current acute decompensated HF (exacerbation of chronic HF 
manifested by signs and symptoms that may require intravenous 
therapy). 
 
Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 
(screening) or < 95 mmHg at Visit 199 (end of run-in). 
 
Estimated GFR < 30 mL/min/1.73 m2 as measured by the 
Japanese formula at Visit 1 (screening), or Visit 199 (end of 
run-in) or > 35% decline in eGFR between Visit 1 and Visit 199 
(according to local measurements). 
 
Serum potassium > 5.2 mmol/L (mEq/L) at Visit 1 (screening) or 
> 5.4 mmol/L (mEq/L) at Visit 199 (end of run-in) (according to 
local measurements). 
 
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. 
 
Coronary or carotid artery disease likely to require surgical or 
percutaneous intervention within the 6 months after Visit 1. 
 
Implantation of a cardiac resynchronization therapy pacemaker 
(CRT-P) or a cardiac resynchronization therapy defibrillator 
(CRT-D) or upgrading of an existing conventional pacemaker or 
an implantable cardioverter defibrillator (ICD) to CRT device 
within 3 months prior to Visit 1 or intent to implant such a device. 
Also, patients who had implantation of a conventional pacemaker 
or an ICD or had a revision of a pacemaker or other device leads 
within 1 month before Visit 1 are excluded. 
 
Heart transplant or ventricular assistance device (VAD) or intent 
to transplant (on transplant list) or implant a VAD. 
 
History of severe pulmonary disease. 
 
Diagnosis of peripartum or chemotherapy induced 
cardiomyopathy within the 12 months prior to Visit 1. 
 
Documented untreated ventricular arrhythmia with syncopal 
episodes within the 3 months prior to Visit 1. 
 
Symptomatic bradycardia or second (except asymptomatic 
Wenckebach block) or third degree heart block without a 
pacemaker. 
 
Presence of hemodynamically significant mitral and/or aortic 
valve disease, except mitral regurgitation secondary to left 
ventricular dilatation. 
 
Presence of other hemodynamically significant obstructive lesions 
of left ventricular outflow tract, including aortic and sub-aortic 


Novartis 
Confidential 
Page 18 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
stenosis. 
 
Presence of bilateral renal artery stenosis. 
 
History of malignancy of any organ system (other than localized 
basal cell carcinoma of the skin or in-situ cervical cancer), treated 
or untreated, within the past 5 years, regardless of whether there 
is evidence of local recurrence or metastases. 
 
Presence of any other disease with a life expectancy of < 3 years. 
Open-label extension (OLE) epoch: Patients fulfilling any of the following 
criteria at Visit 301, are not eligible for inclusion in the OLE epoch. 
 
Patients who discontinued study drug treatment during the core 
part due to an event or intercurrent illness. Eligibility can be re-
considered if the event has resolved and no longer represents a 
risk to the patient and the patient can safely tolerate the 
administration of LCZ696 per the investigator’s assessment. 
 
Any medical condition that in the opinion of the investigator is 
likely to prevent the patient from safely tolerating LCZ696 or 
complying with the requirements of the study. 
 
Patients who have experience of angioedema event(s) which 
occurred and reported by the investigator during the core part of 
study. 
Investigational 
and 
reference therapy 
Core part: 
LCZ696 
50 mg b.i.d.(dose level 1), 100 mg b.i.d.(dose level 2), 200 mg b.i.d.(dose 
level 3) 
Enalapril 
2.5 mg b.i.d.(dose level 1), 5 mg b.i.d.(dose level 2), 10 mg b.i.d.(dose 
level 3) 
Open-label extension (OLE) epoch: 
LCZ696 50 mg b.i.d.(dose level 1), 100 mg b.i.d.(dose level 2), 200 mg 
b.i.d.(dose level 3) 
Efficacy assessments 
Core part: 
The primary composite endpoint consists of the following components: 
 
CV death 
 
HF hospitalization 
The key secondary endpoints are: 
 
Changes in NT-proBNP from baseline 
 
CV death, HF hospitalization or intensification of treatments due 
to documented episode(s) of worsening HF defined as: worsening 
signs and symptoms of HF requiring addition of a new drug for 
HF treatment, initiation of IV treatment, increase of diuretic dose 
for persistent use for ≥ 4 consecutive weeks, or institution of 
mechanical or circulatory support such as mechanical ventilation, 
ultrafiltration, hemodialysis, intra-aortic balloon pump or 
ventricular assist device 
 
CV death 
 
HF hospitalization 


Novartis 
Confidential 
Page 19 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 
Intensification of treatments due to documented episode(s) of 
worsening HF 
 
Changes in NYHA class from baseline 
 
Clinical summary score (assessed by KCCQ) 
The other secondary endpoints are: 
 
Composite of CV death and total (first and recurrent) HF 
hospitalizations 
 
Clinical composite score (assessed by NYHA classification and 
patient global assessment) 
 
All-cause mortality 
 
Hospitalization (all-cause, cause-specific) 
 
Changes in biomarkers from baseline 
 
Health resource utilization 
Other endpoints during OLE epoch 
 
Changes in NYHA class from OLE baseline (Visit 301) 
 
Changes in echocardiographic parameters from OLE baseline 
(Visit 301) 
 
Changes in biomarkers from OLE baseline (Visit 301) 
Safety assessments 
Core part: 
 
AEs and SAEs 
 
Sitting systolic, diastolic BP, and pulse pressure 
 
Heart rate 
 
Symptomatic hypotension and/or SBP < 90 mmHg 
 
Angioedema 
 
Hyperkalemia 
 
Renal dysfunction 
 
Cough 
 
Drug-related hepatic disorders 
 
Other relevant laboratory values 
 
ECG changes 
Open-label extension (OLE) epoch: Same as the core part 
Other assessments 
 
 
Data analysis 
Core part:  
The primary efficacy variable, the CEC adjudicated time to the first 
occurrence of the composite endpoint, which is defined as either CV death 
or HF hospitalization, will be analyzed using Cox proportional hazards 
model with treatment and the stratification factor of screening NT-proBNP 
(< 1,600 pg/mL, ≥ 1,600 pg/mL) as fixed-effect factors. The estimated 
hazards ratio and the corresponding two-sided 95% confidence interval 
and p-value will be provided. The frequency of patients with composite 
primary endpoint events and the treatment exposure adjusted event rate 
will be provided for individual treatment arm. The FAS will be used for the 
primary analysis. The primary objective of verifying the consistency 
between this study and PARADIGM-HF study is met when the hazard ratio 
(LCZ696 over enalapril) point estimate is less than 1. Above analysis will 
be repeated for the PP population as supportive analysis. Same analysis 


Novartis 
Confidential 
Page 20 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
will be repeated for each of the components of the composite endpoint. 
The key secondary efficacy variables are: 
 
Changes in NT-proBNP from baseline at pre-defined time points 
(Weeks 4 and 8, Month 6) 
 
Time to the first occurrence of CV death, HF hospitalization or 
intensification of treatments due to documented episode(s) of 
worsening HF 
 
Changes in NYHA classification from randomization to each of 
the post-randomization visits 
 
Clinical summary score of KCCQ, computed as the mean of the 
available domain scores of total HF symptom and physical 
limitation 
Open-label extension (OLE) epoch: 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. 
Key words 
Chronic heart failure and reduced ejection fraction, Japanese patients, 
Cardiovascular death, Heart failure hospitalization, NYHA, NT-proBNP, 
Kansas City Cardiomyopathy Questionnaire. 
 


Novartis 
Confidential 
Page 21 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
1 
Introduction 
1.1 
Background 
Heart failure (HF) is a complex clinical syndrome that results from structural or functional 
impairment of ventricular filling or ejection. It is a major public health problem associated 
with high mortality rate, frequent hospitalizations, and poor quality of life. The overall 
prevalence of HF is increasing across the world due to population ageing and improvement in 
the treatment of acute conditions, such as acute coronary syndrome. Approximately 5.7 
million persons in US (Roger et al. 2012) and 15 million persons in EU (Braunschweig et al. 
2011) have HF. In Japan, there are currently 1-2 million CHF patients and the prevalence will 
continue to rise significantly since the elderly population (≥ 65 years) is expected to increase 
to 40% by 2050 and also due to precipitation by westernized dietary pattern, obesity, reduced 
physical activity, and increasing trend of cardiovascular/metabolic diseases (Shiba et al. 2011). 
HF is a progressive disease characterized by increasing symptoms that lead to repeated 
hospitalizations and significantly greater risk of premature death. HF can be exhibited in 
patients with reduced left ventricular ejection fraction (HF-rEF) as well as preserved ejection 
fraction (HF-pEF). Therapies targeted at improving outcomes in HF-rEF patients have been 
well studied over the past few decades, leading to an improvement in survival as well as a 
decrease in morbidity, mostly in the form of decrease in HF hospitalization, with angiotensin 
converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers and 
mineralocorticoid antagonists (MRAs) (CONSENSUS Trial Study Group 1987, SOLVD 
Investigators 1991, SOLVD Investigators 1992, RALES Investigators 1996, Pitt et al. 1999, 
MERIT-HF Study group 1999, CIBIS II Investigators 1999, Cohn and Tognoni 2001, Packer 
et al. 2002, Pfeffer et al. 2003, Flather et al. 2005). However, despite the advances in 
pharmacological (and device) therapies, the prognosis of HF patients remains poor. The 
absolute mortality rate for HF is approximately 50% within 4 years of diagnosis, and 40% of 
HF patients admitted to the hospital will either die or be readmitted within 1 year (Dickstein et 
al. 2008). Thus, HF represents a major cause of cardiac mortality and morbidity with a 
significant unmet medical need. 
LCZ696 (sacubitril valsartan sodium hydrate) is a first-in-class angiotensin receptor neprilysin 
(neutral endopeptidase 24.11; NEP) inhibitor (ARNI). Following oral administration, LCZ696 
dissociates into valsartan and the pro-drug AHU377, which is further metabolized to the NEP 
inhibitor LBQ657. LCZ696 exhibits the novel mechanism-of-action of an ARNI by 
simultaneously inhibiting NEP via LBQ657 and by blocking the angiotensin II type 1 (AT1) 
receptor via valsartan. The therapeutic effects of NEP inhibition by LBQ657 are attributable 
to increased levels of biologically active natriuretic peptides and/or other vasoactive peptides. 
The effects of AT1 receptor blockade by valsartan are related to inhibition of the deleterious 
effects of angiotensin II and its effectors on the cardiovascular system. The pharmacodynamic 
effects of LCZ696 include initial increased natriuresis and diuresis, vasodilation and 
subsequent blood pressure reduction, reduction of sympathetic tone, and inhibition of adverse 
cardiovascular remodeling, including anti-fibrotic and anti-hypertrophic effects. Therefore, 
LCZ696, through its unique dual mode of action, may fulfill the promise of providing a novel, 
more effective therapy for HF-rEF patients to address the high unmet medical need. 


Novartis 
Confidential 
Page 22 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
The phase III PARADIGM-HF study (CLCZ696B2314, n=8,442) was a large event-driven 
outcome study comparing LCZ696 at a target dose of 200 mg twice daily to enalapril 10 mg 
twice daily in patients with HF-rEF and was conducted globally in 47 countries. It 
demonstrated the superiority of LCZ696 over enalapril on the reduction of CV death and HF 
hospitalization (McMurray et al. 2014). When compared to enalapril, LCZ696 reduced the 
risk of composite of CV death or HF hospitalizations by 20% (one-sided p = 0.0000002), and 
it also significantly reduced the risk of CV death by 20% (one-sided p = 0.00004). LCZ696 
200 mg b.i.d. was well tolerated in the PARADIGM-HF study, with the overall frequency of 
adverse events similar to enalapril, and no event of severe angioedema associated with airway 
compromise was reported. 
There is no clinical study of LCZ696 conducted in HF patients in Japan. The PK of LCZ696 
is similar between Japanese and Caucasian healthy subjects. Several studies have been 
conducted in Japanese hypertensive patients. In a Phase III pivotal study (CLCZ696A1306) 
comparing LCZ696 to an ARB olmesartan, a total of 1,161 hypertensive patients received 
LCZ696 (200 mg or 400 mg once daily, n=772) or olmesartan (20 mg once daily, n=389). 
This study showed LCZ696 was superior to olmesaltan in blood pressure lowering effect, and 
was safe and well tolerated in Japanese hypertensive patients. 
The multicenter, randomized, double-blind, parallel group and active controlled study  
CLCZ696B1301 described here is planned to assess the efficacy/safety of LCZ696 on 
morbidity and mortality compared to enalapril, the current gold standard for RAS blockade in 
HF treatment, in Japanese HF-rEF patients. 
1.2 
Purpose 
The purpose of the core part, which is comprised of screening epoch, single-blind active 
treatment run-in epoch and double-blind randomized treatment epoch, is to assess the effect of 
LCZ696 at a target dose of 200 mg b.i.d. compared to enalapril 10 mg b.i.d., in addition to the 
background HF treatment, on delaying time to first occurrence of either CV death or HF 
hospitalization events in Japanese patients with stable CHF, NYHA classes II-IV and reduced 
ejection fraction (LVEF ≤ 35%). Data from the core part are intended to be used to support 
registration of LCZ696 for treatment of HF patients in Japan. 
The purpose of the open-label extension (OLE) is to provide access to LCZ696 for the eligible 
patients until marketed product is available in Japan or 2 years from the date of the first 
patient enrolled in the OLE epoch, whichever occurs first, and also to assess the safety, 
tolerability and efficacy of the treatment with LCZ696. 
2 
Study objectives 
Unless specifically stated otherwise, the study objectives listed below apply only to the core 
part of this study, which ends at Visit 299 (the end visit of double-blind treatment epoch). 
2.1 
Primary objective(s) 
To assess the effect of LCZ696 and enalapril on delaying time to first occurrence of the 
composite endpoint, which is defined as either CV death or HF hospitalization in patients with 
HF and reduced ejection fraction. 


Novartis 
Confidential 
Page 23 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
2.2 
Secondary objectives 
2.2.1 
Key secondary objectives 
 To assess the effect of LCZ696 100 mg b.i.d. and 200 mg b.i.d. on changes in NT-
proBNP from baseline at predefined time points (Weeks 4, 8 and Month 6) 
 To assess the effect of LCZ696, compared to enalapril, on delaying the time to first 
occurrence of CV death, HF hospitalization, or intensification of treatments due to 
documented episode(s) of worsening HF defined as: worsening signs and symptoms 
of HF requiring addition of a new drug for HF treatment, initiation of IV treatment, 
increase of diuretic dose for persistent use for ≥ 4 consecutive weeks, or institution of 
mechanical or circulatory support such as mechanical ventilation, ultrafiltration, 
hemodialysis, intra-aortic balloon pump or ventricular assist device 
 To assess the effect of LCZ696, compared to enalapril, on changes in NYHA 
classification from baseline at predefined time points (Weeks 4, 8 and Month 6) 
 To assess the effect of LCZ696, compared to enalapril, on improving the clinical 
summary score for HF symptoms and physical limitations, as assessed by the Kansas 
City Cardiomyopathy Questionnaire (KCCQ) at predefined time points (Week 8 and 
Month 6) 
 To assess safety and tolerability of LCZ696 compared to enalapril 
2.2.2 
Other secondary objectives 
 To assess the effect of LCZ696, compared to enalapril, on reducing the rate of the 
composite endpoint of CV death and total (first and recurrent) HF hospitalizations 
 To assess the effect of LCZ696, compared to enalapril, on the clinical composite 
score (as assessed by NYHA classification and patient global assessment) at 
predefined time point (Month 6) 
 To assess the effect of LCZ696, compared to enalapril, on delaying the time to 
all-cause mortality 
 To assess the effects of LCZ696, compared to enalapril, on reducing the number of 
patients hospitalized and number of hospital admission (all-cause and cause-specific) 
 To assess the effects of LCZ696, compared to enalapril, on reducing healthcare 
resource utilization, e.g., number of days/stays in ICU, number of rehospitalizations, 
and number of ER visits for HF 
 To assess the effects of LCZ696 and enalapril on changes in pre-specified and/or 
other relevant biomarkers (e.g., cardiac, vascular, renal, collagen, metabolism, and 
inflammatory biomarkers) from baseline to predefined timepoints (Weeks 2, 4, 8, 
Month 6 and 18) 
2.2.3 
Objectives during the open-label extension 
 To evaluate the safety and tolerability of LCZ696 treatment during the OLE epoch 
 To assess the proportion of patients reaching target dose level 3 of LCZ696 at Week 8 
and maintained at Month 4 


Novartis 
Confidential 
Page 24 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 To assess the effect of LCZ696 on change in NYHA classification from OLE baseline 
(Visit 301) at Month 12 
 To assess the effects of LCZ696 on change in cardiac measurements by 
echocardiography (LV end systolic and diastolic volume indices, LVEF, and LA 
volume index, etc.) from OLE baseline (Visit 301) at Month 12 
 To assess the effects of LCZ696 on changes in pre-specified biomarkers from OLE 
baseline (Visit 301) to predefined timepoints (Weeks 2-4, 8, Month 4 and 12) 
 To assess the association between change in concentration of NT-proBNP and change 
in structural cardiac measurements (LV end systolic and diastolic volume indices, 
LVEF, and LA volume index) from OLE baseline (Visit 301) at Month 12 
 To assess the effects of long-term treatment with LCZ696 on the safety and 
tolerability throughout the study period 
 
 
 
 
 
 
3 
Investigational plan 
3.1 
Study design 
The core part of this study is a multicenter, randomized, double-blind, double-dummy, 
parallel-group, active-controlled study to assess the effect of LCZ696 at a target dose of 
200 mg b.i.d. and enalapril 10 mg b.i.d. on CV mortality and morbidity reduction in Japanese 
HF patients with reduced ejection fraction. Patients who qualify the eligibility criteria at 
screening will first enter a 2 week, single-blind, active treatment run-in epoch in which they 
will receive LCZ696 50 mg b.i.d. Patients who tolerate the LCZ696 50 mg b.i.d. for 2 weeks 
will be randomized in a 1:1 ratio to receive LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. 
(Figure 3-1) for 4 weeks during the double-blind treatment epoch. The patient randomization 
is stratified by using NT-proBNP measured at the screening visit as a stratification factor. The 
patients will then be titrated up to the target dose of LCZ696 200 mg b.i.d. or enalapril 10 mg 
b.i.d. if they tolerate 4 weeks treatment of LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. Dose 
adjustment (LCZ 50-100 mg b.i.d. & enalapril 2.5-5 mg b.i.d.) is permitted if not tolerated at 
the target dose of study drugs during the double-blind treatment epoch (Section 5.5.5). 
An open-label extension to the study will be conducted following the completion of the core 
part (Figure 3-2).  
Every consenting trial participant who is eligible to receive study drug (refer to Section 4.1 
and 4.2) will start the OLE epoch. For all patients, the first visit of the OLE epoch will occur 
on the same day as the EOS visit of the core part. At Visit 301, patients will be switched to an 
open-label LCZ696 from double-blinded study drug. Dose adjustments and temporary 
interruptions of study treatment are permitted if not tolerated during OLE epoch following the 
pre-specified protocol guidance (Section 5.5.5). 


Novartis 
Confidential 
Page 25 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
The core part will be event-driven in which patients will remain in the study (regardless of 
whether receiving investigational treatment) until the projected number of patients with 
primary events (approximately 57 events) has been reached. 
It is planned that approximately 220 patients will be randomized and the total trial duration 
will be approximately 40 months, with a projected recruitment period of 22 months and a 
follow-up period of 18 months after the enrollment of the last patient into the trial. It is 
expected that the average follow-up time will be approximately 28.5 months. 
The OLE epoch (Figure 3-2) is expected to continue until marketed product is available in 
Japan or for 2 years from the date of the first patient enrolled in the OLE epoch, whichever 
comes first. 
Figure 3-1 
Study design (Core) 
 
w = week; m = month 
a 
Down-titration to lower dose level (LCZ 50 mg b.i.d. or enalapril 2.5 mg b.i.d.) is allowed if not tolerated 
during the first 4 weeks. Dosage should be up-titrated at Visit 203 if tolerated, and follow the general 
protocol guidance regarding maintenance dose (Section 5.5.5). 
b 
Dose adjustment (LCZ 50-100 mg b.i.d. or enalapril 2.5-5 mg b.i.d.) is permitted if not tolerated at the 
target dose, ie, LCZ696 200 mg b.i.d. or enalapril 10 mg b.i.d., during the double-blind treatment epoch 
following the general protocol guidance regarding maintenance dose (Section 5.5.5). 
c 
Projected duration of the trial is 40 months. Actual duration of the trial is event-driven. 


Novartis 
Confidential 
Page 26 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Figure 3-2 
Study design (OLE) 
 
w = week; m = month 
a 
Patients receiving double-blind study drug at dose level 2 have options to start with either the open-label 
LCZ696 100 mg b.i.d. (dose level 2) or LCZ696 50 mg b.i.d. (dose level 1) at the investigator’s discretion. 
b 
Dosage should be up-titrated at Visit 302 if tolerated in accordance with Table 3-3, and follow the general 
protocol guidance regarding maintenance dose (Section 5.5.5). 
c 
Dose adjustment is permitted if not tolerated at the dose during the OLE epoch following the general 
protocol guidance regarding maintenance dose (Section 5.5.5). 
d 
Attempt should be made to up-titrate and maintain the patient at the target LCZ696 dose (dose level 3) 
for as long as possible. 
3.1.1 
Study visits 
3.1.1.1 
Screening 
Screening Visit (Visit 1) 
All patients must provide informed consent before any study-specific procedure is performed. 
At Visit 1, patients’ eligibility for entering the active treatment run-in epoch will be assessed 
by the investigator. LVEF measurements required for eligibility will be based on locally 
obtained echocardiograms, MUGA scans, CT scans, MRIs, or ventricular angiographies 
performed within the last 6 months provided that no subsequent measurements were above 
35%. If a LVEF measurement within the last 6 months is not available, the patient may enter 
the trial based on a LVEF ≤ 35% obtained during the screening epoch, i.e., before assigning 
any run-in study medication. If a patient has an implanted cardiac resynchronization therapy 
device, the LVEF values used to qualify for the study must be obtained at least three months 
after the implantation of that device. Screening NT-proBNP will be assessed by sending blood 
samples to the central laboratory and only patients with the required values per the entry 
criteria will be eligible for entering the treatment run-in epoch, which will begin at Visit 101. 
A patient may qualify for inclusion into the study based on a NT-proBNP value according to 
the inclusion criteria mentioned in Section 4.1. 


Novartis 
Confidential 
Page 27 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Since it may take several days to obtain the results of the clinical laboratory assessments to 
evaluate the patient’s eligibility for the study, it is recommended that at Visit 1 the site 
schedules Visit 101 approximately one to two weeks after Visit 1. 
First morning urine void samples for biomarker assessments will be taken at Visit 101. Site 
should give the patient a urine collection container and instructions on how to collect the first 
morning urine void, which should be performed before returning to the site for Visit 101. 
The site personnel should also instruct the patient not to take any ACEIs or ARBs on the day 
of Visit 101 and thereafter. 
3.1.1.2 
Single-blind active treatment run-in epoch 
Patients who are successfully screened into the study at Visit 1 will enter the single-blind 
active treatment run-in epoch. Since this epoch will be a single-blind period, the site staff 
working with patients should exercise caution when discussing the study procedures and the 
study drug with patients to keep the patient blinded to the identity of the study drug. 
Please refer to Table 6-1 for a detailed list of study procedures and assessment to be 
performed at each run-in epoch visit. 
Visit 101 
Once patients’ eligibility has been ascertained, they will attend Visit 101 approximately one to 
two weeks after Visit 1 to start LCZ696 50 mg b.i.d. for 2 weeks. Patients should continue to 
take their background medications for CHF, with the exception of ACEIs or ARBs which 
must be discontinued at Visit 101. 
If patients meet the criteria in Table 3-1, they will start to take the LCZ696 50 mg b.i.d. run-in 
medication the day after Visit 101. An approximately 36-48 hour wash-out period stopping 
concomitant ACEIs or ARBs should be included before the enrolled patients start taking the 
first dose of LCZ696. For example, if a patient’s Visit 101 is on Wednesday, he/she must not 
take any doses of ACEIs or ARBs after the last dose on Tuesday. The patient will then start 
taking the first dose of LCZ696 50 mg b.i.d. run-in medication on Thursday morning. 
End of treatment run-in visit (Visit 199) 
A Visit 199 (end of treatment run-in visit) will be completed for all patients who enter the 
treatment run-in epoch. Patients not tolerating LCZ696 50 mg b.i.d. (Table 3-1) will be 
considered run-in failures and withdrawn from the study. For patients who discontinue during 
the treatment run-in epoch, Visit 199 will be their discontinuation visit. 
Only patients who tolerate LCZ696 50 mg b.i.d. for 2 weeks will be eligible for 
randomization. For patients that are eligible to be randomized, Visit 199 will be their end of 
treatment run-in disposition visit and may be performed on the same day as Visit 201. Table 
6-1 lists all procedures to be performed at Visit 199. 
 
 


Novartis 
Confidential 
Page 28 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Safety and tolerability monitoring during the active treatment run-in epoch 
Patients will be eligible for entering the run-in epoch at Visit 101, and for randomization at 
Visit 201 if they meet all the inclusion criteria and none of the exclusion criteria, including the 
serum potassium, eGFR, blood pressure, and postural symptoms listed in Table 3-1. Local 
laboratory assessments at Visits 1 and 199 are used to ascertain if patient doesn’t meet the 
exclusion criteria of serum potassium and eGFR. 
During the treatment run-in epoch, non-disease modifying medications (such as nitrates, 
CCBs, α-blockers, and diuretics) may be changed (dose reduced or discontinued) in response 
to the occurrence of adverse events, such as hyperkalemia, hypotension, and renal dysfunction, 
in an attempt to allow patients to meet the safety criteria in Table 3-1. The doses of 
background disease modifying drugs, such as β-blockers or aldosterone antagonists, may be 
reduced to facilitate maintenance of study drug if in the opinion of the investigator they are 
believed to be the cause of the adverse effect in question. 
The reason for patient discontinuation during the active treatment run-in epoch must be 
carefully documented in the appropriate eCRFs. 
Patients who experience angioedema at any time during the treatment run-in epoch must be 
withdrawn from the study. 
Table 3-1 
Safety monitoring criteria that must be met at Visit 1 (screening) and 
Visit 199 
Parameter 
Visit 1 (screening) 
Visit 199 (end of run-in) 
Serum 
potassium level 
K ≤ 5.2 mmol/L (mEq/L)  
(local assessment) 
K ≤ 5.4 mmol/L (mEq/L)  
(local assessment) 
Kidney function eGFR ≥ 30 mL/min/1.73 m2  
(local assessment) 
eGFR ≥ 30 mL/min/1.73 m2 
eGFR reduction ≤ 35% compared to Visit 1 
(local assessments) 
Blood pressure No symptomatic hypotension and 
SBP ≥ 100 mmHg 
No symptomatic hypotension and 
SBP ≥ 95 mmHg 
Adverse events 
(AEs) or 
conditions 
No postural symptoms or any 
conditions that preclude continuation 
according to the investigator’s judgment 
No postural symptoms or any AEs that 
preclude continuation according to the 
investigator’s judgment 
3.1.1.3 
Double-blinded randomized treatment epoch 
The randomized treatment epoch will begin at Visit 201. Patients who successfully complete 
the run-in and tolerate LCZ696 50 mg b.i.d. will be randomized to receive LCZ696 100 mg 
b.i.d. or enalapril 5 mg b.i.d. for 4 weeks and be up-titrated to the target dose of LCZ696 
200 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio in a double-blind manner. Please refer to 
Table 6-1 for a detailed list of study procedures and assessment to be performed at each 
randomized treatment epoch visit. 
The study medication will be added to the prescribed background HF therapy. Concomitant 
administration of ACEIs or ARBs with the study medication is strictly prohibited. Please refer 
to Section 5.5.7 for more information on co-administration of other medications. 
Reported trial outcome endpoint events will be collected as they occur throughout the 
randomized treatment epoch. All laboratory evaluations for planned visits after randomization 


Novartis 
Confidential 
Page 29 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
will be performed through the central laboratory or other authorized laboratory. Unscheduled 
laboratory assessments can be performed locally as necessary. 
Visit 201 will be considered the reference visit for all study visits during the randomized 
treatment epoch. Regardless of the occurrence of any unscheduled visits, scheduled visits 
should occur within the timeframe in relation to Visit 201 as outlined in Table 6-1. 
Randomization Visit (Visit 201) 
Patients who have met all the inclusion criteria and none of the exclusion criteria at the end of 
the active treatment run-in epoch will be randomized to either LCZ696 100 mg b.i.d. or 
enalapril 5 mg b.i.d. in a 1:1 ratio. 
Site personnel should instruct the patient to refrain from taking their run-in medication on the 
day of Visit 201. Site personnel will document the date and time of the last dose of the 
LCZ696 run-in medication. This is necessary to ensure a 36-hour wash-out period to avoid 
overlapping of LCZ696 with enalapril and minimize the potential risk of occurrence of 
angioedema. 
If appropriate, the patient will start to take the double-blind study medication (LCZ696 
100 mg b.i.d. or enalapril 5 mg b.i.d.) the day after Visit 201. For example, if a patient’s 
Visit 201 is on Wednesday, he/she must not take any doses of the LCZ696 50 mg b.i.d. run-in 
medication after Tuesday evening. The patient will then start taking the first dose of the 
double-blind study medication on Thursday morning. 
Table 6-1 lists all procedures to be performed at Visit 201. 
Visits 202 up to end visit for double-blind treatment epoch 
In the first 6 months of the randomized treatment epoch, patients will return to the site for 
study visits at two, four, eight, twelve weeks and 6 months after randomization. Visits after 
the first 6 months of the randomized treatment epoch will be scheduled for every four months. 
In addition to the protocol-required visits, patients may be seen at anytime throughout the 
study at the discretion of the investigator to follow any new laboratory abnormalities or AEs. 
All randomized patients should continue to receive double-blind treatment, if deemed 
appropriate by the investigator, until the trial is completed. 
At Visit 203 (4 weeks after randomization), patients’ medication compliance, safety, and 
tolerability of the study medication will be assessed, including signs and symptoms of 
hypotension, potassium level, and renal function. Dosage should be up-titrated to the target 
doses (LCZ696 200 mg b.i.d. or enalapril 10 mg b.i.d.) at Visit 203 if tolerated, and follow the 
general protocol guidance regarding maintenance dose (Section 5.5.5). Down-titration to 
lower dose level (LCZ 50 mg b.i.d. or enalapril 2.5 mg b.i.d.) is allowed if not tolerated 
during the first 4 weeks after randomization.  
Monitoring of safety and tolerability will include: (1) hyperkalemia; (2) symptomatic 
hypotension; (3) increase in serum creatinine; (4) angioedema; and (5) AEs and SAEs. If, in 
the opinion of the investigator, the patient cannot tolerate the target dose of study drug, the 
investigator should consider whether non-disease-modifying medication (e.g., CCBs, diuretics, 
nitrates, α-blockers) can be modified to rectify the situation before considering reducing the 


Novartis 
Confidential 
Page 30 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
dose of the study drug to the lower dose level. The dose of background disease modifying 
drugs, such as β-blockers and aldosterone antagonists, may be modified to facilitate 
maintenance of study drug if they are believed to be the cause of the adverse effect in question. 
If the situation is not rectified despite adjusting/discontinuing other concomitant medications 
or if adjusting other concomitant medications is not possible, patients who no longer tolerate 
the intermediate or target doses at any time during the double-blind treatment epoch of the 
trial can be down-titrated to the lower dose level at the investigator’s discretion (please refer 
to Table 5-1 for dose levels available for titration). However, every attempt should be made to 
re-challenge the patients so that they are kept on the maximal tolerated dose of study drug for 
as long a duration as possible throughout the randomized treatment epoch of the trial. Please 
refer to Section 5.5.5 for guidance on study drug dose adjustment. 
If the study drug is temporarily discontinued, it should be reintroduced as soon as medically 
justified in the opinion of the investigator. After randomization, study drug discontinuation for 
any reason does not constitute withdrawal from the study and should not lead to the patient 
being withdrawn from the study. On the contrary, even patients who have stopped taking 
study drug are expected to attend all the protocol specified study visits and perform all 
measurements as stipulated in the visit schedule. In case it is not possible for the patient to 
attend any visit(s), the site staff will keep in touch with the patient by means of regular phone 
contact with the patient himself/herself or with the person pre-designated by the patient 
accordance with the patient’s study visit schedule. Data will continue to be collected about the 
patient’s health status, including information on developing of cardiovascular complications 
and vital status. This information may be provided by either the patient himself/herself or 
patient’s designee. Data, such as information on survival information and potential protocol-
specified endpoint, might be also collected from a health care provider, or other sources as 
available as allowed by local regulation or restriction. These data will be collected until the 
conclusion of the study, even if the patient is no longer attending the study visits in person. 
 
 
 
. 
All randomized patients will remain in the trial until the projected number of primary 
endpoint (composite of CV death or HF hospitalization) is reached. Table 6-1 lists all 
procedures to be performed at Visit 202 and all the remaining visits in the study. 
Patients will be instructed to take the last dose of the double-blind study drug on the day 
before the core part EOS visit (Visit 299), and visit the study sites without taking the study 
drug on the day of Visit 299. 
3.1.1.4 
Open-label extension (OLE) epoch 
Upon completion of the core part of study, all eligible trial patients will be offered the option 
to enter the OLE epoch. Informed consent will be obtained at Visit 301, the start of the OLE 
epoch, and before any study-specific procedure for OLE epoch is performed. The last dose of 
study medication that the patient is taking during the core part should be considered in 
determining the starting dose level of LCZ696 (Table 3-2). The same principles of study drug 
monitoring for safety and tolerability during the core part must be applied during the OLE. 


Novartis 
Confidential 
Page 31 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Treatment guidelines for hyperkalemia, management of BP and renal dysfunction are 
provided in Appendix 3, Appendix 4 and Appendix 5, respectively. Please refer to Table 6-2 
for a detailed list of study procedures and assessment to be performed at each OLE epoch visit. 
Attempt should be made to up-titrate and maintain the patient at the target LCZ696 dose (dose 
level 3) as soon as possible. At Visit 302 (Week 2-4), patients who meet the safety monitoring 
criteria (Table 3-3) and tolerate open-label LCZ696 should be up-titrated to the next higher 
level of daily dose. If patient does not meet the safety monitoring criteria, then investigator 
should try to modify background medication in line with Section 5.5.5 in order to re-challenge 
the patient with a higher dose level at the earliest possible opportunity.  
The study medication will be added to the prescribed background HF therapy. Concomitant 
administration of ACEIs or ARBs with the study medication is strictly prohibited. Please refer 
to Section 5.5.7 for more information on co-administration of other medications. 
Unlike the double-blind epoch, permanent discontinuation of study drug constitutes 
withdrawal from the study. 
Visit 301 will be considered the reference visit for all study visits during the OLE epoch. 
Regardless of the occurrence of any unscheduled visits, scheduled visits should occur within 
the timeframe in relation to Visit 301 as outlined in Table 6-2. 
Table 3-2 
Starting dose levels of open-label LCZ696 at the start of the OLE 
epoch 
Final dose level of study medication during 
the double-blind treatment epoch 
Corresponding dose levels of open-label 
LCZ696 treatment upon entering OLE 
3 
100 mg b.i.d. 
2 
50 mg b.i.d. or 100 mg b.i.d. a 
1 
50 mg b.i.d. 
No treatment 
50 mg b.i.d. 
a 
The patient receiving double-blind study drug at dose level 2 has options to start with either the open-label 
LCZ696 100 mg b.i.d. (dose level 2) or LCZ696 50 mg b.i.d. (dose level 1) at the investigator’s discretion. 
Table 3-3 
Safety monitoring criteria for up-titration at Visit 302 (Week 2 to 4) 
Parameter 
Visit 302 (Week 2 to 4) 
Serum potassium level 
K ≤ 5.4 mmol/L (mEq/L) 
(local assessment) 
Kidney function 
eGFR ≥ 30 mL/min/1.73 m2  
eGFR reduction ≤ 35% compared to Visit 301 
(local assessments) 
Blood pressure 
No symptomatic hypotension and SBP ≥ 95 mmHg. 
AEs or conditions 
No postural symptoms or any AEs that preclude continuation 
according to the investigator’s judgment 
 


Novartis 
Confidential 
Page 32 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
OLE epoch initiation visit (Visit 301) 
All patients must provide informed consent before any study-specific procedure for OLE 
epoch is performed. At Visit 301, patients’ eligibility for entering the OLE epoch will be 
assessed by the investigator. 
Patients will start the OLE epoch at this visit. This first visit of the OLE epoch will occur on 
the same day as the end of study (EOS) visit of the core part. Patients will be switched to an 
open-label LCZ696 at this visit. The patients receiving double-blind study drug at dose level 3 
will start with open-label LCZ696 100 mg b.i.d. (dose level 2) (Table 3-2). The patients 
receiving double-blind study drug at dose level 2 will start with either open-label LCZ696 
50 mg b.i.d. (dose level 1) or LCZ696 100 mg b.i.d. (dose level 2) at the investigator’s 
discretion. The patients receiving double-blind study drug at dose level 1 will be also 
switched to an open-label LCZ696 but remain at same dose level (LCZ696 50 mg b.i.d.) up to 
Visit 302. Patients should continue to take their background medications for HF, with the 
exception of ACEIs or ARBs. The patients who have discontinued the double-blind study 
drug before this visit may be enrolled if eligible, however, should start with taking the 
LCZ696 50 mg b.i.d. (dose level 1). 
Prior to Visit 301, site personnel should instruct the patient to refrain from taking their 
double-blind study drug or the open-label ACEIs received by those patients who are not on 
double-blind study drug treatment on the day of Visit 301. This is necessary to ensure a 
36-hour wash-out period to avoid overlapping of LCZ696 with enalapril or the open-label 
ACEIs and minimize the potential risk of occurrence of angioedema. In case patient comes to 
visit after having taken the double-blind study drug or the open-label ACEIs at Visit 301, the 
assessments could nevertheless be conducted. In this case, patient should start taking 
open-label LCZ696 at least approximately 36 hours after the last dose of double-blind study 
drug or the open-label ACEIs. 
The patients who have discontinued the double-blind study drug and are instead receiving 
open-label ARBs or renin inhibitors, are allowed to take these drugs on the day of Visit 301; 
however, approximately 12 hours should transpire between the first dose of open-label 
LCZ696 and the last dose of open-label ARB or renin inhibitor.  
Site personnel will document the date and time of the last dose of the double-blind study drug 
or open-label ACEIs/ARBs/renin inhibitors prior to Visit 301 on source document at site.  
The patient will start to take the open-label LCZ696 the day after Visit 301. For example, if a 
patient’s Visit 301 is on Wednesday, he/she must not take any doses of the double-blind study 
drug after Tuesday evening. The patient will then start taking the first dose of the open-label 
LCZ696 on Thursday morning. 
Table 6-2 lists all procedures to be performed at Visit 301. 
Visits 302 up to end of study (EOS) visit for OLE epoch 
In the first 4 months of the OLE epoch, patients will return to the site for study visits at two to 
four weeks, at eight weeks and 4 months. Visits after the first 4 months will be scheduled for 
every four months. 


Novartis 
Confidential 
Page 33 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
In addition to the protocol-required visits, patients may be seen at anytime throughout the 
study at the discretion of the investigator to follow any new laboratory abnormalities or AEs. 
All patients should continue to receive open-label LCZ696, if deemed appropriate by the 
investigator, until the trial is completed. 
At Visit 302, patients’ medication compliance, safety, and tolerability of the study medication 
will be assessed, including signs and symptoms of hypotension, potassium level, and renal 
function. The patients who meet the safety monitoring criteria (Table 3-3) and tolerate open-
label LCZ696 should be up-titrated to the next higher level of daily dose and follow the 
general protocol guidance regarding maintenance dose (Section 5.5.5). If patient does not 
meet the safety monitoring criteria per Table 3-3, the investigator should try to modify 
background medication in line with Section 5.5.5 in order to re-challenge the patient with a 
higher dose level at the earliest possible opportunity.  
The investigator should aim to up-titrate the open-label LCZ696 dose to the target dose level 
of 200 mg bid by 8 weeks, although a slower up-titration schedule is also allowed per 
patient’s safety and tolerability. 
The investigator should follow the same instructions for the double-blind treatment epoch on 
the monitoring of safety and tolerability, and the adjustments/discontinuation of concomitant 
medications when the patient cannot tolerate the dose of study drug. Please refer to 
Section 5.5.5 for guidance on study drug dose adjustment. 
If the study drug is temporarily discontinued, it should be reintroduced as soon as medically 
justified in the opinion of the investigator. Meanwhile, permanent discontinuation of study 
drug during the OLE epoch constitutes withdrawal from the study. 
Table 6-2 lists all procedures to be performed at Visit 302 and all the remaining visits in the 
study.  
3.2 
Rationale of study design 
A randomized, double-blind, parallel group, active-controlled study is a well-established 
design to evaluate the efficacy and safety of investigational drugs for HF. The core part is 
comprised of three epochs, screening epoch, a single-blind active treatment run-in epoch and 
a double-blind randomized treatment epoch. A randomized treatment epoch is established to 
evaluate the effect of LCZ696 at a target dose of 200 mg b.i.d. compared to enalapril 10 mg 
b.i.d.  
Requisite conditions for approval of CHF drugs in Japan are described in Japanese Guidelines 
for Clinical Evaluation of Drugs for Heart Failure (Ministry of Health, Labour and Welfare 
2011). It indicates HF drug approval may be considered in case positive results of outcome 
study outside Japan are available and the results of clinical study in Japanese patients on 
morbidity show the same trends as overseas, even when it is impossible to conduct a clinical 
trial of a scale that can statistically investigate significant improvement in morbidity in Japan. 
Recently, the superiority of LCZ696 over enalapril on the reduction of CV death and HF 
hospitalization in patients with HF-rEF was demonstrated in overseas outcomes study 
(PARADIGM-HF, CLCZ696B2314) (McMurray et al. 2014). Therefore, this study 
(CLCZ696B1301) is designed to align with the guideline requirement for drug approval, to 
observe a similar trend of LCZ696 better than enalapril in reducing morbidity and mortality in 


Novartis 
Confidential 
Page 34 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Japanese HF patients and capture data of the efficacy variables of PARADIGM-HF so that the 
efficacy of LCZ696 over enalaprill in Japanese HF patients can be assessed in aspects 
comparing with PARADIGM-HF study outcomes. 
Open-label study design is adopted for the OLE epoch because the main objective of this 
epoch is to provide access to LCZ696 for the eligible patients and also to obtain the safety and 
tolerability data of long-term treatment with LCZ696. 
3.2.1 
Rationale for primary endpoint 
Apart from improving symptoms, there is general agreement that the major goal of treating 
HF with a reduced LVEF is to reduce the major fatal and non-fatal consequences of this 
illness, i.e., CV death and hospitalization for worsening HF. CV death accounts for 
approximately 80% of all deaths in HF patients and most CV deaths are due to either sudden 
(presumed arrhythmic) death or death due to worsening heart (i.e., pump) failure. 
Hospitalization for worsening HF is the single most common cause of hospital admission in 
this patient population and is an ominous development in that it portends high subsequent 
risk–both of readmission and of death. HF hospitalization is also the main driver of the huge 
economic burden of this syndrome. 
As CV death and HF hospitalization both reflect disease-specific endpoints related to 
progressive worsening of the HF syndrome, they should both be modifiable by treatments 
improving this condition, which has generally proved to be the case with both drugs (ACEIs, 
aldosterone antagonists, and β-blockers) and devices (cardiac resynchronization therapy). This 
understanding of HF and its treatment has led to the disease-specific composite outcome of 
CV death or HF hospitalization becoming the most commonly used primary endpoint in 
current HF outcomes trials. 
In Japan, it is referred in Japanese Guidelines for Clinical Evaluation of Drugs for Heart 
Failure that total mortality, cardiovascular morbidity, and subjective complaints are 
considered appropriate as the primary endpoints of HF studies (Ministry of Health, Labour 
and Welfare 2011). 
3.2.2 
Rationale for treatment run-in epoch 
Patients start to receive LCZ696 50 mg b.i.d. in the single-blind active treatment run-in epoch. 
During the treatment run-in epoch, patients will continue their background HF medications 
except ACEI and ARB. Patients unable to tolerate LCZ696 50 mg b.i.d. during the treatment 
run-in will not be eligible for randomization, and will be discontinued from the study. This 
design will enable to maximize the number of patients who tolerate at least the lowest dose 
level (dose level 1) of LCZ696 throughout the double blind treatment epoch with long-term 
follow-up. 
There are two short washout periods (approximately 36-48 hours for each) during the 
treatment run-in epoch to minimize the potential risk of angioedema due to overlapping ACE-
NEP inhibition at Visit 101 and Visit 201 (Section 6.5.7): (1) after completing the screening 
epoch receiving conventional ACEIs or ARBs and prior to beginning the LCZ696 run-in at 
Visit 101, and (2) after completing the LCZ696 run-in and prior to starting randomized study 
drug at Visit 201. 


Novartis 
Confidential 
Page 35 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
On the other hand, the risk of HF deterioration associated with stopping concomitant ACEIs 
or ARBs for approximately 36-48 hours, the duration of the ACEI/ARB-free period, will be 
minimal, especially since all patients will be allowed to continue receiving their background 
HF and CV medications. 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
LCZ696 200 mg is associated with ~84% (95% CI, 64 - 100%) of maximum cGMP increase 
(AUEC), indicating near maximal neprilysin inhibition. The target dose of 200 mg b.i.d. has 
been examined in the completed PARADIGM-HF outcome trial evaluating the effect on 
morbidity and mortality in patients with HF-rEF (McMurray et al. 2014). The administration 
of LCZ696 200 mg b.i.d. demonstrated significantly greater effect on delaying time to first 
occurrence of morbidity and mortality events than enalapril 10 mg b.i.d. LCZ696 200 mg b.i.d. 
was also well tolerated in this study, with the frequency of overall adverse events similar to 
enalapril. 
In addition, the efficacy and safety of LCZ696 400 mg once daily have been demonstrated in 
Japanese hypertensive patients. In a Phase III pivotal study (CLCZ696A1306) comparing 
LCZ696 to an ARB olmesartan, a total of 1,161 hypertensive patients received LCZ696 
(200 mg or 400 mg once daily, n=772) or olmesartan (20 mg once daily, n=389) for 8 weeks. 
This study showed LCZ696 was superior to olmesaltan in blood pressure lowering effect in 
hypertensive patients. LCZ696 200 mg and 400 mg daily doses were shown safe and well-
tolerated in hypertension clinical program, including the long-term treatment of 12 months in 
more than 150 Japanese hypertensive patients. 
In order to adequately manage patient’s safety and tolerability, optional titration design is 
adopted in this study, and dose adjustments and temporary interruptions of study treatment are 
also permitted during double blind treatment epoch following the pre-specified protocol 
guidance on maintenance dose. 
Rather than 400 mg once daily dosing of LCZ696 that was used in the hypertension study, 
this dose will be split and LCZ696 will be dosed at 200 mg twice daily in the current HF-rEF 
study. This will ensure sustained NEP inhibition over 24 hours, which is thought to be critical 
for patients with HF. Furthermore, twice daily dosing regimen is anticipated to reduce the 
incidence of post-dose hypotension in HF patients, particularly in elderly patients. 
This core part is an event driven, outcomes trial. The end of the core part will occur when the 
pre-specified number of patients achieves the primary composite endpoint of CV deaths or 
hospitalizations for HF (approximately 57 patients). As an event driven trial, the actual length 
of the trial will depend on the observed event rates, the patient accrual rate, and length of the 
accrual period. Patient should continue to attend the core part and receiving study drugs until 
the completion of the core part. As planned, it is expected to be up to 40 months: total study 
sample size of 220 patients with a recruitment period of approximately 22 months and a 
minimal follow-up of 18 months. 
The main purpose of the OLE is to provide access to LCZ696 for the eligible patients and also 
to assess the safety and tolerability data of long-term treatment with LCZ696. The OLE epoch 


Novartis 
Confidential 
Page 36 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
will continue until marketed product is available in Japan or approximately for 2 years from 
the date of the first patient enrolled in the OLE epoch, whichever comes first.  
The patients receiving double-blind study drug at dose level 3 will be switched to an open-
label LCZ696 and start taking the open-label LCZ696 at the next lower dose level to ensure 
the patient’s safety, then the dosage will be up-titrated to the original dose level after a short 
period if tolerated. 
3.4 
Rationale for choice of comparator 
An ACEI has been selected as the active comparator in this study since major clinical trials 
have established ACEI treatment as the standard of care for RAS blockade and are 
recommended by treatment guidelines as the treatment of choice for all patients with HF-rEF, 
unless ACEI-intolerant. As a well-studied ACEI in HF, enalapril is used as the comparator in 
this study. Enalapril was studied in a number of previous large, outcome-driven studies, such 
as CONSENSUS (CONSENSUS Trial Study Group 1987), SOLVD-Treatment (SOLVD 
Investigators 1991), and SOLVD-Prevention (SOLVD Investigators 1992).  
Enalapril dose of 10 mg b.i.d. has been selected as the comparator target dose for this study 
based on its ability to reduce the risk of death or hospitalization as demonstrated in the 
SOLVD-Treatment study compared to placebo (SOLVD Investigators 1991). Approved 
dosage of enalapril for CHF in Japan is 10 mg/day at maximum. While the clinical benefits at 
this dose level of enalapril in Japanese CHF patients was demonstrated by assessing the global 
improvement rating (Niitani et al. 1990), no study assessing the effect of enalapril on 
morbidity and mortality have been conducted in Japan. Enalapril dose of 10 mg b.i.d. was 
shown generally well tolerated in PARADIGM-HF study, which included more than 1,500 
Asian HF-rEF patients participating in the trial. Considering these backgrounds, higher 
dosage of enalapril has been applied in this study to evaluate the potential effect of LCZ696 
on morbidity and mortality in Japanese patients, compared to a standard-of-care enalapril at 
the dose associated with survival benefit. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not planned.  
3.6 
Risks and benefits 
Patients will be instructed not to take any open-label RAS blockade medications (eg., ACEIs 
or ARBs) once they enter the run-in, and also throughout the double-blind epochs and OLE 
epoch. The risk of wash-out of concomitant ACEIs/ARBs for 36-48 hours prior to the first 
dosing of LCZ696 for the run-in period or withholding the randomized medications and the 
open-label LCZ696 on the day entering the double-blind treatment epoch and the OLE epoch, 
respectively, to reduce the risk of angioedema will be minimal as all patients will still 
continue to receive the other background HF therapies such as β-blockers and/or MRAs 
during the course of study. 
In addition, the risk to patients enrolled in this trial will be minimized by compliance with the 
eligibility criteria and close clinical monitoring comprising of the protocol-defined dose 


Novartis 
Confidential 
Page 37 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
adjustment and pre-specified criteria for drug-related adverse changes in blood pressure, 
potassium and/or renal function, etc. 
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the patient will not reliably comply, they should not 
be entered in the study. 
Since this is a long-term outcome study, participating patients will benefit from careful 
clinical monitoring and follow-up during the entire study duration. 
The OLE epoch following the double-blind core part allows the seamless availability of open-
label LCZ696 to eligible patients which avoids the prolonged treatment interruption.  
4 
Population 
The study population will consist of patients with CHF (NYHA class II-IV), aged 20 years or 
older with LVEF ≤ 35%. Eligible patients should also be on a stable dose of an ACEI or an 
ARB for at least 4 weeks before entering into the study. Patients from approximately 50 
research sites will be randomized in a 1:1 ratio to either LCZ696 treatment arm or enalapril 
treatment arm. The patient randomization is stratified by using NT-proBNP measured at the 
screening visit as a stratification factor. In order to randomize approximately 220 patients 
(110 patients in each arm), it is estimated that approximately 370 patients will have to be 
screened as the screen or run-in failure rate is anticipated to be approximately 40%. 
All participants of the core part who are eligible to receive study drug will be offered the 
option to enter the OLE. It is anticipated that approximately 180 patients will complete the 
core part of the study and that the majority of them will be enrolled into the OLE. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in the core part have to fulfill all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Outpatients ≥ 20 years of age (at the time of signing informed consent), male or female. 
3. Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction: 
 LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using 
echocardiography, MUGA, CT scanning, MRI or ventricular angiography is also 
acceptable, provided no subsequent measurement above 35%) 
 NT-proBNP ≥ 600 pg/ml at Visit 1 OR NT-proBNP ≥ 400 pg/ml at Visit 1 and a 
hospitalization for HF within the last 12 months (according to central laboratory 
measurements) 
4. Patients must be on an ACEI or an ARB at a stable dose for at least 4 weeks before Visit 1. 
5. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a 
stable dose for at least 4 weeks prior to Visit 1 (reason should be documented if patients 
reported contraindications or intolerance). 
6. An aldosterone antagonist should also be considered in all patients, taking account of renal 
function, serum potassium and tolerability. If given, the dose of aldosterone antagonist 


Novartis 
Confidential 
Page 38 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
should be optimized according to guideline recommendations and patient tolerability, and 
should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for HF 
should also be considered e.g. cardiac resynchronization therapy and an implantable 
cardioverter-defibrillator in selected patients, as recommended by guidelines. 
Patients eligible for inclusion into the open-label extension must fulfill the following criteria: 
7. Written informed consent for the open-label extension must be obtained before any 
assessment is performed. 
8. Patients who have completed the double-blind treatment epoch and are able to be safely 
enrolled into the OLE as judged by the investigator. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in the core part. 
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 to any of the study drugs or to drugs of similar chemical 
classes, ACEIs, ARBs, NEP inhibitors as well as known or suspected contraindications to 
the study drugs. 
2. Previous documented history of intolerance to ACEIs or ARBs. 
3. Known history of angioedema. 
4. Requirement of treatment with both ACEIs and ARBs. 
5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy). 
6. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening) or 
< 95 mmHg at Visit 199 (end of run-in). 
7. Estimated GFR < 30 mL/min/1.73 m2 as measured by the Japanese formula at Visit 1 
(Screening), or Visit 199 (end of run-in) or > 35% decline in eGFR between Visit 1 and 
Visit 199 (according to local measurements). 
8. Serum potassium > 5.2 mmol/L (mEq/L) at Visit 1 (screening) or > 5.4 mmol/L (mEq/L) 
at Visit 199 (end of run-in) (according to local measurements). 
9. 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. 
10. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 6 months after Visit 1. 
11. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac 
resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional 
pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 
months prior to Visit 1 or intent to implant such a device. Also, patients who had 
implantation of a conventional pacemaker or an ICD or had a revision of a pacemaker or 
other device leads within 1 month before Visit 1 are excluded. 
12. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on 
transplant list) or implant a VAD. 
13. History of severe pulmonary disease. 


Novartis 
Confidential 
Page 39 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
14. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months 
prior to Visit 1. 
15. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months 
prior to Visit 1. 
16. Symptomatic bradycardia or second (except asymptomatic Wenckebach block) or third 
degree heart block without a pacemaker.  
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. 
19. Presence of bilateral renal artery stenosis. 
20. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases. 
21. Presence of any other disease with a life expectancy of < 3 years. 
22. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of study drugs, including but not limited to any of 
the following: 
 History of active inflammatory bowel disease during the 12 months before Visit 1. 
 Current duodenal or gastric ulcers during the 3 months prior to Visit 1 
 Evidence of hepatic disease as determined by any one of the following: AST or ALT 
values exceeding 3 × the upper limit of normal (ULN), bilirubin values exceeding 
1.5 × the ULN at Visit 1, history of hepatic encephalopathy, history of esophageal 
varices, or history of portacaval shunt 
 Active treatment with cholestyramine or colestipol resins 
23. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, 
whichever is longer. 
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 off study medication. Highly effective contraception methods 
include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment. 
 Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 


Novartis 
Confidential 
Page 40 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 Combination of any two of the following (a+b, a+c or b+c): 
a. Use of oral, injected* or implanted* hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
< 1%), for example hormone vaginal ring or transdermal hormone contraception*. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps*) with spermicidal foam*/gel*/film*/cream*/vaginal 
suppository* 
*: not approved in Japan, approved methods should be used. 
 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
 
Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. , age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
Patients fulfilling any of the following criteria at Visit 301, are not eligible for inclusion in the 
OLE epoch. No additional exclusions may be applied by the investigator.  
26. Patients who discontinued study drug treatment during the core part due to an event or 
intercurrent illness. Eligibility can be re-considered if the event has resolved and no longer 
represents a risk to the patient and the patient can safely tolerate the administration of 
LCZ696 per the investigator’s assessment. 
27. Any medical condition that in the opinion of the investigator is likely to prevent the 
patient from safely tolerating LCZ696 or complying with the requirements of the study. 
28. Patients who have experience of angioedema event(s) which occurred and reported by the 
investigator during the core part of study. 
29. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
30. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 7 days after stopping study treatment. Highly effective 
contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 


Novartis 
Confidential 
Page 41 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 Male sterilization (at least 6 months prior to Visit 301). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 
 Use of oral, injected* or implanted* hormonal methods of contraception or placement 
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of 
hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception*. 
*: not approved in Japan, approved methods should be used. 
 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. , age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Treatment run-in epoch 
All eligible patients will enter an active treatment run-in epoch during which they will be 
exposed to LCZ696 treatment. 
The following study drugs will be provided:  
 LCZ696 50 mg film-coated tablets (LCZ696 dose level 1) 
 Placebo to match enalapril 2.5 mg tablets (placebo matching enalapril dose level 1) 
Patients will be required to take the single-blind LCZ696 50 mg and placebo to match 
enalapril 2.5 mg twice daily in addition to their conventional concomitant therapy (except for 
ACEI or ARB). 
Randomized treatment epoch 
All eligible patients will be randomized to receive either LCZ696 or enalapril in addition to 
optimal CHF therapy, as considered appropriate by the investigator and in accordance with 
standard therapy guidelines, but with the exception of an ACEI or ARB. The use of an ACEI 
or an ARB in addition to study drug after randomization is strictly prohibited. 
The following study drugs will be provided:  
 LCZ696 50 mg film-coated tablets (LCZ696 dose level 1) 
 Placebo to match LCZ696 50 mg film-coated tablets (placebo matching LCZ696 dose 
level 1) 


Novartis 
Confidential 
Page 42 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 LCZ696 100 mg film-coated tablets (LCZ696 dose level 2) 
 Placebo to match LCZ696 100 mg film-coated tablets (placebo matching LCZ696 dose 
level 2) 
 LCZ696 200 mg film-coated tablets (LCZ696 dose level 3) 
 Placebo to match LCZ696 200 mg film-coated tablets (placebo matching LCZ696 dose 
level 3) 
 Enalapril 2.5 mg tablets (enalapril dose level 1) 
 Placebo to match enalapril 2.5 mg tablets (placebo matching enalapril dose level 1) 
 Enalapril 5 mg tablets (enalapril dose level 2) 
 Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2) 
 Enalapril 10 mg tablets (enalapril dose level 3) 
 Placebo to match enalapril 10 mg tablets (placebo matching enalapril dose level 3) 
Target doses: LCZ696 200 mg b.i.d. and enalapril 10 mg b.i.d. 
Patients not tolerating the intermediate and target dose (LCZ696 100-200 mg b.i.d. or 
enalapril 5-10 mg b.i.d.) will be titrated down to the lower dose level twice a day, at the 
investigator’s discretion, based on the defined safety and tolerability criteria (Appendix 3, 
Appendix 4 and Appendix 5). 
All tablets (LCZ696 50 mg, LCZ696 100 mg, LCZ696 200 mg, enalapril 2.5 mg, enalapril 
5 mg, enalapril 10 mg) have different shapes and colors. Therefore, the study will be designed 
as a double-blind, double-dummy trial to ensure the blinding during the entire course of the 
study. To maintain the blinding, patients will be required to take their assigned active 
treatment tablet along with placebo matching the opposite treatment twice daily (morning and 
evening dose) in addition to their conventional concomitant therapy.  
LCZ696 and its matching placebo will be provided in high density polyethylene (HDPE) 
bottles. Enalapril 2.5 mg and its matching placebo will be provided in HDPE bottles, while 
enalapril 5 mg and 10 mg and its matching placebo will be provided in blister packs. LCZ696 
and enalapril will be packaged separately to limit the number of pack types which will allow 
more flexibility in the drug supply process to cover all the different treatment possibilities 
(treatment arm and medication level) (Section 5.5.4). 
Open-label extension epoch 
All eligible patients will receive open-label LCZ696 twice daily in addition to optimal 
background HF therapy, as considered appropriate by the investigator and in accordance with 
standard therapy guidelines. The use of an ACEI or an ARB in addition to the study drug 
throughout the OLE epoch is strictly prohibited. 
The sponsor will provide the following open-label extension study drugs in bottles: 
 LCZ696 50 mg film-coated tablets (dose level 1) 
 LCZ696 100 mg film-coated tablets (dose level 2) 
 LCZ696 200 mg film-coated tablets (dose level 3) 


Novartis 
Confidential 
Page 43 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.1.2 
Additional study treatment 
The patient should be on an optimal medical regimen of background HF medications. This 
must include an individually optimized dose of a β-blocker at a stable dose for at least 4 
weeks prior to study entry, unless contraindicated or not tolerated. Use of an aldosterone 
antagonist should be considered if indicated in patients eligible for this study (see 
Section 5.5.7). 
5.2 
Treatment arms 
At randomization visit, patients will be assigned to double-blind treatment groups in a ratio of 
1:1 of either: 
 LCZ696 200 mg b.i.d.: patients will start with 100 mg b.i.d. for 4 weeks at Visit 201, 
patients will then be up-titrated to 200 mg b.i.d. at Visit 203 if they are tolerant to 100 mg 
b.i.d.  
 Enalapril 10 mg b.i.d.: patients will start with 5 mg b.i.d. for 4 weeks at Visit 201, patients 
will then be up-titrated to 10 mg b.i.d. at Visit 203 if they are tolerant to 5 mg b.i.d. 
In the OLE epoch, all patients will receive open-label LCZ696 administered twice daily.  
5.3 
Treatment assignment, randomization 
At Visit 201, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of 
investigational treatment to be dispensed to the patient. The randomization number will not be 
communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).  
Randomization will be stratified by the level of NT-pro BNP obtained at Visit 1 (≥ or 
< 1600 pg/ml). 
No randomization process will be applied to the OLE epoch. During the OLE, all patients will 
be treated with LCZ696. IRT system will be used to enroll patients into the OLE epoch and 
dispense study drug in the same manner as in the randomized treatment epoch described 
above. 


Novartis 
Confidential 
Page 44 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.4 
Treatment blinding 
Single-blind LCZ696 will be dispensed to patients during the active treatment run-in epoch. 
During the active treatment run-in epoch, patients will receive LCZ696 and placebo to match 
enalapril. Patients, investigator staff, persons performing the assessments, and data analysts 
will remain blind to the identity of the treatment from the time of randomization until the core 
part database lock, using the following methods: (1) Randomization data are kept strictly 
confidential until the time of unblinding, and will not be accessible by anyone else involved in 
the study, and (2) the identity of the treatments will be concealed by the use of investigational 
treatment that are all identical in packaging, labeling, schedule of administration, appearance, 
and odor. A double-dummy design is used because the identity of the investigational 
treatment cannot be disguised, as the drug products are visibly different. Unblinding will only 
occur in the case of patient emergencies (see Section 5.5.12) and at the conclusion of the core 
part. 
 
 
 
In the OLE, the treatment will not be blinded to either the investigators or the patients. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. The same Subject Number will 
be used throughout the core part and open label extension epoch of the study. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site should 
select the CRF book with a matching Subject Number from the EDC system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Epoch Disposition CRF. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
The investigational treatment packaging has a 2-part label. A unique randomization number is 
printed on each part of this label which corresponds to one of the two treatment arms for the 
double-blind epoch or LCZ696 for the OLE epoch, 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. 


Novartis 
Confidential 
Page 45 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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. 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
Novartis will supply the investigators with all medications sufficient for the course of the 
study. Patients will be provided with medication packs containing study drug corresponding 
to their assigned treatment arm and dose level, sufficient to last until the next scheduled visit. 
In order to adequately blind the double-blind study drug, patients will be required to take a 
total of two tablets (one tablet from the LCZ696/LCZ696 matching placebo pack and one 
tablet from the enalapril/enalapril matching placebo pack) twice a day for the duration of the 
double-blind treatment epoch. Patients participating the OLE epoch will be required to take 
one LCZ696 tablet twice a day for the duration of this epoch. 
Patients will receive LCZ696 50 mg and placebo to match enalapril 2.5 mg (dose level 1) 
twice daily during the active treatment run-in epoch. Table 5-1 and Table 5-2 summarizes the 
study drug that will be taken during the randomized treatment epoch and the OLE epoch, 
respectively. 


Novartis 
Confidential 
Page 46 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Table 5-1 
Study drug dispensed during the randomized treatment epoch 
Study visit 
Dose level LCZ696 
Enalapril 
Visit 203 and all 
subsequent visits 
3a 
200 mg or matching placebo 
b.i.d. 
10 mg or matching placebo b.i.d. 
Available for any 
visit after Visit 201 
2b 
100 mg or matching placebo 
b.i.d. 
5 mg or matching placebo b.i.d. 
Available for any 
visit after Visit 201 
1c 
50 mg or matching placebo b.i.d. 2.5 mg or matching placebo 
b.i.d. 
a 
This dose level must be maintained for as long a duration as possible. If down-titration is 
necessary due to side effects, the patient should be re-challenged as soon as medically possible 
per the investigator’s judgment. 
b 
Up to Visit 203 after randomization, or if dose level 3 is not tolerated despite modification of other 
non-disease-modifying or disease-modifying medications. 
c 
Only if dose level 2 is not tolerated despite modification of other non-disease-modifying or 
disease-modifying medications. 
Table 5-2 
Study drug dispensed during the OLE epoch 
Study visit 
Dose level 
LCZ696 
Visit 302 and all subsequent visits 
3 a 
200 mg b.i.d. 
Available for any visit after Visit 301 
2 
100 mg b.i.d. 
Available for any visit after Visit 301 
1 
50 mg b.i.d. 
a 
This dose level should be attempted and maintained for as long as possible. If down-titration is 
necessary due to side effects, the patient should be re-challenged as soon as medically possible 
per the investigator’s judgment. 
 
Patients will be instructed to take their morning study drug doses at approximately 8 AM and 
their evening study drug doses at approximately 7 PM. The study medications should be taken 
with a glass of water with or without food. If the patient misses taking any study drug dose, 
he/she should take it as soon as possible, unless if it is almost time for the following scheduled 
dose. In this case, the patient should skip the missed dose and return back to his/her regular 
study drug administration schedule. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded in the IRT and on the Dosage Administration Record eCRF. 
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 investigational treatment as prescribed.  


Novartis 
Confidential 
Page 47 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments and temporary interruptions of study treatment are permitted in order to keep the 
patient on study drug. The following guidelines should be followed:  
Every attempt should be made to maintain patients on the target study drug dose level for as 
long a duration as possible throughout the trial. If, however, in the opinion of the investigator, 
the patient does not tolerate the target dose of study drug (dose level 3), the investigator 
should consider whether non-disease-modifying medication (e.g., CCBs, diuretics, nitrates, α- 
blockers) can be modified to rectify the situation, before considering to reduce the dose of the 
study drug to the next lower dose level. Also, the investigator may 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. 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 study drug to the next lower level up to complete withdrawal 
of the study drug. The patient should be re-challenged with the higher dose when the 
investigator feels it is appropriate to do so per the directions provided below in this section. If 
needed, the study drug may be stopped completely, but the patient should continue to attend 
the study visits and be followed until the completion of the study. Ultimately the goal is to 
keep the patient on the target dose level of study drug for as long as possible and to follow the 
patient in the study as long as possible. 
Study drug dose level adjustments should mainly be based on overall safety and tolerability 
with special focus on a) hyperkalemia; b) symptomatic hypotension; and c) clinically 
significant decrease in eGFR/increase in serum creatinine (see Appendix 3, Appendix 4 and 
Appendix 5 for treatment guidelines for hyperkalemia, management of BP, and renal 
dysfunction, respectively). 
Adjustment of study drug dose level 
If despite adjustment of concomitant medications per the guidance provided above does not 
rectify the situation, the investigator may consider adjusting the study medication according 
the following instructions. 
Study drug dose adjustments during the single-blind treatment run-in epoch – There are 
no study drug dose adjustments in run-in epoch. Patients not tolerating LCZ696 50 mg b.i.d. 
will be considered run-in failures and withdrawn from the study.  
Study drug dose adjustments during the double-blind randomized treatment epoch – 
During the randomized treatment epoch, down-titration of the study drug at any time will be 
allowed based on the safety and tolerability criteria defined in Appendix 3, Appendix 4 and 
Appendix 5. If down-titration is necessary, the patient should be down-titrated to the next 
lower dose level (Table 5-1). The patient may continue receiving the lower dose level for a 
recommended period of 1 to 4 weeks before re-challenging the patient with the next higher 
dose level. For example, a patient who encounters tolerability problems at the target dose 
level (dose level 3), should receive the study drug at dose level 2 for 1 to 4 weeks. Then, 
he/she should be re-challenged with up-titration back to dose level 3. 


Novartis 
Confidential 
Page 48 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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, up 
to temporary withdrawal of the study drug. Again, once stable, the patient should be re-
challenged with up-titration to the next higher dose level every 1 to 4 weeks in an attempt to 
bring back the patient gradually to the target study drug dose level (dose level 3). As 
discussed in Section 5.3, the IRT should be contacted to register any changes in the patient’s 
study drug dose level, including in cases of temporary and permanent withdrawal of the study 
drug, and to obtain the medication numbers of the study drug supplies required for the new 
study drug dose level. 
In some instances, according to the safety and tolerability criteria and the investigator’s 
judgment, dose level 1 or 2 could be maintained if he/she considers that the patient’s 
condition would not allow any further up-titration to the target dose of study medication (level 
3). In this case it would be acceptable to maintain the patient at dose level 1 or level 2, 
whichever is the higher and tolerated dose level by the patient. 
Study drug dose adjustments during the OLE epoch – The investigator should follow the 
same dosing instruction as the double-blind treatment epoch for the dose adjustment of 
open-label LCZ696 during the OLE epoch.  
Study drug restart after temporary treatment interruption 
Study drug should be reintroduced in those who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator. 
Once the investigator considers the patient’s condition appropriate for receiving the study 
drug, the investigator should re-start the patient on the study drug at the most appropriate and 
allowable dose level (Table 5-1) per his/her medical judgment. If tolerated based on the safety 
and tolerability criteria in Appendix 3, Appendix 4 and Appendix 5, the patient should be up-
titrated up to the target dose level 3 every 1 to 4 weeks, as per the investigator’s judgment. 
Patients re-started on the study drug will retain their original randomization and study 
identification numbers. Should the patient not tolerate the re-start study drug dose level, 
he/she may be down-titrated again (if appropriate) or discontinue the study medication again 
and a new attempt to up-titrate or reintroduce the study drug could be considered by the 
investigator as soon as medically justified in his/her medical judgment. This will also apply to 
the OLE epoch. 
Study visits should occur as close as possible to the time points indicated in Table 6-1 (core 
part) or Table 6-2 (OLE epoch). The timeframe 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 Table 6-1 or 
Table 6-2. For example, if the patient’s treatment needs to be adjusted between Visit 206 and 
Visit 207, Visit 207 will still be planned 4 months after Visit 206, irrespective of the number 
of unscheduled visits that may have occurred between these two visits or the additional period 
that the medication pack dispensed could have covered. 
Any changes in the study drug dose level, including temporary/permanent withdrawal or 
restart of the study drug, must be recorded on the Dosage Administration Record eCRF and 
registered in the IRT. 


Novartis 
Confidential 
Page 49 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
In case of pregnancy discovered during the treatment run-in epoch, the patient will be 
withdrawn from the study immediately. 
In case of pregnancy discovered during the randomized treatment epoch, the patient should be 
instructed to stop taking the study drug immediately. Study drug intake should be resumed as 
soon as possible after the completion of the pregnancy and lactation period. Meanwhile, the 
patient should continue to attend scheduled study visits.  
In case pregnancy is discovered during the OLE epoch, the patient should be instructed to stop 
taking the study drug immediately and must be withdrawn from the study. 
See Section 7.4 for further details on pregnancies and reporting guidelines. 
5.5.6 
Rescue medication 
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in Appendix 3, Appendix 4 and Appendix 5, respectively. Patients may receive 
open-label ACEIs and/or ARBs during the double-blind treatment epoch ONLY if the study 
medication has been discontinued either temporarily or permanently. 
Patients may receive open-label ACEIs and/or ARBs during the OLE epoch ONLY if the 
study medication has been temporarily discontinued. Permanent discontinuation of study drug 
during the OLE epoch constitutes withdrawal from the study. In this case, patients may 
receive open-label ACEIs and/or ARBs after withdrawal from the study. Resuming ACEI 
therapy requires a 36 hours washout from the last LCZ696 dose. 
Use of rescue medication must be recorded on the Concomitant medications in the eCRF. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded. 
Heart failure medications and other cardiovascular medications 
The patient should be on an optimal medical regimen of background HF medications. This 
must include an individually optimized dose of a β-blocker at a stable dose for at least 4 
weeks prior to study entry, unless contraindicated or not tolerated. Use of an aldosterone 
antagonist should be considered in patients eligible for this study. Every effort should be 
made to keep the dose level of these disease-modifying 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 disease-modifying 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. 
If a patient experiences any AEs that may be contributed to by the study drug, other HF 
medications, or other CV medications, the investigator should adjust non-disease-modifying 


Novartis 
Confidential 
Page 50 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
medications (e.g., CCBs, nitrates, a-blockers, and diuretics) first in an attempt to alleviate the 
AEs. 
Medications known to raise potassium levels 
Potassium-sparing diuretics, potassium supplements, aldosterone antagonists, and any other 
medications known to raise potassium levels should be used with caution while the 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 in 
those who are receiving these medications. 
Phosphodiesterase-5 (PDE-5) inhibitors 
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of occurrence of hypotension. 
Intravenous nitrates 
In the event a study patient requires the concomitant administration of i.v. nitrates with the 
study medications, the investigator should consider starting them at a lower dose or a slower 
infusion rate while monitoring the patient’s blood pressure carefully. 
5.5.8 
Prohibited Treatment 
Use of the treatments displayed below is NOT allowed after the start of investigational 
treatment. 
ACEIs, ARBs and renin inhibitors 
The concomitant use of open-label ACEIs, ARBs or a renin inhibitor is strictly prohibited 
while the patient is receiving investigational treatment, regardless of study epoch (active 
treatment run-in epoch, randomized treatment epoch or OLE epoch). 
In case the study medication should be stopped and the investigator judges that and the 
replacement use of an open-label ACEI, ARB or renin inhibitor is necessary, ACEI should be 
started ≥ 36 hours after the last dose of study medication, and ARB or renin inhibitor should 
be started on and after the next day of stopping study medication. If not already treated with 
an aldosterone antagonist, consideration should be given to adding this therapy rather than an 
ACEI, ARB or renin inhibitor. 
Similarly, if investigational treatment is to be restarted, the open-label ACEI should be 
discontinued ≥ 36 hours prior to resuming study medication and ARB or renin inhibitor 
should be discontinued the day prior to resuming study medication.  
At the end of the randomized treatment epoch, patients who are not taking double-blind study 
medication but are taking an open-label ACEI must stop the ACEI ≥ 36 hours prior to 
initiating open-label LCZ696 treatment upon entering the OLE epoch. Similarly, patients 
taking open-label LCZ696 in the OLE epoch must stop LCZ696 ≥ 36 hours prior to initiating 
open-label ACEI instead. If the investigator discontinues LCZ696 and replaces it with an 
ARB or renin inhibitor, approximately 12 hours should transpire between the start of the last 
dose of LCZ696 and the start of the first dose of ARB or renin inhibitor (i.e., the next 
regularly scheduled dosing). 


Novartis 
Confidential 
Page 51 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.5.9 
Discontinuation of study treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. The 
investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
Study treatment discontinuation during the double-blind treatment epoch does not constitute 
withdrawal from the study, does not constitute withdrawal of consent and should not lead to 
the patient being withdrawn from the entire study unless the patient specifically withdraws 
his/her consent. Patients who have discontinued study drug are expected, and should be 
encouraged to, attend all the protocol specified study visits and perform all measurements as 
stipulated in the visit schedule (Table 6-1) and remain in follow up for the duration of the trial. 
If they fail to return for these assessments for unknown reasons, every effort (e.g., telephone, 
e-mail, letter) should be made to contact them as specified in Section 5.5.11. The investigator 
must also contact the IRT to register the patient’s discontinuation from study treatment.  
During the OLE epoch, permanent discontinuation of LCZ696 constitutes withdrawal from 
the study. Under these circumstances, the patient should be evaluated at a final study visit 
(Visit 399). The investigator must also notify the IRT of the patient’s discontinuation of 
LCZ696 and record it on the Drug Administration Record of the eCRF. 
If the patient does not attend the study visits, follow-up should continue according to the 
specified schedule by telephone to determine if any AEs/endpoints pre-specified in the 
protocol have occurred, except in the case that the patient specifically refuses such follow-up 
and withdraws his/her consent. 
The emergence of the following circumstances will require permanent investigational drug 
discontinuation: 
 Withdrawal of informed consent 
 Investigator thinks that continuation would be detrimental to the patient’s well-being. 
 Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator. 
The emergence of the following circumstances will require temporary or permanent 
discontinuation (study drug may be restarted once these circumstances no longer exist except 
the case of permanent discontinuation during the OLE epoch): 
 Pregnancy and post-pregnancy during lactation period 
Study drug may be discontinued at the investigator’s discretion if any of the following occurs: 
 Any severe suspected drug-related AE 
 Any other protocol deviation that results in a significant risk to the patient’s safety 
 
Depending on the serum potassium, blood pressure, or eGFR, patients may need to have 
their study drug dose or the dose of another concomitant medication reduced or 
discontinued, or, if appropriate, have potentially contributing agents adjusted. Please refer 
to Appendix 3, Appendix 4 and Appendix 5 for treatment guidelines for hyperkalemia, 
hypotension, or renal dysfunction, respectively. 


Novartis 
Confidential 
Page 52 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  
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. 
Investigational treatment must be discontinued and no further assessments conducted. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
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, the patient’s family, friends and family physician as agreed in the informed consent 
and by documenting in the source documents steps taken to contact the patient, e.g., dates of 
telephone calls, registered letters, etc. A patient should not be 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 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IRT. When the investigator contacts the system to break a treatment code for a patient, 
he/she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide protocol number, investigational treatment name if available, patient number, and 
instructions for contacting the local Novartis Country Pharma Organization CPO (or any 
entity to which it has delegated responsibility for emergency code breaks) to the patient in 
case an emergency treatment code break is required at a time when the investigator and 
backup are unavailable.  
The patient must discontinue the study treatment after an emergency treatment code break. 
An emergency breaking of treatment assignment is not applicable for the OLE epoch. 


Novartis 
Confidential 
Page 53 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
5.5.13 
Study completion and post-study treatment 
The core part will be completed when either: the target total number of endpoints is obtained 
or a recommendation is made by the DMC to prematurely stop the study. 
At the end of the core part, all patients will return for the core part end of study (EOS) visit 
(Visit 299) and patients will be asked to return the remaining study drug. 
The OLE epoch will be completed when 2 years from the date of the first patient enrolled or 
marketed product is available in Japan, whichever comes first.  
When the patient has completed all scheduled study visits or permanently discontinued from 
the OLE epoch, the investigator must call the IRT to record the patient’s completion within 
IRT.  At the end of the OLE epoch, all patients will return for the OLE epoch EOS visit 
(Visit 399) and patients will be asked to return all remaining open-label LCZ696 tablets. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.  
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 
Ethics Committee (IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Core part 
Table 6-1 lists all of the assessments for the core part and indicates with an “x” when the 
visits are performed. All patients, including those who discontinue the study medication 
before completing the core part, should continue attending the scheduled visits as outlined in 
Table 6-1 until the core part ends. At that point all patients will return to the study sites as 
soon as possible to undergo the core part EOS visit (Visit 299) assessments.  
Patients should be seen for all visits on the designated day as close to it as possible. If one 
visit is postponed or brought forward, it should not result in the next visit being postponed or 
brought forward. The next visit, if at all possible, should adhere to the original time schedule. 
A Visit 199 (end of treatment run-in visit) will be completed for all patients who enter the 
treatment run-in epoch. For patients who discontinue during the treatment run-in epoch, 
Visit 199 will be their discontinuation visit. For patients that are randomized, Visit 199 will be 
their end of treatment run-in disposition visit and may be performed on the same day as 
Visit 201. Inclusion/exclusion criteria, vital signs and laboratory evaluations for 
randomization (Visit 201) are reflected at Visit 199 in Table 6-1. 
After randomization, study drug discontinuation (permanent or temporary) for any reason 
does not constitute withdrawal from the study and should not lead to the patient being 


Novartis 
Confidential 
Page 54 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
withdrawn from the study. Patients who discontinue study drug should be requested to return 
for all of the assessments outlined in Table 6-1 as scheduled. If any patient refuses to return 
for these assessments or is unable to do so, every effort should be made to contact him/her or 
knowledgeable informant by telephone to ask if any of the study endpoint events have 
occurred at the foreseen visit dates for the remaining duration of the study. Documentation of 
attempts to contact the patient should be recorded in the source documentation. 
At a minimum, patients who not participating in the OLE epoch will be contacted for safety 
evaluations during the 30 days following the last study visit or following the last 
administration of investigational treatment if there are post-treatment follow-up visits 
(whichever is later), including a final contact at the 30-day point. Documentation of attempts 
to contact the patient should be recorded in the source documentation.  
Patients should be instructed NOT to eat or drink anything (except water) for approximately 8 
hours prior to each scheduled fasting laboratory evaluation (see Section 6.5.4). If the patient 
has not fasted, the study visit collection of samples for laboratory evaluations should still take 
place. 
Patients will be instructed to take the last dose of the double-blind study drug on the day 
before the core part EOS visit (Visit 299), and visit the study sites without taking the study 
drug on the day of Visit 299. 
Patients will also be instructed to take study drug, as usual, on the morning of their site visits 
(except for Visit 201 and Visit 299), with or without food. If a patient did not take his/her 
study drug on the morning of his/her scheduled visit, the study visit could nevertheless be 
conducted. The only exception to this rule is for visits when the pre-study drug dose blood 
and urine samples for biomarker 
 are collected. In this case, the patient 
should not take the study drug before attending the study visit, but the study visit should be 
scheduled so that the biomarker 
 are obtained immediately before the time 
when the patient usually takes his/her study medication.  
There are two short washout periods (approximately 36-48 hours for each) during the 
treatment run-in epoch to minimize the potential risk of angioedema due to overlapping ACE-
NEP inhibition at Visit 101 and Visit 201 (Section 6.5.7): (1) after completing the screening 
epoch receiving conventional ACEI or ARBs and prior to beginning the LCZ696 run-in at 
Visit 101, and (2) after completing the LCZ696 run-in and prior to starting randomized study 
drug at Visit 201. For example, if a patient’s Visit 101 is on Wednesday, he/she must not take 
any doses of ACEIs or ARBs after the last dose on Tuesday. The patient will then start to take 
the first dose of the single-blind LCZ696 run-in medication on Thursday morning. The same 
is true for Visit 201. If a patient’s Visit 201 is on Wednesday, he/she must not take any doses 
of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to 
take the first dose of double blind medication on Thursday morning. 
Open-label extension epoch 
Table 6-2 lists all of the assessments for the OLE epoch and indicates with an “x” when the 
visits are performed. At the study end, all patients will return to the study sites as soon as 
possible to undergo the EOS visit (Visit 399) assessments. 


Novartis 
Confidential 
Page 55 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Patients should be seen for all visits on the designated day as close to it as possible. If one 
visit is postponed or brought forward, it should not result in the next visit being postponed or 
brought forward. The next visit, if at all possible, should adhere to the original time schedule.  
First visit of OLE epoch at Week 0 (Visit 301) will occur on the same day as the core part 
EOS visit (Visit 299). For patients who discontinue the study during the OLE epoch, Visit 399 
will be their discontinuation visit. Permanent discontinuation of study drug constitutes 
withdrawal from the study. 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit or following the last administration of investigational treatment if there are 
post-treatment follow-up visits (whichever is later), including a final contact at the 30-day 
point. Documentation of attempts to contact the patient should be recorded in the source 
documentation. 
Patients should be instructed NOT to eat or drink anything (except water) for approximately 8 
hours prior to each scheduled fasting laboratory evaluation (see Section 6.5.4). If the patient 
has not fasted, the study visit collection of samples for laboratory evaluations should still take 
place. 
Patients will also be instructed to take study drug, as usual, on the morning of their site visits, 
with or without food. If a patient did not take his/her study drug on the morning of his/her 
scheduled visit, the study visit could nevertheless be conducted. The only exception to this 
rule is for visits when blood and urine samples for biomarker assessments are collected. At 
these visits, the patient should not take the study drug before attending the study visit, but the 
study visit should be scheduled so that the biomarker samples are obtained immediately 
before the time when the patient usually takes his/her study medication, except for Visit 301 
as no double-blind study drug should be taken at this visit. 
There is a short washout period (approximately 36 hours) during the start of OLE epoch after 
patients completing the double-blind treatment and prior to starting the first dose of open label 
LCZ696 to minimize the potential risk of angioedema due to overlapping ACE-NEP 
inhibition at Visit 301. The patient will start to take the open-label LCZ696 the day after 
Visit 301. For example, if a patient’s Visit 301 is on Wednesday, he/she must not take any 
doses of the double-blind study drug after Tuesday evening dosing. The patient will then start 
taking the first dose of the open-label LCZ696 on Thursday morning. In case patient comes to 
visit after having taken the double-blind study drug or the open-label ACEIs at Visit 301, the 
assessments could nevertheless be conducted. In this case, patient should start taking open-
label LCZ696 at least approximately 36 hours after the last dose of double-blind study drug or 
the open-label ACEIs. 


Novartis 
Confidential 
Page 56 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Table 6-1 
Assessment schedule (Core part) 
Epoch 
 
Screening Treatment 
run-in 
Randomized treatment* 
Visit 
DS/S 
1 
101 199† 
201 
202 203 204 205 206 207 208 209 210 211 212 213 214* UNS 299††(EOS) 
Weeks (w) / Months (m) 
 
−4 to −3w −2w 
- 
0w 
2w 4w 8w 12w 6m 10m 14m 18m 22m 26m 30m 34m 38m 
- 
EOS 
Informed consent form 
S 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Call to IRT1 
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Inclusion/Exclusion criteria2 
DS 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/Medical history 
(including alcohol and smoking 
history) 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heart Failure and Diabetes History 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular disease History 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Heart Failure and CV Medications 
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exam3 
S 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs (BP and pulse) 
DS 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
DS 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Waist/hip circumference 
DS 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
NYHA Classification  
(HF signs and symptoms) 
DS 
x 
x 
 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
QOL questionnaire  (KCCQ)  
DS 
 
x 
 
x15 
 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
Patient Global Assessment 4 
DS 
 
 
 
x4, 15 
 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
Echocardiography 5 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG evaluation 
DS 
x14 
 
 
x15 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
(x) 
x 
Plasma NT-proBNP  
(for eligibility assessment) 
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma / serum biomarkers (including 
NT-proBNP)  and biobanking 6 
DS 
 
x 
x 
 
x16 
x 
x 
 
x 
 
 
x16 
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 57 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Epoch 
 
Screening Treatment 
run-in 
Randomized treatment* 
Visit 
DS/S 
1 
101 199† 
201 
202 203 204 205 206 207 208 209 210 211 212 213 214* UNS 299††(EOS) 
Weeks (w) / Months (m) 
 
−4 to −3w −2w 
- 
0w 
2w 4w 8w 12w 6m 10m 14m 18m 22m 26m 30m 34m 38m 
- 
EOS 
1st Urine morning void7 
DS 
 
x 
x 
 
 
x 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
Local laboratory assessments9 
DS 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(x) 
 
Complete laboratory assessments 10 
DS 
x 
 
x 
 
 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
(x) 
x 
Abbreviated chemistry panel 11 
DS 
 
 
 
 
x 
 
 
x 
 
x 
x 
 
x 
x 
 
x 
x 
(x) 
 
Pregnancy tests (Serum / Urine) 12 
DS 
x 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
AEs / SAEs 
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Screening epoch disposition  
DS 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Run-in medication dispensation 
S 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug accountability 
S 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
Run-in epoch disposition 13 
DS 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
DS 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Double blind medication dispense 
S 
 
 
 
x15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
 
Treatment epoch disposition 
DS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Endpoint information 
DS 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
UNS = Unscheduled visit 
EOS = End of Study 
DS = assessment to be recorded in clinical database 
S = assessment to be recorded on source document 
(x) = optional assessment 
† = Visit 199 (end of treatment run-in visit) will be completed for all patients who enter the treatment run-in epoch. For patients who discontinue during the treatment run-in 
epoch Visit 199 will be their discontinuation visit. For patients that are randomized, Visit 199 will be their end of treatment run-in disposition visit and may be performed on 
the same day as Visit 201. Inclusion/exclusion criteria, vital signs and laboratory evaluations for randomization (Visit 201) will be recorded at Visit 199. 
†† = Visit 299 (end of randomized treatment visit: End Of Study [EOS]) will be completed for all patients that enter the randomized treatment epoch. 
° UNS = Unscheduled visit. Assessments marked with (x) are optional procedures that may be performed at the investigator’s discretion. 
* If the trial is extended, Visits 215, 216, 217 and so forth to be performed at the same intervals and with same measurements as at visits 212, 213, 214 and so forth. 
1 Except for unscheduled visits when no dose changes will occur and only laboratory samples will be provided, phone calls to IRT have to be performed at all visits 
(including unscheduled visits) and when the patient is on study drug interruption. 


Novartis 
Confidential 
Page 58 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
2 During the single-blind active treatment run-in at Visits 101 and 199, patient safety will be monitored to ensure eligibility to continue to the next phase until randomization 
at Visit 201. Reason for not qualifying for randomization must be documented in detail in the eCRFs. 
3 Complete physical examination required at Visits 1, 201, 203 and 206 and yearly thereafter up until Visit 299 (EOS visit). Short physical exam required at all interim visits. 
4 At Visit 201, the investigator should call the patient’s attention to how he/she feels about his/her condition at that time and to explain that periodically the patient will be 
asked to rate how he/she feels compared to at this point in the study. No assessment is required at Visit 201. 
5 LVEF will be measured at Visit 1 unless local measurement was made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular 
angiography, or in case the value of subsequent measurement was above 35%. 
6 Plasma/serum biomarkers samples will be taken before morning study drug dose. 
7 First morning urine void samples will be taken before morning study drug dose. Sites will give the urine collection containers and instructions at Visits 1, 101, 202, 203 
and 205. 
 
 
9 Serum potassium and eGFR (estimated by using serum creatinine value). 
10 Complete laboratory evaluations (hematology, blood chemistry, and urine) will be collected in the fasting state and sent to the central laboratory.  
11 Abbreviated chemistry panel including serum potassium, blood urea nitrogen (BUN), and serum creatinine will be measured at interim visits at the central laboratory.  
12 Women of childbearing potential only. At Visit 1, 299 and in case of a positive urine pregnancy result, a confirmatory serum pregnancy test has to be performed at the 
central laboratory. A Urine pregnancy test will be performed locally at Visit 199, 205 and every 4 months up until Visit 299 (except for Visit 299). If positive with serum 
/urine pregnancy test during the screening or treatment run-in epoch, the patient must be discontinued from the trial. After randomization (Visit 201) a positive pregnancy 
test requires immediate interruption of study drug.  
13 Run-in disposition page to be completed for all patients who entered into the treatment run-in epoch. 
14 Screening ECG performed within the 6 months before Visit 1 is accepted. 
15 Procedure completed only for patients to be randomized at Visit 201 
16 At Visit 202, plasma sample for biomarkers such as NT-proBNP will be collected. At Visit 209, serum sample for selected biomarkers related to fibrosis/remodeling will 
be collected. 
 
 
 
 
 
 


Novartis 
Confidential 
Page 59 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Table 6-2 
Assessment schedule (OLE epoch) 
Epoch 
 
Open-label extension 
Visit 
DS/S 
301† 
302 
303 
304 
305 
306 
307 
308 
UNS° 
399††(EOS/ ITD) 
Weeks (w) / Months (m) 
 
0w 
2 to 4w 
8w 
4m 
8m 
12m 
16m 
20m 
- 
EOS†† 
Informed consent form 
S 
x 
 
 
 
 
 
 
 
 
 
Call to IRT 1 
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Inclusion/Exclusion criteria 
DS 
x 
 
 
 
 
 
 
 
 
 
Concomitant medications  
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exam 2 
S 
x 10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs (BP and pulse) 
DS 
x 10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
DS 
x 10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
NYHA Classification  
(HF signs and symptoms) 
DS 
x 10 
x 
x 
x 
x 
x 
x 
x 
 
x 
Echocardiography 3 
DS 
x  
 
 
 
 
x 
 
 
 
 
12-lead ECG evaluation 
DS 
x 10 
 
 
 
 
x 
 
 
(x) 
x 
Complete laboratory assessments 4 
DS 
x 10 
 
 
x 
 
x 
 
 
(x) 
x 
Abbreviated chemistry panel 5 
DS 
 
x 
x 
 
x 
 
x 
x 
(x) 
 
Local laboratory assessments 6 
S 
x 
x 
 
 
 
 
 
 
 
 
Pregnancy tests (Serum / Urine) 7 
DS 
x 
 
 
x 
x 
x 
x 
x 
(x) 
x 
Plasma / Urine biomarkers 8 
DS 
x 
x 
x 
x 
 
x 
 
 
 
 
AEs / SAEs  
DS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Extension medication dispensation 
S 
x 
x 
x 
x 
x 
x 
x 
x 
(x) 
 
Drug accountability 
S 
 
x 
x 
x 
x 
x 
x 
x 
(x) 
x 
OLE epoch disposition 9 
DS 
 
 
 
 
 
 
 
 
 
x 
UNS = Unscheduled visit 
EOS = End of Study 
ITD = investigational treatment discontinuation 
DS = assessment to be recorded in clinical database 
S = assessment to be recorded on source document 
(x) = optional assessment 


Novartis 
Confidential 
Page 60 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
† = First visit of OLE epoch at Week 0 (Visit 301) will occur on the same day as the core part EOS visit (Visit 299). 
†† = Visit 399 (end of OLE visit) will be completed for all patients that enter the OLE epoch. For patients who discontinue the study drug permanently during the OLE 
epoch, Visit 399 will be their study discontinuation visit. The OLE epoch will continue until marketed product is available in Japan or approximately for 2 years from the 
date of the first patient enrolled, whichever comes first. 
° UNS = Unscheduled visit. Assessments marked with (x) are optional procedures that may be performed at the investigator’s discretion. 
1 Except for unscheduled visits when no dose changes will occur and only laboratory samples will be provided, phone calls to IRT have to be performed at all visits 
(including unscheduled visits) and when the patient is on study drug interruption. 
2 Complete physical examination required at Visits 301, 304, 306 and Visit 399 (EOS visit). Short physical exam required at all interim visits. 
3 Echocardiograms will be recorded to digital media in DICOM format (CD, or Magneto-Optical Disc) and sent to the core laboratory for analysis. All echocardiographic 
measurements will be made at the core laboratory. 
4 Complete laboratory evaluations (hematology, blood chemistry, and urine) will be collected in the fasting state and measured at the central laboratory. 
5 Abbreviated chemistry panel including serum potassium, blood urea nitrogen (BUN), and serum creatinine will be measured at interim visits at the central laboratory. 
6 Serum potassium and eGFR (estimated by using serum creatinine value). 
7 Women of childbearing potential only. At Visit 399, and in case of a positive urine pregnancy result, a confirmatory serum pregnancy test has to be performed at the 
central laboratory. A Urine pregnancy test will be performed locally at Visit 301 and every 4 months up until Visit 399 (except for Visit 399). A positive urine pregnancy 
result requires immediate interruption of study drug, and a confirmatory serum pregnancy test will be performed at the central laboratory. If serum pregnancy test result is 
positive, the patient must be discontinued from the trial. 
8 Plasma and urine biomarker samples will be taken before morning study drug dose. 
9 OLE epoch disposition page to be completed for all patients who entered into the OLE epoch. 
10 Procedure will not be required unless it has been done at Visit 299 (Completion of the core part). The data at Visit 299 will be utilized as the data at Visit 301. 
 


Novartis 
Confidential 
Page 61 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the run-in epoch will have 
the disposition page for the screening epoch, demographics, inclusion/exclusion, and serious 
adverse event (SAE) data collected. Adverse events that are not SAEs will be followed by the 
investigator and collected only in the source data. These patients are considered screening 
failures. 
All patients that sign informed consent and take treatment run-in study drug will have the visit 
specific CRFs and Run-in disposition (Visit 199) collected. The reason for patient 
discontinuation during the treatment run-in period must be carefully documented in the 
appropriate CRF. These patients are considered treatment run-in failures. 
For all patients who have signed informed consent and receive study treatment all AEs 
occurring after informed consent is signed will be recorded on the Adverse Event CRF. 
Re-screening 
If a patient is not eligible to enter into the treatment run-in epoch and screen-fails, the 
investigator may consider re-screening the patient at a later time if he/she believes that the 
patient’s condition has changed and may potentially be eligible. In this case, a completely new 
patient number will be allocated to the subject and he/she will need to re-perform all Visit 1 
procedures. 
A patient who is successfully screened and enters into the active treatment run-in epoch but is 
later found not to be eligible for randomization due to intolerance to LCZ696 50 mg b.i.d. 
may be re-screened at a future time if the investigator feels that the circumstances that may 
have contributed to the patient’s intolerance are no longer present. In this case, a completely 
new patient number is to be allocated to the subject and he/she will need to re-perform all 
Visit 1 assessments. 
For the core part, a patient may be re-screened up to two times. A minimum of 2 or 4 weeks 
must elapse between re-screenings if the patient was never exposed to study medication or if 
the patient was exposed to the run-in study medication, respectively. This is to ensure all the 
entry criteria are met, including the required minimum stability period on pre-study 
medications (refer to Section 4.1). Patient must provide new written informed consent before 
each time they are to be re-screened. 
In the event of an extension, re-screening will not be allowed. 
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 and ethnicity, relevant medical history/current medical condition 
present before signing informed consent. Where possible, diagnoses and not symptoms will be 
recorded. HF medications and other CV medications will be recorded in eCRFs separately 
from other medications. Likewise, detailed HF history and other relevant CV medical history 
will be recorded on eCRFs separately from other medical history. 


Novartis 
Confidential 
Page 62 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
6.3 
Treatment exposure and compliance 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the care giver. This information should be captured in the 
source document at each visit. Patient compliance should be at least 80% during the double 
blind treatment epoch and OLE epoch. The investigator and/or study personnel will counsel 
the patient if compliance is below 80%. Study drug accountability will also be determined by 
the site monitor while performing routine site visits and at the completion of the study. 
Duration of double-blind study drug exposure and extension study drug exposure will be 
calculated based upon the start and stop dates recorded in the eCRF. 
6.4 
Efficacy 
6.4.1 
Primary and secondary efficacy endpoints 
The primary composite endpoint for the core part consists of the following components: 
 CV death 
 HF hospitalization 
The key secondary endpoints for the core part are:  
 Changes in NT-proBNP from baseline 
 CV death, HF hospitalization or intensification of treatments due to documented 
episode(s) of worsening HF defined as: worsening signs and symptoms of HF requiring 
addition of a new drug for HF treatment, initiation of IV treatment, increase of diuretic 
dose for persistent use for ≥ 4 consecutive weeks, or institution of mechanical or 
circulatory support such as mechanical ventilation, ultrafiltration, hemodialysis, intra-
aortic balloon pump or ventricular assist device 
 CV death 
 HF hospitalization 
 Intensification of treatments due to documented episode(s) of worsening HF 
 Changes in NYHA class from baseline  
 Clinical summary score (assessed by KCCQ) 
The other secondary endpoints for the core part are: 
 Composite of CV death and total (first and recurrent) HF hospitalizations 
 Clinical composite score (assessed by NYHA classification and patient global assessment) 
 All-cause mortality 
 Hospitalization (all-cause, cause-specific) 
 Changes in biomarkers from baseline 
 Healthcare resource utilization 
Other endpoints during OLE epoch are: 
 Changes in NYHA class from OLE baseline (Visit 301) 
 Changes in echocardiographic parameters from OLE baseline (Visit 301) 
 Changes in biomarkers from OLE baseline (Visit 301) 


Novartis 
Confidential 
Page 63 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
6.4.2 
Endpoint committee 
All of the following events, which could potentially fulfill the criteria for the primary or 
secondary endpoints will be assessed during the active treatment run-in epoch or the double-
blind treatment epoch, and reported to the Endpoint Adjudication Committee for adjudication 
or assessment: 
 All death events 
 HF hospitalization 
 Intensification of HF treatments due to documented episode(s) of worsening HF 
(regardless of hospital admission or not) 
The Endpoint Adjudication Committee will be responsible for classifying all death events and 
for determining whether pre-specified endpoint criteria were met for the non-fatal events. 
Sites are instructed to take a conservative approach when reporting endpoints; if the 
investigator suspects an endpoint may have occurred, it is best to report the event to the 
Endpoint Adjudication Committee for the final determination.  
Novartis’ reporting guidelines for AE and SAE as outlined in Section 7.1 and Section 7.2 
must be followed, independent from the circumstance that an event is also reported as a 
suspected study endpoint. 
The OLE epoch will collect all safety events (serious and non-serious AEs), however, no 
clinical endpoint adjudication of these events, which occur during the OLE epoch, will be 
performed. 
6.4.3 
Heart failure symptoms reduction and reduction in physical limitation 
The KCCQ is a self-administered questionnaire and requires, on average, 4-6 minutes to 
complete. It contains 23 items, covering physical function, clinical symptoms, social function, 
self-efficacy and knowledge, and Quality of Life (QoL), each with different Likert scaling 
wording, including limitations, frequency, bother, change in condition, understanding, levels 
of enjoyment and satisfaction. A change of 5 points on the scale scores, either as a group 
mean difference or an intra-individual change appears to be clinically significant. The KCCQ 
is a valid, reliable and responsive health status measure for patients with CHF and may serve 
as a clinically meaningful outcome in CV clinical research, patient management and quality 
assessment (Green et al. 2000). 
The HF symptoms and physical limitation domains scores show the best the correlation for 
improvements following a CHF exacerbation (Green et al. 2000). Thus, one of the secondary 
endpoints is a clinical summary score based on the HF symptoms and physical limitation 
domains scores of the KCCQ at 6 months. The KCCQ questionnaire will be completed at 
Visits 201, 204, 206, 209, 212, and 299 (EOS). 
In the OLE epoch, the KCCQ will not be assessed. 
6.4.4 
Biomarkers 
Biomarkers related to cardiac and renal function/injury and associated comorbidities and their 
consequences in the HF-rEF population will be obtained from blood and first morning void 
(FMV) urine. Biomarkers will be used to elucidate the effect of study drugs. They may also be 


Novartis 
Confidential 
Page 64 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
used to determine which biomarkers are most predictive of event risk. Blood biomarkers of 
potential interest may include such as: NT-proBNP, aldosterone, Cystatin-C, high-sensitivity 
troponin T, amino-terminal propeptide of procollagen type I (PINP) and type III (PIIINP) or 
other biomarkers important in heart failure. FMV urine biomarkers may include markers such 
as cGMP, creatinine, and urine albumin to creatinine ratio (UACR). The list of blood and 
urine biomarkers may change during the course of the study as new or more relevant 
biomarkers are determined. Biomarker analysis may also occur retrospectively after study 
close with biomarker decisions dependent on study outcome and/or new biomarkers relevant 
to the HF-rEF patient population. 
In the core part, NT-proBNP will be obtained in all patients by using a central laboratory at 
Visit 1 to determine eligibility for the trial. In addition, biomarker measurements will be 
obtained from serum, plasma, and first morning void (FMV) urine samples at Visits 101, 199, 
202 (only selected biomarkers such as NT-proBNP), 203, 204, 206 and 209 (only selected 
biomarkers at Visit 209) to determine effects of treatments on biomarkers. Biomarkers related 
to fibrosis/remodeling such as PINP and PIIINP will be measured only at Visits 101 and 209. 
Values of selected biomarkers at Visit 101 may also be used to determine which biomarker 
best predicts risk of clinical events. 
In the OLE, biomarker measurements will be obtained from plasma and spot urine samples at 
Visits 301, 302, 303, 304, and 306 to determine effects of LCZ696 treatments on biomarkers. 
BNP, NT-proBNP, and urine cGMP at these visits will be assessed. 
These samples will be obtained before patients take their morning study drug dose. 
The results of the biomarkers analyzed during the conduct of the core part, with the exception 
of the Visit 1 NT-proBNP results, will be blinded to the site and the Novartis clinical study 
team until the core part database lock. The Novartis clinical study team will only be unblinded 
to biomarker data following the core part database lock.  
Unblinded (e.g. local) measurements of BNP or NT-proBNP after screening should be limited 
to cases requiring safety evaluations until the core part database lock.  
6.4.5 
Clinical composite score 
The clinical composite score is one of the secondary endpoints of this study. It is derived from 
two instruments: the patient global assessment and the NYHA functional classification. 
The patient global assessment is a seven-point patient self-evaluation scale. At Visit 201 
(randomization), the investigator should call the patient’s attention to how he/she feels about 
his/her condition at that time and to explain that periodically the patient will be asked to rate 
how he/she feels compared to at this point in the study. Subsequently, patients will be asked to 
rate how well they feel compared to Visit 201 (randomization/baseline) (Packer et al. 2002). 
This evaluation is combined with the NYHA functional class, one of the most reliable 
instruments for rating HF patients’ functionality, and with occurrence of death and 
hospitalization for heart failure to arrive at an overall evaluation of whether a patient is 
considered to have improved, worsened, or unchanged after a pre-specified period of time 
(Packer 2001).  
The patient global assessment will be conducted at Visits 204, 206, 209, 212 and 299 (EOS). 
HF signs and symptoms/NYHA classification will be conducted at all visits. 


Novartis 
Confidential 
Page 65 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
In the OLE epoch, the patient global assessment will not be conducted and clinical composite 
score will not be assessed. 
6.4.6 
Echocardiogram 
In the core part, LVEF will be measured at Visit 1 unless local measurement was made within 
the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular 
angiography, or in case the value of subsequent measurement was above 35% to assess the 
patient’s eligibility. 
In the OLE, echocardiograms will be performed at the sites by qualified echocardiographic 
personnel (technicians or physicians) in accordance with the details of procedures outlined in 
the manual provided to all participating sites. 
The echocardiogram will be performed at Visit 301 and also before administration of study 
medication at Visit 306. Cardiac parameters related to LV and LA structure, LV systolic and 
diastolic function etc. (including LV end systolic and diastolic volume indices, LVEF, and LA 
volume index) will be assessed. 
Echocardiograms will be recorded to digital media in DICOM format (CD, or 
Magneto-Optical Disc) and sent to the core laboratory for analysis. All echocardiographic 
measurements will be made at the core laboratory. 
The echo data obtained during baseline (Visit 301) and Visit 306 will be sent to a core 
laboratory for evaluation and analysis.  A detailed manual of all echo procedures will be 
provided to all sites. 
6.4.7 
Appropriateness of efficacy assessments 
These measurements are standard and have been used in previous HF trials.  
The definition of CV endpoints is consistent with the FDA CV endpoints draft guidelines 
(Hicks et al. 2012). It is referred in Japanese Guidelines for Clinical Evaluation of Drugs for 
Heart Failure that total mortality, cardiovascular morbidity, and subjective complaints are 
considered appropriate as the primary endpoints (Ministry of Health, Labour and Welfare 
2011).  
6.5 
Safety 
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety 
profile of the study drugs. Such information may include diagnostic procedure reports, 
discharge summaries, autopsy reports, and other relevant information that may help in 
assessing the reported AE. All additional information will be de-identified prior to collection 
by Novartis or its agents. 
6.5.1 
Physical examination 
A complete physical examination will be performed at Visits 1, 201, 203 and 206 and then at 
yearly intervals thereafter until the core part EOS visit, and also at Visits 301, 304, 306 and 
the OLE epoch EOS visit. It will include the examination of general appearance, skin, neck 


Novartis 
Confidential 
Page 66 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will include the examination of general appearance and vital signs 
(blood pressure [SBP and DBP] and pulse). A short physical exam will be at all visits starting 
from Visit 101, except where a complete physical exam is required (see above). 
Information for about all physical examinations must be included in the source documentation 
at the study site. Significant findings that are present prior to signing informed consent must 
be included in the Medical History part of the eCRF. Significant findings made after signing 
the informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the eCRF. 
6.5.2 
Vital signs 
Vital signs will be assessed at every visit. Vital signs include BP and pulse measurements. BP 
will be measured in the sitting position after 5 minutes of rest using an automated validated 
device (e.g., OMRON) or a standard sphygmomanometer with an appropriately sized cuff on 
the non-dominant arm. Guidelines for the management of BP (i.e., hypotension) are provided 
in Appendix 4. 
Vital signs will also be assessed at every visit during the OLE epoch. 
6.5.3 
Height and weight 
Height in centimeters (cm) will be measured at Visit 1. 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured at all visits, until the core part EOS visit. Body weight will be measured at all visits 
during the OLE epoch as well. 
Waist/hip circumference (to the nearest centimeter [cm] in indoor clothing) will be measured 
at Visit 199 and at the core part EOS visit. Waist circumference is measured by horizontally 
positioning the tape measure on a bare abdomen, halfway between the lowest rib and the 
superior anterior iliac crest. In the OLE epoch, waist/hip circumference will not be measured. 
6.5.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
In the core part, complete laboratory evaluations (hematology, blood chemistry, and urine; 
Table 6-3) for the assessment of safety will be performed in a fasting state at Visits 1, 199, 
203, 204, 206 and then at yearly intervals until the end of the study and at Visit 299 (core part 
EOS visit). Abbreviated laboratory evaluations will be performed as indicated in Table 6-1. 
In the OLE, complete laboratory evaluations will be performed in the same manner as the core 
part at Visits 301, 304, 306 and at Visit 399 (OLE EOS visit). Abbreviated laboratory 
evaluations will be performed as indicated in Table 6-2. 


Novartis 
Confidential 
Page 67 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Local laboratory will be used for the assessment of serum potassium values and eGFR at 
Visits 1, 199, 301 and 302. In addition, local laboratory assessments may be performed on an 
as-needed basis to monitor tolerability to investigational treatment at unscheduled visits 
during the randomized treatment epoch and the OLE epoch.  
All central laboratory results will be communicated to the investigators and the sponsor, with 
the exception of plasma/serum and urinary biomarkers, of which only the Visit 1 NT-proBNP 
will be reported to the investigator and the sponsor. Details on the collection, shipment of 
samples and reporting of results by the central laboratory will be provided to investigators in 
the laboratory manual. 
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator in the patient's CRF and additional laboratory evaluations 
should be performed, as judged appropriate by the investigator. If the laboratory abnormality 
induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or 
medical condition must be entered on the AE part of the eCRF. If the laboratory abnormality 
is the primary reason for an unforeseen hospitalization or otherwise fulfills the seriousness 
category of an AE, then the procedure for rapid notification of SAEs must be followed 
(Section 7.2). If the laboratory abnormality leads to study drug discontinuation (temporarily or 
permanently), the patient must be followed until the abnormality resolves or until it is judged 
to be permanent. This investigation may include continued monitoring by repeat laboratory 
testing or by performing additional laboratory tests as deemed necessary by the investigator or 
the Novartis medical monitor. 
Table 6-3 
Routine laboratory examinations 
Hematology 
Biochemistry 
Urine measurements 
Red Blood Cells count 
White Blood Cells count 
Platelet Count 
Hemoglobin 
Hematocrit 
WBC Differential 
Glucose 
Sodium  
Potassium * 
Chloride  
Calcium 
Blood urea nitrogen (BUN) * 
Creatinine * 
Total Bilirubin 
Fractionated bilirubin (if total 
bilirubin > 2 × ULN) 
Aspartate amino-transferase (AST) 
Alanine amino-transferase (ALT) 
Alkaline phosphatase 
Total protein 
Albumin 
Uric Acid 
Serum Pregnancy Test a 
Lipid profile (total cholesterol, LDL, 
HDL, and triglycerides) 
Hemoglobin A1c 
Urinalysis 
* Laboratory assessments for the abbreviated biochemistry test performed at visits where the complete 
laboratory test is not performed.  
a. At Visits 1, 299, 399 and in case of positive urine pregnancy test only. 
 


Novartis 
Confidential 
Page 68 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
6.5.4.1 
Hematology 
In the core part, hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential counts, and platelet count will be measured at Visits 1, 199, 203, 204, 206 and 
then at yearly intervals until the end of the core part and at Visit 299 (core part EOS visit) 
(Table 6-1). In the OLE, the laboratory evaluations will be performed in the same manner as 
the core part at Visits 301, 304, 306 and at Visit 399 (OLE EOS visit). 
6.5.4.2 
Clinical chemistry 
In the core part, blood urea nitrogen (BUN), glucose, creatinine, total bilirubin, AST (SGOT), 
ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, hemoglobin A1c, 
total protein, albumin, uric acid, and lipid profile will be measured at Visits 1, 199, 203, 204, 
206 and then at yearly intervals until the end of the core part and at Visit 299 (core part EOS 
visit). In the OLE, the laboratory evaluations will be performed in the same manner as the 
core part at Visits 301, 304, 306 and at Visit 399 (OLE EOS visit). Fractionated bilirubin will 
be performed for all patients whose total bilirubin value is > 2 × ULN.  
In the core part, BUN, serum potassium, and serum creatinine value for eGFR calculation will 
be obtained from patients at Visit 202 and at every visit when a complete serum chemistry test 
is not done (i.e., Visits 202, 205, 207, 208, 210, 211, 213 and 214). In the OLE, the laboratory 
evaluations will be performed in the same manner as the core part at Visits 302, 303, 305, 307, 
308. Local laboratory assessments may be performed on an as-needed basis to monitor 
tolerability to investigational treatment at unscheduled visits during the randomized treatment 
epoch and the OLE epoch. 
6.5.4.3 
Potassium and Estimated glomerular filtration rate (eGFR) 
assessments by local laboratory 
In addition to the central laboratory assessments, potassium and eGFR will be measured 
locally at Visit 1 and Visit 199 to determine eligibility of the patient into the trial. Local 
laboratory assessments at Visits 1 and 199 are used to ascertain if patient doesn’t meet the 
exclusion criteria (Table 3-1). These parameters will also be measured locally at Visits 301 
and 302 to monitor safety for up-titration at Visit 302. Local potassium and eGFR 
measurements may be performed during the randomized treatment epoch and the OLE epoch, 
mainly at the unscheduled visits, to monitor the tolerability to study medication dose 
administered and adjust medication dose if needed (according to Appendix 3 and Appendix 5). 
Estimated GFR will only be calculated using the following formula for Japanese (Matsuo et al. 
2009): 
Estimated GFR (mL/min/1.73 m2)  
= 194 × (serum creatinine in mg/dL)-1.094 × (age in years)-0.287 × (0.739 if female) 
The results of the local laboratory during the active treatment run-in epoch and the OLE 
epoch will not be reconciled with the central laboratory measurements. 
6.5.4.4 
Urinalysis 
In the core part, dipstick-test determination of specific gravity, pH, blood, total protein, 
bilirubin, ketones, and leukocytes will be measured at central laboratory at Visits 1, 199, 203, 


Novartis 
Confidential 
Page 69 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
204, 206 and then at yearly intervals until the end of the core part and at Visit 299 (core part 
EOS visit). Microscopic examination of red blood cell (RBC) and white blood cell (WBC) 
sediments will be also performed. 
In the OLE, the laboratory evaluations will be performed in the same manner as the core part 
at Visits 301, 304, 306 and at Visit 399 (OLE EOS visit). 
6.5.5 
Electrocardiogram (ECG) 
In the core part, a standard 12-lead ECG will be performed at screening (Visit 1, unless an 
ECG performed within the last 6 months is available), randomization (Visit 201), Visit 206, 
and at yearly intervals thereafter until the end of the study and at Visit 299 (core part EOS 
visit).  
In the OLE epoch, a standard 12-lead ECG will also be performed at Visits 301, 306 and at 
Visit 399 (OLE epoch EOS visit). 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula 
(QTcF) should be used for clinical decisions. 
Each ECG tracing should be labeled with study number, 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 at baseline must be discussed with the sponsor before administration with 
investigational treatment. 
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/AE eCRF page as appropriate. 
6.5.6 
Pregnancy and assessments of fertility 
In the core part, all female patients of childbearing potential will have a serum pregnancy test 
performed at Visit 1 (central laboratory) and Visit 299 (core part EOS visit). Additionally, 
these patients will have urine pregnancy tests performed at the investigational sites at 
Visit 199, Visit 205 and all visits thereafter (except Visit 299). A positive urine pregnancy 
result requires immediate interruption of study drug, and a confirmatory serum pregnancy test 
will be performed at the central laboratory. If serum pregnancy test result is positive, the 
patient must discontinue study drug until after the pregnancy and lactation period. 
In the OLE epoch, all female patients of childbearing potential will have urine pregnancy tests 
performed locally at Visit 301 and every 4 months up until Visit 399 (except for Visit 399). 
Additionally, these patients will have a serum pregnancy test performed at the central 
laboratory at Visit 399. A positive urine pregnancy result requires immediate interruption of 
study drug, and a confirmatory serum pregnancy test will be performed at the central 
laboratory. If serum pregnancy test result is positive, the patient must be discontinued the trial. 


Novartis 
Confidential 
Page 70 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
6.5.7 
Angioedema 
The occurrence of angioedema or angioedema-like events must be monitored and reported 
during this study. This procedure will also be applied to the OLE epoch. 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway 
compromise.  
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an 
Angioedema-like Event form (provided by Novartis) to summarize the event, its treatment, 
and its ultimate outcome. This report along with the requisite medical documentation must be 
submitted to Novartis as soon as possible. Follow-up reports must be communicated to 
Novartis as soon as new information regarding the event becomes available. All hospital 
records related to the event must be communicated to Novartis.  
The investigator may also be contacted by Novartis regarding AEs that may resemble an 
angioedema-like event. A list of terms that are considered “angioedema-like” (e.g., periorbital 
swelling) will be provided to sites in a manual. The investigator or his/her delegated staff 
must complete the required forms and provide the required medical records for all such events, 
regardless of whether the investigator views the event in question as angioedema or not. 
All angioedema reports received during both the core part and OLE epoch will be forwarded 
to an Angioedema Adjudication Committee by Novartis for assessment. 
Information regarding this committee is outlined in Section 8.5.2. Details on the procedures 
for reporting angioedema events will be provided to investigators in a manual. 
6.5.8 
Appropriateness of safety measurements  
The safety assessments except angioedema selected are standard for this indication/patient 
population.  
Bradykinin has been implicated as the putative mediator of angioedema. 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. Simultaneous inhibition of multiple breakdown pathways of 
bradykinin is thought to significantly increase the risk of occurrence of angioedema (Sulpizio 
et al. 2004). Therefore, cases of suspected angioedema will be collected and adjudicated by an 
independent angioedema adjudication committee in this study.   
6.6 
Other assessments 
6.6.1 
Resource utilization 
Analyses will be undertaken, as appropriate, to assess the effects of treatment on Healthcare 
Resource Utilization (RU) parameters. These measures may include hospitalization (e.g. 


Novartis 
Confidential 
Page 71 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
number of hospital days), physician visits, other drugs used, and laboratory tests and 
procedures performed. 
At Visit 202 and each subsequent scheduled visit, the level of healthcare resource utilization 
will be assessed through procedures during hospital stays. The frequency and duration of any 
inpatient hospitalization will be recorded along with the primary reason for the hospital 
admission and discharge. All attempts will be made to collect RU variables in all patients 
throughout the duration of the study to avoid selection bias. There may also be circumstances 
when the collection of such data after completion of the core part may be warranted. 
The information of RU will not be collected in the OLE epoch. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.3 
Other biomarkers 
The list of blood and urine biomarkers may change during the course of the study as new or 
more relevant biomarkers are determined. Biomarker analysis may also occur retrospectively 
after study close with biomarker decisions dependent on study outcome and/or new 
biomarkers relevant to the HF-rEF patient population. This will also be applied to the OLE 
epoch. 


Novartis 
Confidential 
Page 72 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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. 
An untoward medical occurrence may be a study endpoint as well as meeting the definition 
for an AE. Specific guidance on the appropriate recording and reporting of events that meet 
the criteria for both a study endpoint and an AE are provided in Section 7.2.3. 
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 investigational 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) 
 action taken regarding investigational treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 


Novartis 
Confidential 
Page 73 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria: 
 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  


Novartis 
Confidential 
Page 74 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 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. 
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. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit 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 (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form or the electronic Serious Adverse Event 
Form within the Oracle Clinical/Remote Data Capture (OC/RDC) system (where available). 
The Investigator must assess the relationship to each specific component of the study 
treatment (if the study treatment consists of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of 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 


Novartis 
Confidential 
Page 75 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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. 
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first. 
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. 
7.2.3 
Protocol specific unblinding rules for SUSARs that are also efficacy 
endpoints 
In studies such as this one, where the efficacy endpoints potentially meet the requirements for 
SUSAR reporting, the integrity of the study may be compromised if the endpoints are 
systematically unblinded for expedited reporting to competent authorities/relevant ECs and 
investigators. In such cases, regulations allow an exemption from SUSAR unblinding and 
expediting aimed at ensuring the validity of an outcome study (European Commission 
ENTR/CT12 2006, FDA 2012). Therefore, the following rules for unblinding SUSARs during 
the study period will be applied. 
The study specific exemption does not apply to the OLE epoch. During the OLE epoch, ALL 
adverse events will be reported as AEs following the procedures described in Section 7.1 and 
Section 7.2. No clinical endpoint adjudication of events during the OLE epoch will take place. 
7.2.3.1 
Primary and secondary endpoints 
The primary endpoint (CV death and HF hospitalization) will not be unblinded even if they 
meet the definition of a SUSAR. Novartis will not expedite a report to competent 
authorities/relevant ECs and will not issue an IN. If specifically requested by a local Health 
Authority, these endpoints that also meet criteria for SUSARs will be expedited to this Health 
Authority as blinded reports. INs will not be issued for these events. Above will be also 
applied to CV hospitalization and prolongation of existing CV hospitalization. However, non-
CV death will be unblinded if it meets the criteria for a SUSAR. 


Novartis 
Confidential 
Page 76 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
7.2.3.2 
Adverse events that are commonly seen in the study population 
Investigators will report AEs or SAEs that are commonly seen in the study population (Table 
7-1) but they will not be unblinded and will not be reported as SUSARs to regulatory agencies, 
ECs, or investigators during the study. If specifically requested by a local Health Authority, 
these AE or SAEs that also meet criteria for SUSARs will be expedited to this Health 
Authority as blinded reports. INs will not be issued for these events. These events will be 
presented in the clinical study report (CSR) at the end of the study. 
Table 7-1 
Adverse events commonly seen in study population 
Cardiovascular events 
Non-cardiovascular events 
Unstable angina 
Generalized edema 
Arthralgia/Arthritis 
COPD (including 
bronchitis and 
emphysema) 
Arrhythmia 
Hypertension 
Constipation 
Cough 
Transient ischemic 
attack 
Hypotension 
Diarrhea 
Fatigue 
Renal impairment 
Peripheral edema 
Headache 
Sepsis 
Chest pain 
Syncope 
Nausea 
Nasopharyngitis 
Dizziness/vertigo 
Angina pectoris 
Anemia 
Pneumonia 
 
Cerebrovascular 
accident 
Dyspnea 
Upper respiratory 
infection/insufficiency 
 
Myocardial infarction 
Stroke 
 
 
7.2.3.3 
Other SAEs that meet the definition of SUSARs 
All other SAEs that do not meet the criteria in Section 7.2.3.1 and Section 7.2.3.2 but do meet 
SUSAR criteria will be unblinded and reported to regulatory agencies and investigators during 
the study. 
7.3 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study: 
 Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
 Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 


Novartis 
Confidential 
Page 77 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Every liver laboratory trigger or liver event as defined in Table 14-1 in Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2. 
For the liver laboratory trigger: 
 Repeating the LFT within the next week to confirm elevation. 
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages. 
 If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
 Repeating the LFT to confirm elevation as appropriate 
 Discontinuation of the investigational drug if appropriate 
 Hospitalization of the patient if appropriate 
 A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
 An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate eCRF pages, including the liver 
event overview CRF pages. 
7.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 


Novartis 
Confidential 
Page 78 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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 analyse 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. 
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.  
8.3 
Database management and quality control 
Novartis staff 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. 


Novartis 
Confidential 
Page 79 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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. 
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. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked. The core and OLE data will be locked separately for each analysis, according to Data 
Management Plan. The treatment codes will be unblinded and made available at the core part 
database lock. Any changes to the database after each database lock can only be made after 
written agreement by Novartis Development management. 
8.4 
Data Monitoring Committee 
An external data monitoring committee (DMC) independent of Novartis will be appointed to 
monitor the study conduct 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. 
The membership of the DMC and the responsibilities of the DMC and Novartis will be 
defined in a separate document entitled the ”Data Monitoring Committee Charter.” The DMC 
Charter will include information about data flow, purpose and timing of DMC meetings, 
guidance in the decision making process, communication strategy, procedures for ensuring 
confidentiality, procedures to address conflicts of interest and statistical monitoring guidelines. 
The DMC will only cover the core part. 


Novartis 
Confidential 
Page 80 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
8.5 
Adjudication Committee 
8.5.1 
Clinical Endpoint Committee 
All events, which could potentially fulfill the criteria for the primary or secondary endpoints 
will be assessed during the core part and reported to the Clinical Endpoint Committee (CEC) 
for adjudication. 
The CEC will be responsible for classifying all death events and for determining whether pre-
specified endpoint criteria were met for the non-fatal events. Sites are instructed to take a 
conservative approach when reporting endpoints; if the investigator suspects an endpoint may 
have occurred, it should report the event to the CEC for the final determination. The 
membership and responsibilities of the CEC Committee will be defined in a separate 
document provided to the sites. This document will include definitions for endpoints and 
guidelines on the endpoint reporting process. 
No adjudication of clinical endpoint events during the OLE epoch will take place. 
8.5.2 
Angioedema Adjudication Committee 
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis). 
Details on the process of reporting angioedema and angioedema-like events are outlined in a 
manual provided to investigators. 
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
If an angioedema-like event satisfies the definition of an SAE, the investigator must submit an 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event. 
All angioedema reports will be forwarded to an angioedema adjudication committee by 
Novartis for assessment. The membership and responsibilities of the Angioedema 
Adjudication Committee are defined in a separate document that will be provided to the sites. 
The process above will also be applied to the OLE epoch. 
 


Novartis 
Confidential 
Page 81 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
9 
Data analysis 
9.1 
Analysis sets 
The following populations will be used for the core part statistical analyses: 
The Screened Set (SCR) will consist of all patients who signed the informed consent. The 
screened set includes only unique screened patients, i.e., in the case of re-screened patients 
only the chronologically last screening data is counted.  
The Enrolled Set (ENR) (run-in epoch) will consist of all patients who received at least one 
dose of run-in study medication. 
The Randomized Set (RAN) will consist of all patients who received a randomization number, 
regardless of receiving double-blind investigational drug. 
The Full Analysis Set (FAS) will consist of all randomized patients with the exception for 
those patients who have not been qualified for randomization and have not received 
investigational drug, but have been inadvertently randomized into the study. Following the 
intent-to-treat principle, patients will be analyzed according to the treatment to which they 
were assigned at randomization. Efficacy variables will be analyzed based on the FAS as the 
primary population. 
The Safety Population (SAF) will consist of all randomized patients who received at least one 
dose of double-blind medication. Patients will be analyzed according to the treatment actually 
received. The safety population will be used for the analyses of safety variables. 
The Per-protocol (PP) population will be a subset of the FAS which will consist of the 
patients who do not have major deviations from the protocol procedures in the double-blind 
study stage. Major protocol deviations will be pre-specified prior to un-blinding treatment 
codes for analyses. This supplemental efficacy population will be used to support the primary 
analysis results. 
The following populations will be used for the OLE statistical analyses: 
The Extension Population (EXT): All eligible patients who have completed the core part and 
have signed the informed consent for the OLE epoch. 
The Full Analysis Set for OLE epoch (FAS-Ext): All patients who receive at least one dose of 
the extension study drug. The FAS-Ext population is the analysis set for both safety and 
efficacy analysis.   
9.2 
Patient demographics and other baseline characteristics 
In the core part, baseline value is defined as the last non-missing assessment prior to the first 
dose of randomized study medication unless specified otherwise. 
In the OLE epoch, value at Visit 301 is defined as OLE baseline. 
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (< 65 years vs. ≥ 65 years; < 75 years vs. ≥ 75 years), 
sex, race, ethnicity, weight, height, body mass index (BMI), category of prior CHF 


Novartis 
Confidential 
Page 82 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
medication, prior HF hospitalization, NYHA class, LVEF, NT-proBNP, eGFR, and vital signs. 
BMI will be calculated as weight (kg) ∕ height2 (m2) from the collected height and weight at 
Visit 1 (Screening Visit). Continuous variables will be summarized using n, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency and percentage. 
The difference between treatment groups will be compared using the Chi-square test for 
categorical variables or using t-test for continuous variables. The p-values will be provided for 
descriptive purposes and will not be considered to define any formal basis for determining 
factors to be included in statistical models. If a substantial imbalance of treatment groups with 
respect to some variables does occur, supplemental analyses with addition of these variables 
in model may be performed to assess the potential impact on efficacy as appropriate. 
The FAS will be the patient population for the above analyses. 
Similarly, summary statistics as given above will be presented in the OLE epoch. 
9.3 
Treatments 
The overall duration on the double-blind investigational treatment will be summarized by 
treatment group using mean, standard deviation, median, minimum, and maximum. 
Additionally, the number and percentage of patients will be summarized by treatment group 
for duration category. Mean doses and dose levels will be summarized by treatment group and 
visit. The overall duration on the investigational product in the OLE epoch will be analyzed 
similarly. 
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date respectively, will be summarized by therapeutic class, preferred term, and 
treatment group for the safety population. Concomitant therapies used during the single-blind 
run-in epoch will also be similarly summarized. Concomitant medications in the OLE epoch 
will also be similarly summarized. 
The number and percentage of patients on different CHF background medications (e.g., 
mineralocorticoid receptor antagonist, β-blockers, diuretics, digoxin) will be tabulated by 
treatment at baseline and during the double-blind stage. Similarly, the number and percentage 
of patients on different CHF background medications will be tabulated in the OLE epoch. 
9.4 
Analysis of the primary variable 
9.4.1 
Variable 
The primary efficacy variable is time to the first occurrence of the composite endpoint, which 
is defined as either CV death or HF hospitalization. The confirmation of the primary 
composite events is based on an adjudication process by independent CEC (Section 8.5.1). 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary efficacy variable will be analyzed using Cox proportional hazards model with 
treatment and the stratification factor of screening NT-proBNP (< 1,600 pg/mL, 
≥ 1,600 pg/mL) as fixed-effect factors. The primary hypothesis to be tested is H10: λ2 ∕ λ1 ≥ 1 
versus H1a: λ2 ∕ λ1 < 1, where λ1 and λ2 are hazards for enalapril treatment and LCZ696 


Novartis 
Confidential 
Page 83 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
treatment, respectively. The frequency of patients with composite primary endpoint events 
and the treatment exposure adjusted event rate will be provided for individual treatment arm. 
The FAS will be used for the primary analysis. 
The primary objective is met when the hazard ratio point estimate is less than 1. 
9.4.3 
Handling of missing values/censoring/discontinuations 
The primary efficacy variable, the time to the first occurrence of either CV death or HF 
hospitalization, will be considered as censored for patients who have no event and at least one 
of the following applies: 
 withdrawal of informed consent, 
 loss to follow-up, or 
 death from non-CV causes.  
For those patients without events, the censoring date will be defined as the following 
(whichever occurs first): 
 date when the patient withdrew informed consent, 
 date of the patient’s last visit, 
 date of death from non-CV causes.  
9.4.4 
Supportive analyses  
In addition to the primary analysis, the primary efficacy variable will also be analyzed using 
the same primary analysis model in the PP population as supportive.  
A supplemental log-rank test will be performed for both the FAS and the PP population. 
Survival function for each treatment group will be estimated by Kaplan-Meier method and the 
Kaplan-Meier curves will be presented for both the FAS and the PP populations.  
The frequency and percentage of patients who reach the primary composite endpoint will be 
provided by treatment group for both the FAS and the PP population.  
Additionally, similar analyses will be performed for each of the components of the composite 
endpoint with all events for that component that occurred during the double-blind treatment 
epoch of the study to quantify the strength of the effect for each component in the primary 
composite endpoint. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
In the core part, FAS will be used for the following key and other secondary analyses for 
efficacy endpoints. 
A cut-off data analysis will be carried during the OLE epoch after all patients have been 
enrolled into the OLE, and completed Visit 304 (Month 4) or discontinued. 
The cut-off date is defined as the latest of Visit 304 date or discontinuation date (the last visit 
prior to Visit 304). All data on or prior to this cut-off date during the OLE epoch will be used 


Novartis 
Confidential 
Page 84 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
for analysis. 
 
 
9.5.1.1 
Changes in NT-proBNP from baseline at pre-defined time points 
(Weeks 4 and 8, Month 6) 
Described in Section 9.5.1.10 Biomarkers. 
9.5.1.2 
Time to the first occurrence of CV death, HF hospitalization or 
intensification of treatments due to documented episode(s) of 
worsening HF 
In the core part, it will be analyzed using the same Cox proportional hazards model used for 
the primary endpoint. Analysis will be repeated for each of the components of the composite 
endpoint. 
The analysis above will not be applied for the OLE epoch. 
9.5.1.3 
NYHA classification 
In the core part, the change from randomization to each of the post-randomization visits in 
NYHA classification will be analyzed using Cochran-Mantel-Haenszel test for different row 
(treatment) means, stratified for screening NT-proBNP classification, based on the modified 
ridit scores which are also referred to as the standardized mid-ranks. 
In the OLE epoch, the change from baseline (Visit 301) to each of the post baseline visits in 
NYHA classification will be summarized. FAS-Ext will be used, and analyses will be done by 
the treatment arm in the double-blind treatment epoch. Additionally, analyses will be repeated 
for subset of FAS-Ext with only patients in the LCZ arm of the double-blind treatment epoch, 
throughout the period from run-in epoch to OLE epoch using Visit 101 as baseline. 
9.5.1.4 
KCCQ 
The KCCQ instrument includes several domains. Only the domains that address HF 
symptoms and physical limitations will be analyzed. The clinical summary score of KCCQ is 
computed as the mean of the available domain scores of total HF symptom and physical 
limitation. The clinical summary score of KCCQ will be analyzed based on a repeated 
measures ANCOVA model in which treatment, screening NT-proBNP classification, visit, 
and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as 
a covariate, with a common unstructured covariance for each treatment arm. The analysis will 
be performed based on all available data and based on likelihood method. The estimated 
treatment effect with the corresponding confidence interval will be provided. The primary 
treatment comparison between LCZ696 and enalapril is to be made at Week 8 and Month 6. 
9.5.1.5 
Composite of (total) HF hospitalizations and CV death 
The composite endpoint of recurrent hospitalizations (including the first) due to HF and death 
due to CV during the double-blind period will be analyzed using a negative binomial model 
(McCullagh and Nelder 1989) with the count data as the dependent variable, treatment group 
and the stratification factor screening NT-proBNP as fixed-effect factors, and log(follow-up 
duration) as the off-set. The estimated event rates (intensities/risk rate) and their 95% 


Novartis 
Confidential 
Page 85 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
confidence intervals will be provided by treatment group. The treatment comparison will be 
performed through the estimated ratio of risk rates. 
9.5.1.6 
Clinical composite score 
The clinical composite score will be analyzed at all time-points when both NYHA 
classification and Global Assessment are measured, using Cochran-Mantel-Haenszel (CMH) 
test for different row (treatment) means, stratified for screening NT-proBNP classification, 
based on the modified ridit scores which are also referred to as the standardized mid-ranks. 
9.5.1.7 
Time to all-cause death 
It will be analyzed using the same Cox proportional hazards model used for the primary 
endpoint. 
9.5.1.8 
Hospitalizations (all-cause and cause-specific) 
It will be analyzed using the same negative binomial model for the composite endpoint of 
total HF hospitalizations and CV death described in Section 9.5.1.5. Analysis will be 
performed for all-cause hospitalizations and cause-specific hospitalizations as well. 
Time to the first occurrence of hospitalization will be analyzed using the same Cox 
proportional hazards model used for the primary endpoint. Analysis will be performed for all-
cause hospitalizations and cause-specific hospitalizations as well. 
9.5.1.9 
Echocardiogram 
Summary statistics for change from baseline (Visit 301) of echo parameters will be presented. 
FAS-Ext will be used, and analyses will be done by the treatment arm in the double-blind 
treatment epoch. 
Pearson’s correlation coefficient and its two-sided 95% confidence interval between change in 
NT-proBNP and change in structural cardiac measurements (LV end systolic and diastolic 
volume indices, LVEF, and LA volume index) from baseline (Visit 301) to Month 12 will be 
analyzed. Similarly spearman’s correlation coefficient and its two-sided 95% confidence 
interval will be analyzed. 
Above analysis is repeated for change in log transformed NT -proBNP. 
9.5.1.10 Biomarkers 
In the core part, for the treatment comparisons of LCZ696 vs enalapril, change from baseline 
(Visit 101) to the pre-defined time-points in logarithmic scale will be analyzed using a 
repeated measures ANCOVA model with treatment, the stratification factor screening NT-
proBNP, visit and treatment-by-visit interaction as fixed effect factors and the logarithmic 
baseline biomarker value as a covariate, with a common unstructured covariance matrix 
among visits for each treatment. The estimated treatment effects in terms of ratios of 
geometric means, based on the least-squared means for within and between treatment groups 
from the ANCOVA model, and the corresponding two-sided 95% confidence intervals will be 
provided. The analysis will be performed based on all available data in the FAS and based on 
likelihood method with an assumption of missing at random for missing data. Descriptive 


Novartis 
Confidential 
Page 86 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
summary statistics (mean, median, standard deviation, min, max, Q1, Q3, geometric mean, 
95% CI for geometric mean) for the change from Visit 101 to each post-baseline visit will be 
presented. Graphical mean plots with 95% CIs will also be provided. 
Analysis will be conducted for all of the FAS population with relevant biomarker measures. 
To characterize the effect of the two LCZ696 dosages (100 mg b.i.d., 200 mg b.i.d.) on NT-
proBNP, the estimates of ratio from baseline (Visit 101) at Week 4 and Week 8 of LCZ696 
treatment arm from the ANCOVA model described above are presented, and comparison of 
change from baseline at each dose level will be made using a t-test. Descriptive summary 
statistics for the changes from Visit 199 to post-randomization visits (Visits 202, 203, 204, 
206) will be presented for LCZ696 treatment arm. In addition, descriptive summary for the 
change from Visit 199 to Visit 206 (Month 6) will be summarized by actual dose level 
immediately prior to Visit 206 for LCZ696 treatment arm. Graphical mean plots with 95% 
CIs will be provided as well. Analysis will be conducted for all of the FAS population with 
NT-proBNP measures. Same analysis will be conducted for the patients who did not require 
any dose adjustment(s) up to Week 8 in the FAS population with NT-proBNP measures. 
Analysis described above will be repeated for the subgroups, defined by the stratification for 
randomization – screening NT-proBNP (< 1,600 pg/mL, ≥ 1,600 pg/mL). 
For reference, same analysis will be performed for enalapril treatment arm to characterize the 
effects of enalapril dosages (5 mg b.i.d., 10 mg b.i.d.). 
In the OLE epoch, for biomarkers, descriptive summary statistics (mean, median, standard 
deviation, min, max, Q1, Q3, geometric mean, 95% CI for geometric mean) for the change 
from baseline (Visit 301) to each post-baseline visit will be presented. FAS-Ext will be used, 
and analyses will be done by the treatment arm in the double-blind treatment epoch. 
Additionally, analyses in NT-proBNP will be repeated for subset of FAS-Ext with only 
patients in the LCZ arm of the double blind treatment epoch, throughout the period from run-
in epoch to OLE epoch biomarker visits (Visits 301, 302, 303, 304 and 306) using Visit 101 
as baseline. 
9.5.2 
Safety variables 
The safety and tolerability assessments are listed below: 
 AEs and SAEs 
 Sitting systolic, diastolic BP, and pulse pressure 
 Heart rate 
 Symptomatic hypotension and/or SBP < 90 mmHg 
 Angioedema 
 Hyperkalemia 
 Renal dysfunction 
 Cough 
 Drug-related hepatic disorders 
 Other relevant laboratory values 
 ECG changes 


Novartis 
Confidential 
Page 87 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
The assessment of safety will be based primarily on the frequency of adverse events, SAEs, 
and laboratory abnormalities. Other safety data will be summarized as appropriate. 
The incidence of treatment-emergent adverse events (new or worsened) will be summarized 
by primary system organ class, preferred term, severity, and relationship to study drug. In 
addition, the incidence of death, SAEs, and AEs leading to discontinuation will be 
summarized separately by primary system organ class and preferred term. 
Laboratory data will be summarized by presenting shift tables using extended 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. 
Data from other tests (e.g., ECG or vital signs) will be listed, notable values will be flagged, 
and any other information collected will be listed as appropriate.  
Safety analyses will be performed based on the safety population. There will be no formal 
statistical inference analysis. 
In addition to the above safety analyses for the randomized double-blinded treatment epoch, 
the AEs, SAEs, and reasons for active run-in failures will be summarized for the active run-in 
epoch.  
One cut-off data analysis will be carried during the OLE epoch after all patients have been 
enrolled into the OLE, and completed Visit 304 (Month 4) or discontinued. 
The cut-off date is defined as the latest of Visit 304 date or discontinuation date (the last visit 
prior to Visit 304). All data on or prior to this cut-off date during the OLE epoch will be used 
for analysis. All specified safety analyses in this section will be performed for this cohort. 
For AEs/SAEs, FAS-Ext will be used, and all analyses will be done for total, and by the 
treatment arm in the double-blind treatment epoch. Additionally, all analyses will be repeated 
for subset of FAS-Ext with only patients in LCZ arm of double blind treatment epoch, 
throughout the period from run-in epoch to OLE epoch. 
Change from baseline (Visit 301) of lab parameters, vital signs and ECG will be summarized 
as given above. Shift from baseline of ECG data will be presented using shift table. FAS-Ext 
will be used, and all analyses will be done for total, and by the treatment arm in the double-
blind treatment epoch. Additionally, all analyses will be repeated for subset of FAS-Ext with 
only patients in LCZ arm of double blind treatment epoch, throughout the period from run-in 
epoch to OLE epoch using Visit 201 as baseline. 
Proportion of patients reaching target dose level 3 of LCZ696 at Week 8 and maintained at 
Month 4 will be presented. FAS-Ext will be used, and analyses will be done for total, and by 
the treatment arm in the double-blind treatment epoch. 
9.5.3 
Resource utilization  
Data relating to resource utilization for the core part will be used for the purpose of economic 
evaluation which will be carried out and reported as a separate activity. 


Novartis 
Confidential 
Page 88 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
9.5.4 
Health-related Quality of Life 
Described in Section 9.5.1.4. 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
9.5.6 
Biomarkers 
See Section 9.5.1.1 and Section 9.5.1.10. 
9.5.7 
D 
See Section 9.5.5. 
9.6 
Interim analyses 
Not planned. 
9.7 
Sample size calculation 
The sample size for the core part is primarily based on feasibility considerations. 
The target sample size is determined to ensure that there is at least 80% of probability in 
observing a hazard ratio (λ2 ∕ λ1) < 1 to verify the consistency between this study and 
PARADIGM-HF study, where λ1 and λ2 are hazards of enalapril treatment arm and LCZ696 
treatment arm respectively. Assuming a hazard reduction of 20% for the primary endpoint 
(composite of CV death and HF hospitalization) in LCZ over enalapril, approximately 57 
primary endpoint events will be required. 


Novartis 
Confidential 
Page 89 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Assuming an annual event rate of 13% in the enalapril group, an enrollment period of 22 
months and a minimum follow-up of 18 months, a total sample size of 220 patients will be 
required to obtain approximately 57 primary endpoint events. 
The assumption of 13% annual event rate in enalapril for the primary endpoint of HF 
progression and 20% hazard reduction of LCZ over enalapril are based on the PARADIGM-
HF study results (Table 9-1). 
Table 9-1 
Primary composite endpoint of PARADIGM-HF study 
Variable 
FAS entire population 
Asia population (excluding India) 
EAIR [95%CI] 
Hazard ratio 
[95%CI] 
EAIR [95%CI] 
Hazard ratio 
[95%CI] 
LCZ696 
N = 4187 
Enalapril 
N = 4212 
LCZ696 
N = 424 
Enalapril 
N = 427 
Primary composite 
endpoint 
10.5 
[9.81, 11.18] 
13.2 
[12.39, 13.95] 
0.80 
[0.731, 0.871] 
11.9 
[9.68, 14.44] 
14.7 
[12.17, 17.55] 
0.82 
[0.627, 1.065] 
EAIR = Total number of events ∕ 100 patients years  
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 


Novartis 
Confidential 
Page 90 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
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. 
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 


Novartis 
Confidential 
Page 91 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
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. 


Novartis 
Confidential 
Page 92 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
12 
References 
References are available upon request 
 
Braunschweig F, Cowie MR, Auricchio A (2011) What are the costs of heart failure? 
Europace; 13:ii13-7. 
CIBIS II Investigators (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a 
randomized trial. Lancet; 353(9146):9-13. 
Cohn JN and Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker 
valsartan in chronic heart failure. N Engl J Med; 345(23):1667-75. 
CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive 
heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study 
(CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med; 316(23):1429-35. 
Dickstein K, Cohen-Solal A, Filippatos G, et al. (2008) ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. 
Developed in collaboration with the Heart Failure Association of the ESC (HFA) and 
endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J; 
29(19):2388-442. 
European Commission ENTR/CT3 (2006) Detailed guidance on the collection, verification 
and presentation of adverse reaction reports arising from clinical trials on medicinal products 
for human use. 
FDA (2012) Guidance for Industry and Investigators: Safety reporting requirements for INDs 
and BA/BE studies. 
Flather MD, Shibata MC, Coats AJ, et al. (2005) Randomized trial to determine the effect of 
nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart 
failure (SENIORS). Eur Heart J; 26(3):215-25. 
Green CP, Porter CB, Bresnahan DR, et al. (2000) Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol; 35(5):1245-55. 
Hicks KA, Hung J, Mahaffey KW, et al. (2012) Standardized definitions for end point events 
in cardiovascular trials. Draft guidance; February 4, 2012. 
Matsuo S, Imai E, Horio M, et al. (2009) Revised equations for estimated GFR from serum 
creatinine in Japan. Am J Kidney Dis; 53(6):982-92. 
McCullagh P and Nelder JA (1989) Generalized Linear Models. 2nd ed; London: Chapman 
and Hall. 
McMurray JJ, Packer M, Desai AS, et al. (2014) Angiotensin-neprilysin inhibition versus 
enalapril in heart failure. N Engl J Med; 371(11):993-1004. 
MERIT-HF Study group (1999) Effect of metoprolol CR/XL in chronic heart failure: 
Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). 
Lancet; 353(9169):2001-7. 


Novartis 
Confidential 
Page 93 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Ministry of Health, Labour and Welfare (2011) Guidelines for Clinical Evaluation of Drugs 
for Heart Failure. Notification No. 0329-18 of the Medical Devices Investigation Office, 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau. (Article in 
Japanese) 
Niitani H, Yasuda H, Kawai C, et al. (1990) Studies on clinical usefulness of enalapril 
maleate (MK-421) for chronic heart failure. Multi-institutional cooperative double blind 
comparative tests (Article in Japanese). Journal of Clinical and Experimental Medicine 
(IGAKU NO AYUMI); 152(10):677-92. 
Packer M (2001) Proposal for a new clinical end point to evaluate the efficacy of drugs and 
devices in the treatment of chronic heart failure. J Card Fail; 7(2):176-82. 
Packer M, Fowler MB, Roecker EB, et al. (2002) Effect of carvedilol on the morbidity of 
patients with severe chronic heart failure: results of the carvedilol prospective randomized 
cumulative survival (COPERNICUS) study. Circulation; 106(17):2194-9. 
Pfeffer MA, Swedberg K, Granger CB, et al. (2003) Effects of candesartan on mortality and 
morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet; 
362(9386):759-66. 
Pitt B, Zannad F, Remme WJ, et al. (1999) The effect of spironolactone on morbidity and 
mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study 
Investigators. N Engl J Med; 341(10):709-17. 
RALES Investigators (1996) Effectiveness of spironolactone added to an angiotensin-
converting enzyme inhibitor and loop diuretic for severe chronic congestive heart failure (the 
Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol; 78(8):902-7. 
Roger VL, Go AS, Lloyd-Jones DM, et al. (2012) Heart Disease and Stroke Statistics – 2012 
Update: A Report From the American Heart Association. Circulation; 125(1):e2-e220. 
Shiba N, Nochioka K, Miura M, et al. (2011) Trend of westernization of etiology and clinical 
characteristics of heart failure patients in Japan – first report from the CHART-2 Study. Cir J; 
75(4):823-33. 
SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left 
ventricular ejection fractions and congestive heart failure. N Engl J Med; 325(5):293-302. 
SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart 
failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med; 
327(10):685-91. 
Sulpizio AC, Pullen MA, Edwards RM, et al. (2004) The effect of acute angiotensin-
converting enzyme and neutral endopeptidase 24.11 inhibition on plasma extravasation in the 
rat. J Pharmacol Exp Ther; 309(3):1141-7. 


Novartis 
Confidential 
Page 94 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
13 
Appendix 1: Clinically notable laboratory values and vital 
signs 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
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 
Alkaline phosphatase 
> 100% increase 
ALT (SGPT) 
> 150% increase 
AST (SGOT) 
> 150% increase 
BUN 
> 50% increase 
Calcium 
> 10% increase, > 10% decrease 
Chloride 
> 10% increase, > 10% decrease 
Creatinine 
> 50% increase 
Potassium 
> 20% increase, > 20% decrease 
Total bilirubin 
> 100% increase 
Uric acid 
> 50% increase 


Novartis 
Confidential 
Page 95 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
14 
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements 
Table 14-1 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY 
TRIGGERS 
 3 x ULN < ALT / AST ≤ 5 x ULN 
 1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
 ALT or AST > 5 × ULN 
 
 ALP > 2 × ULN (in the absence of known bone pathology) 
 
 TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
 ALT or AST > 3 × ULN and INR > 1.5  
 
 Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
 
 Any clinical event of jaundice (or equivalent term) 
 
 ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
 Any adverse event potentially indicative of a liver toxicity *  
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms 


Novartis 
Confidential 
Page 96 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
 Discontinue the study drug 
immediately 
 Hospitalize, if clinically appropriate 
 Establish causality 
 Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
ALT or AST 
> 8 × ULN 
 Discontinue the study drug 
immediately 
 Hospitalize if clinically appropriate 
 Establish causality 
 Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
> 3 × ULN and 
INR > 1.5 
 Discontinue the study drug 
immediately 
 Hospitalize, if clinically appropriate 
 Establish causality 
 Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
> 5 to ≤ 8 × ULN 
 Repeat LFT within 48 hours 
 If elevation persists, continue follow-
up monitoring 
 If elevation persists for more than 2 
weeks, discontinue the study drug 
 Establish causality 
 Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
> 3 × ULN 
accompanied by 
symptomsb 
 Discontinue the study drug 
immediately 
 Hospitalize if clinically appropriate 
 Establish causality 
 Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
> 3 to ≤ 5 × ULN  
(patient is 
asymptomatic) 
 Repeat LFT within the next week 
 If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
 Repeat LFT within 48 hours 
 If elevation persists, establish 
causality 
 Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
 Repeat LFT within 48 hours 
 If elevation persists, discontinue the 
study drug immediately 
 Hospitalize if clinically appropriate 
 Establish causality 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 


Novartis 
Confidential 
Page 97 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Criteria 
Actions required 
Follow-up monitoring 
 Complete liver CRF 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
 Repeat LFT within the next week 
 If elevation is confirmed, initiate close 
observation of the patient  
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
Jaundice 
 Discontinue the study drug 
immediately 
 Hospitalize the patient 
 Establish causality 
 Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion) 
Any AE potentially 
indicative of a liver 
toxicity* 
 Consider study drug interruption or 
discontinuation  
 Hospitalization if clinically appropriate 
 Establish causality 
 Complete liver CRF 
Investigator discretion 
*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 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death. 


Novartis 
Confidential 
Page 98 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
15 
Appendix 3: Treatment guidelines for hyperkalemia (serum 
potassium greater than 5.3 mmol/L[mEq/L]) 
General principles 
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken. 
Any patient who experiences a potassium level ≥ 5.5 mmol/L (mEq/L) confirmed by repeated 
testing at Visit 199 should be withdrawn from the study. Any patient with a serum potassium 
> 5.3 mmol/L (mEq/L) at any time after randomization requires the investigator to confirm 
the potassium concentration in a non-hemolyzed sample via an immediate repeat lab sample 
to both the clinic local lab and the study central lab. Regular, repeated checks of potassium 
concentration (beyond that prescribed in the protocol) should continue until it is clear that the 
potassium concentration is stable and not rising into the range of concern (≥ 5.5 and 
< 6.0 mmol/L [mEq/L]) or potential danger (≥ 6.0 mmol/L [mEq/L]). 
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below. Hyperkalemia should be followed until resolution. 
Corrective action for management of hyperkalemia 
Serum potassium > 5.3 and less than or equal to 5.5 mmol/L (mEq/L) 
 Confirm potassium concentration in a non-hemolyzed sample 
 Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
coffee, etc.)  
 Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents: 
 Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 
 Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics  
 Potassium supplements, e.g., potassium chloride 
 Salt substitutes  
 Non-steroidal anti-inflammatory drugs (NSAIDs) 
 Cyclo-oxygenase-2 (COX-2) inhibitors 
 Trimethoprim-containing combination products, such as Baktar® and Bactramin® 
(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 


Novartis 
Confidential 
Page 99 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
 Assess patient for dehydration or any condition that could lead to dehydration (e.g., 
diarrhea, vomiting) and/or hypovolemia and initiate appropriate corrective measures of 
rehydration. 
 Repeat serum potassium measurement within 3 to 5 days 
 If serum potassium remains > 5.3 and ≤ 5.5 mmol/L (mEq/L), regularly monitor serum 
potassium levels to ensure stability (suggested once monthly) 
 Consider down-titration of study medication, according to investigator’s medical 
judgment. 
Serum potassium > 5.5 and < 6.0 mmol/L (mEq/L) 
 Confirm potassium concentration in a non-hemolyzed sample  
 Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment.  
 Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L (mEq/L) 
 Repeat serum potassium measurement after 2-3 days 
 If serum potassium < 5.5 mmol/L (mEq/L), consider resumption of study drug at lower 
dose with repeat potassium within 5 days 
Serum potassium greater than or equal to 6.0 mmol/L (mEq/L) 
 Immediately discontinue study drug 
 Confirm potassium concentration in a non-hemolyzed sample 
 Urgently evaluate patient and treat hyperkalemia as clinically indicated  
 Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L (mEq/L) 
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee. 


Novartis 
Confidential 
Page 100 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
16 
Appendix 4: Guidelines for the management of blood 
pressure 
Guidelines 
1. Investigator should monitor blood pressure closely  
2. If symptomatic hypotension occurs: 
a. Correct any treatable cause, e.g. hypovolemia 
b. If hypotension persists, any antihypertensive drug and non-disease-modifying drugs, 
such as diuretics, CCBs, nitrates, and α-blockers, should be down-titrated or stopped 
first before down-titration of the study drug is considered 
c. If hypotension persists, the study drug should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medications adjust guidelines described in 
Section 5.5.5 should be adhered to as much as possible. 


Novartis 
Confidential 
Page 101 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
17 
Appendix 5: Guidelines for the management of renal 
dysfunction 
General principles: 
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, 
renal dysfunction may develop or may deteriorate in some patients after study drug 
administration. These recommendations have been developed to guide the investigators in 
managing patients with renal dysfunction after randomization. 
Any patient who experiences a decline in eGFR > 35% from Visit 1 or an eGFR 
< 30 mL/min/1.73 m2 at Visit 199 will be considered a run-in failure and withdrawn from the 
study. 
Two types of response to serum creatinine increase are described: 
Surveillance situation 
Core part 
If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (Visit 199) (or if 
serum creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will 
check for potentially reversible causes of renal dysfunction such as: 
 Non-steroidal anti-Inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia 
 Volume decrease, including that resulting from excessive dosing of diuretics 
 Urinary infection 
 Urinary tract obstruction 
 Study medication 
Open-label extension epoch 
The same as above is applied to OLE epoch using OLE baseline (Visit 301). 
Action situation 
Core part 
If a patient eGFR decreases by ≥ 40% from baseline (Visit 199) (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). 
The investigator may consider down-titration of study drug. If the investigator judges that 
study medication has to be stopped, he/she will have to contact the Novartis medical monitor 
or his/her designee. Thereafter, serum creatinine assessments will have to be repeated at least 
each week until levels return to acceptable values. If study medication was stopped, every 
effort will be done to restart it again, according to clinical conditions. 


Novartis 
Confidential 
Page 102 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 
Open-label extension epoch 
The same as above is applied to OLE epoch using OLE baseline (Visit 301). 


Novartis 
Confidential 
Page 103 
Amended Protocol Version 04 Clean 
 
Protocol No. CLCZ696B1301 
 
 

SAP_001.pdf: 
Clinical Development
LCZ696B
LCZ696B1301OLE / NCT02468232
A multicenter, randomized, double-blind, parallel group, active-controlled 
study to evaluate the efficacy and safety of LCZ696 compared to 
enalapril on morbidity and mortality in Japanese patients with chronic 
heart failure and reduced ejection fraction (Open-label extension epoch)
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Amendment 2
Release date:
11-Mar-2021
Number of pages:
27
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
LCZ696B1301OLE
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
14-
Dec-
2018
Prior 
to first 
patient 
first 
visit
Creation 
of final 
version
n.a.
11-
Jul-
2019
Prior to 
DBL at 
month 4
Core SAP 
amended
Amendment 1 created.
Scope of Protocol deviation added.
Section 2.3.1
Definition of baseline, at screening 
or OLE baseline, clarified.
Section 2.3.2,
2.3.3
FAS-Ext is used in place of EXT 
population for medical history.
Section 2.3.3
Formula for mean daily dose 
corrected.
Section 2.4.1
Use of TEAEs instead of all AEs 
clarified.
Section 2.8.1
Scope of urinalysis analysis 
clarified.
Section 2.8.3
Specifications for the liver enzyme 
abnormality analysis clarified to be 
consistenet with CLCZ696B2314.
Section 2.8.3
Baseline visit corrected for analyses 
based on LCZ-Ext set.
Section 2.8.3, 
2.8.4.1, 2.8.4.2.
An irrelevant imputation rule 
removed.
Section 5.1.2
Several obvious mistakes and scope 
of month 4 analysis corrected.
11-
Mar-
2021
Prior 
to 
DBL 
Minor 
update
Amendment 2 created.
Unnecessary KM plot for permanent 
discontinuation deleted.
Section 2.4.1


Novartis
For business use only
Page 3
SAP
LCZ696B1301OLE
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
% for selection of most common 
AEs updated
Section 2.8.1
Definition of core baseline clarified.
Section 
2.8.3, 
2.8.4.1, 2.8.4.2
Descriptive summary statistics for 
ECG clarified.
Section 2.8.4.1


Novartis
For business use only
Page 4
SAP
LCZ696B1301OLE
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................10
2.2.1
Subgroup of interest ..............................................................................10
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................11
2.3.2
Demographics and other baseline characteristics .................................11
2.3.3
Medical history from core part of the study..........................................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................13
2.4.1
Study treatment / compliance................................................................13
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Efficacy endpoints.................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................17
2.5.3
Handling of missing values/censoring/discontinuations.......................17
2.6
Analysis of the key secondary objective ...............................................................17
2.7
Analysis of secondary efficacy objective(s)..........................................................18
2.8
Safety analyses.......................................................................................................18
2.8.1
Adverse events (AEs)............................................................................18
2.8.2
Deaths....................................................................................................20
2.8.3
Laboratory data .....................................................................................20
2.8.4
Other safety data ...................................................................................23
2.9
Pharmacokinetic endpoints....................................................................................24
2.10
PD and PK/PD analyses.........................................................................................25
2.11
Patient-reported outcomes .....................................................................................25
2.12
Biomarkers.............................................................................................................25
2.13
Other Exploratory analyses....................................................................................25
2.14
Interim analysis......................................................................................................25
3
Sample size calculation .....................................................................................................25


Novartis
For business use only
Page 5
SAP
LCZ696B1301OLE
4
Change to protocol specified analyses ..............................................................................25
5
Appendix ...........................................................................................................................25
5.1
Imputation rules.....................................................................................................25
5.1.1
Study drug.............................................................................................25
5.1.2
AE date imputation ...............................................................................26
5.1.3
Concomitant medication date imputation .............................................26
5.2
AEs coding/grading ...............................................................................................26
5.3
Laboratory parameters derivations ........................................................................26
5.4
Statistical models...................................................................................................27
5.5
Rule of exclusion criteria of analysis sets..............................................................27
6
Reference...........................................................................................................................27


Novartis
For business use only
Page 6
SAP
LCZ696B1301OLE
List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
b.i.d.
Twice a day
BMI
body mass index
BNP
B-type natriuretic peptide
BP
Blood pressure
Bpm
beats per minute
BUN
Blood urea nitrogen
cGMP
Cyclic guanosine monophosphate
CHF
Chronic heart failure
CI
Confidence interval
CRT
Cardiac resynchronization therapy
CRT-D
Cardiac resynchronization therapy defibrillator
CRT-P
Cardiac resynchronization therapy pacemaker
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
estimated glomerular filtration rate
EOS
end of study
HDL
high density lipoprotein
HF
heart failure
ICD
implantable cardioverter defibrillator
LA
left atrial
LBB
left bundle branch
LDL
low density lipoprotein
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRA
mineralocorticoid antagonist
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PD
Pharmacodynamics
OLE
Open-label extension
PK
Pharmacokinetics
RBB
right bundle branch
RBC
red blood cell
SAE
Serious adverse event
SBP
systolic blood pressure
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase


Novartis
For business use only
Page 7
SAP
LCZ696B1301OLE
TBL
total bilirubin
ULN
upper limit of normal
WBC
white blood cell


Novartis
For business use only
Page 8
SAP
LCZ696B1301OLE
1
Introduction
An open-label extension (OLE) to the study will be conducted following the completion of the 
core part in which patients are treated with open-label LCZ696. All participants of the core 
part who are eligible to receive study drug will be offered the option to enter the OLE. The 
purpose of this OLE is to provide access to LCZ696 for the eligible patients until marketed 
product is available in Japan or approximately 2 years from the date of the first patient 
enrolled in the OLE epoch, whichever occurs first, and also to assess the safety, tolerability 
and efficacy of the treatment with LCZ696.
Data will be analyzed according to the data analysis section 9 of the study protocol.
Descriptive statistics for continuous variables will be n, mean, standard deviation, median, 
minimum, the first quartile, the third quartile, and maximum. For in-text tables, the first 
quartile and the third quartile will not be presented. Categorical variables will be described 
using frequency and percentage.
1.1
Study design
An open-label extension to the study will be conducted following the completion of the core
part.
w = week; m = month
a.
Patients receiving double-blind study drug at dose level 2 have options to start with 
either the open-label LCZ696 100 mg b.i.d. (dose level 2) or LCZ696 50 mg b.i.d. 
(dose level 1) at the investigator’s discretion.
b. Dosage should be up-titrated at Visit 302 if tolerated in accordance with Table 1-1, 
and follow the general protocol guidance regarding maintenance dose (Protocol 
section 5.5.5).
c.
Dose adjustment is permitted if not tolerated at the dose during the OLE epoch 
following the general protocol guidance regarding maintenance dose (Protocol section 
5.5.5).


Novartis
For business use only
Page 9
SAP
LCZ696B1301OLE
d. Attempt should be made to up-titrate and maintain the patient at the target LCZ696 
dose (dose level 3) for as long as possible.
Table 1-1
Safety monitoring criteria for up-titration at Visit 302 (Week 2 to 4)
Parameter
Visit 302 (Week 2 to 4)
Serum potassium level
K ≤5.4 mmol/L (mEq/L)
(local assessment)
Kidney function
eGFR ≥30 mL/min/1.73m2 
eGFR reduction ≤35% compared to Visit 301
(local assessment)
Blood pressure
No symptomatic hypotension and SBP ≥95 mmHg.
AEs or conditions
No postural symptoms or any AEs that preclude 
continuation according to the investigator’s judgment
Every consenting trial participant who is eligible to receive study drug will start the OLE 
epoch. Informed consent will be obtained before any study-specific procedure for OLE epoch 
is performed. The last dose of study medication that the patient is taking during the core part 
should be considered in determining the starting dose level of LCZ696. For all patients, the 
first visit of the OLE epoch will occur on the same day as the EOS visit of the core part. At 
Visit 301, patients will be switched to an open-label LCZ696 from double-blinded study drug. 
Dose adjustments and temporary interruptions of study treatment are permitted if not tolerated 
during OLE epoch following the pre-specified protocol guidance (Protocol section 5.5.5).
Table 1-2 Starting dose levels of open-label LCZ696 at the start of the OLE
Final dose level of study medication during
the double-blind treatment epoch
Corresponding dose levels of open-label
LCZ696 treatment upon entering OLE
3
100 mg b.i.d.
2
50 mg b.i.d. or 100 mg b.i.d.a
1
50 mg b.i.d.
No treatment
50 mg b.i.d.
a The patient receiving double-blind study drug at dose level 2 has options to start with either 
the open-label LCZ696 100 mg b.i.d. (dose level 2) or LCZ696 50 mg b.i.d. (dose level 1) at 
the investigator’s discretion.
1.2
Study objectives and endpoints
Below are the objectives during the open-label extension.

To evaluate the safety and tolerability of LCZ696 treatment during the OLE epoch

To assess the proportion of patients reaching target dose level 3 of LCZ696 at Week 8 
and maintained at Month 4

To assess the effect of LCZ696 on change in NYHA classification from OLE baseline 
(Visit 301) at Month 12


Novartis
For business use only
Page 10
SAP
LCZ696B1301OLE

To assess the effects of LCZ696 on change in cardiac measurements by 
echocardiography (LV end systolic and diastolic volume indices, LVEF, and LA 
volume index, etc.) from OLE baseline (Visit 301) at Month 12

To assess the effects of LCZ696 on changes in pre-specified biomarkers from OLE 
baseline (Visit 301) to predefined timepoints (Weeks 2-4, 8, Month 4 and 12)

To assess the association between change in concentration of NT-proBNP and change 
in structural cardiac measurements (LV end systolic and diastolic volume indices, 
LVEF, and LA volume index) from OLE baseline (Visit 301) at Month 12

To assess the effects of long-term treatment with LCZ696 on the safety and 
tolerability throughout the study period
2
Statistical methods
2.1
Data analysis general information
In addition to analyses at study completion, a cut-off data analysis will be carried during the 
OLE epoch after all patients have been enrolled into the OLE, and completed Visit 304 
(Month 4) or discontinued.
The cut-off date is defined as the latest of Visit 304 date or discontinuation date (the last visit
prior to Visit 304). All data on or prior to this cut-off date during the OLE epoch will be used
for analysis. Specified efficacy and safety analyses will be performed.
2.1.1
General definitions
Physical exam, vital signs, Weight, NYHA classification, ECG and lab data at Visit 299 will be 
utilized as the data at Visit 301(Protocol Table 6-2). OLE baseline is Visit 301. If not specified 
otherwise, baseline is OLE baseline.
2.2
Analysis sets
The Extension Population (EXT): All eligible patients who have completed the core part and
have signed the informed consent for the OLE epoch.
The Full Analysis Set for OLE epoch (FAS-Ext): All patients in the EXT who receive at least 
one dose of the extension study drug. The FAS-Ext population is the analysis set for both safety 
and efficacy analysis.
Patients from FAS-Ext who were randomized in LCZ group in randomized epoch (LCZ-Ext): 
All patients in the FAS-Ext who receive at least one dose of the extension study drug and were 
randomized to LCZ in randomized epoch. The LCZ-Ext population is used to assess the effects 
of long-term treatment with LCZ696 on the safety and tolerability throughout the study period.
2.2.1
Subgroup of interest
Subgroups listed below will be formed for the analyses to explore the consistency of treatment 
effects and safety profiling between the subgroups and the overall population. 
1. Treatment arms in the double blind treatment epoch
LCZ696, Enalapril


Novartis
For business use only
Page 11
SAP
LCZ696B1301OLE
2. Age subgroups
<65, ≥65 at OLE baseline
<75, ≥75 at OLE baseline
3. Gender 
Male, Female
4. Baseline eGFR (mL/min/1.73m2)
<60, ≥60 at OLE baseline
Note that only important parameters or variables in these analyses will have subgroup 
analyses. The details about the parameters having subgroup analyses will be presented in the 
corresponding sections below. In principle, there will be no adjustment for multiple 
comparisons for subgroup analyses.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number and percentage of subjects successfully enrolled in OLE epoch, receive at least one 
dose of the study drug in OLE epoch, completed/discontinued the OLE epoch, and the reason 
for discontinuation will be presented for total, and by the treatment arm in the double blind
treatment epoch based on EXT population.
All PDs are specified in the “Protocol Deviations” of Data  Review Plan(SSD3). Number and 
percentage of subjects with protocol deviation during OLE epoch will be tabulated by deviation 
category for total, and by the treatment arm in the double blind treatment epoch based on EXT 
population.
2.3.2
Demographics and other baseline characteristics
Baseline characteristics will be summarized according to OLE baseline. In OLE epoch, value 
at Visit 301 is defined as OLE baseline. Core baseline value is defined as the available 
measurement at screening visit.
Summary statistics will be provided for total, and by the treatment arm in the double blind 
treatment epoch based on the EXT population for the demographic, disease characteristics, 
heart failure and cardiovascular diseases parameters listed below. 
Summary statistics will be provided for demographics and baseline characteristics, including:
Demographics

Age (years) at visit 301

Age group 1 [<65 years, ≥65 years] at visit 301

Age group 2 [<75 years, ≥75 years] at visit 301

Gender [Male, Female]

Race [Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other]

Ethnicity [Hispanic or Latino, Chinese, Japanese, Korean, Other East Asian, Southeast 
Asian, South Asian, West Asian, Mixed ethnicity, Unknown, Other]


Novartis
For business use only
Page 12
SAP
LCZ696B1301OLE

Weight (kg) at visit 301

Height (cm) at screening visit in core part

Body Mass Index (BMI) (kg/m2) – calculated as weight/height2 from the collected
height at screening visit in core part and weight at visit 301

BMI group [<25, ≥25 & <30, ≥30 (kg/m2)]

SBP (mmHg) at visit 301

DBP (mmHg) at visit 301

Pulse pressure (mmHg) at visit 301

eGFR (mL/min/1.73m2) at visit 301

eGFR group [< 60, ≥60 (mL/min/1.73 m2)] at visit 301
Disease characteristics

NYHA class [Class I, Class II, Class III, Class IV] at visit 301

Hypertension [No, Yes] at screening

Diabetes mellitus [No, Yes] at screening
2.3.3
Medical history from core part of the study
Medical history data are captured in the core part of the study with the following eCRF pages: 
Medical History, Heart Failure and Diabetes History, Cardiovascular Medical History, 
Protocol Solicited Medical History, Medical History Possibly Contributing to Liver 
Dysfunction, Alcohol History, Smoking History, Vaccination Medical History, which are 
collected at screening visit.
Heart failure and cardiovascular disease history
Summary statistics will be provided for total, and by the treatment arm in the double blind 
treatment epoch based on FAS-Ext population for the parameters listed below. 

Prior HF hospitalization [No, Yes]

Number of hospitalization for HF within 12 months prior to screening [0, 1 ,2 , >2]

Time from diagnosis of CHF (years)

Time from diagnosis of CHF group [>0 to 3 months, >3 to 6 months, >6 to 12
months, >1 to 2 years, >2 to 5 years, >5 years]

Primary HF etiology [Ischemic, Non-ischemic]

Prior MI [No, Yes] at screening

Prior stroke [No, Yes] at screening

Prior TIA [No, Yes] at screening

Atrial Fibrillation [No, Yes] at screening

Prior coronary artery bypass graft [No, Yes] at screening

Prior percutaneous coronary intervention [No, Yes] at screening

Prior angina pectoris [No, Yes] at screening

Angina class [Class I, Class II, Class III, Class IV] at screening

CRT [No, Yes] at screening

CRT-P [No, Yes] at screening

CRT-D [No, Yes] at screening

CRT/ICD [No, Yes] at screening

ICD only [No, Yes] at screening


Novartis
For business use only
Page 13
SAP
LCZ696B1301OLE
Protocol Solicited Medical History, Medical History Possibly Contributing to Liver Dysfunction
Protocol solicited medical history/Medical History Possibly Contributing to Liver
Dysfunction will be summarized by occurrence (No, Yes, Unknown) and ongoing status (No, 
Yes, NA) based on FAS-Ext population. 
Alcohol History and Smoking History
Alcohol History will be summarized by amount consumed on average for each substance 
based on FAS-Ext population. 
Vaccination Medical History
Vaccination Medical History will be summarized by occurrence of each vaccination based on 
FAS-Ext population. 
Medical History
Any condition entered on the eCRF pages of Medical History will be coded using the most
updated version of MedDRA dictionary.
Number of subjects with medical history will be summarized by primary system organ class 
and preferred term based on FAS-Ext population.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of treatment (including interruptions) for each subject will be computed regardless 
of temporary interruptions of usage of the study drug as follows.

date of last study drug intake in OLE epoch – date of first study drug intake in OLE 
epoch + 1.
Duration of exposure to study drug (excluding interruptions) for each subject will be 
computed as follows.

date of last study drug intake in OLE peoch – date of first study drug intake in OLE 
epoch + 1 – number of days of no treatment.
The duration of treatment (including interruptions) and the duration of exposure to study drug 
(excluding interruptions) will be descriptively summarized for total, and by the treatment arm 
in the double blind treatment epoch as well as frequencies per duration category defined 
below. 

<4 weeks

4 to <8 weeks

8 weeks to < 4 months

4 to < 8 months

8 to < 12 months

≥12 months


Novartis
For business use only
Page 14
SAP
LCZ696B1301OLE
Additionally, above analyses will be repeated for throughout the period from run-in epoch to 
OLE epoch for LCZ-Ext population.
Dose level
Doses and dose levels in the OLE epoch are summarized in Table 2-1.
Table 2-1 Study drug dose levels during OLE
Dose level
LCZ696
0
0 mg bid
1
50 mg bid
2
100 mg bid
3
200 mg bid
Mean daily dose and mean daily dose level for each subject will be computed as follows.
Mean daily dose (mg) =

(	
    
 

 )×(
 

  )×


	
    
  


Mean daily dose level =

(	
    
 

 )× 


	
    
  


Number and percentage of subjects classified by dose level will be presented for total, and by 
the treatment arm in the double blind treatment epoch at OLE baseline, Week 2-4, Week 8, 
Month 4, Month 8, Month 12, Month 16, Month 20 and end of study visit. Same analysis will 
be done for cut-off data analysis at month 4.
Mean daily dose per subject and mean daily dose level per subject will be summarized for 
total, and by the treatment arm in the double blind treatment epoch and visit. Same analysis 
will be done for cut-off data analysis at month 4.
Mean daily dose per subject and mean daily dose level per subject will also be summarized
for throughout the period from run-in epoch to OLE epoch for LCZ-Ext population. 
Number and percentage of subjects on each dose level at last available record will be
presented for total, and by the treatment arm in the double blind treatment epoch. Mean dose 
level at last available record will be summarized for total, and by the treatment arm in the 
double blind treatment epoch. Same analysis will be repeated for the subjects who are alive at 
the last visit.
A treatment exposure interruption episode is defined as any interval during which the
treatment is stopped (i.e. Dispensing Level=No treatment on Dosage Administration


Novartis
For business use only
Page 15
SAP
LCZ696B1301OLE
Record CRF). Any treatment interruption episodes, any treatment interruption episodes >7
days and any treatment interruption episodes >14 days will be classified into the followings: 
“None”, “At least once”, “1”, “2”, “3”, “4”, “5”, ”6”, “7”, “>7”. This categorical variable will 
be summarized for total, and by the treatment arm in the double-blind treatment epoch.
The reasons for all treatment interruptions (As per protocol, Adverse event, Dosing error,
Dispensing error, Technical problems, Subject/guardian decision, Physician decision,
Hyperkalemia, Hypotension, Renal dysfunction, Angioedema/angioedema-like event,
Cough) will be also summarized for total, and by the treatment arm in the double-blind 
treatment epoch. Same analysis will be repeated for cut-off data analysis at month 4.
A treatment down titration is defined as any dose reduction from dose level 3 to 2, 3 to 1,
3 to 0, 2 to 1, 2 to 0 or 1 to 0 (i.e. a lower Dispensing Level in the subsequent
administration record). Treatment down titrations will be summarized by reason for total, and 
by the treatment arm in the double-blind treatment epoch. Subjects experienced treatment 
down titration will be summarized with the number and percentage of subjects by reason for 
study treatment dose reduction. Same analysis will be repeated for cut-off data analysis at 
month 4.
Number and percentage of subjects will be summarised for medication exposure time
categories “1-30 days”, “31-60 days”, “61-90 days”, “91-180 days”, “181 days- 1 year, “>1 
year” by last received drug dose level.
2.4.2
Prior, concomitant and post therapies
Medications will be identified using Novartis Drug and Therapy Dictionary (NovDTD)
including Anatomical Therapeutic Chemical (ATC) code. Medications will be presented in 
alphabetical order, by ATC codes and grouped by anatomical main group (the 1st level of the 
ATC codes). Tables will show the overall number and percentage of subjects receiving at 
least one drug of a particular ATC code and at least one drug in a particular anatomical main 
group.
Prior or concomitant medications will be identified based on recorded or imputed start and
end dates of taking medication. The rules for imputing incomplete (start and end) dates are
described in section 5.1.3.
Prior medications are defined as drugs taken prior to first dose of run-in study medication in 
core part of study(i.e. End date on Concomitant Medications eCRF < first run-in study drug
date). Selected prior medications will be listed based on FAS-Ext population.
Any medication given at least once during the OLE epoch will be a OLE concomitant 
medication, including those which were started before OLE epoch and continued into the 
OLE epoch.
The OLE concomitant medication information will be summarized for total, and by the
treatment arm in the double-blind treatment epoch based on the FAS-Ext population.


Novartis
For business use only
Page 16
SAP
LCZ696B1301OLE
All OLE concomitant medications and heart failure/cardiovascular OLE concomitant 
medications will be summarized separately in the same way. 
More specifically, the following classes of medications will be summarized separately from 
general medications:
HF medications
• Calcium channel blocker (CCB)
• Diuretics
• Beta blockers
• Mineralocorticoid receptor antagonists (MRAs)
• Digitalis glycosides
• Oral anticoagulants
• Antiarrhythmic agents
• Aspirin
• Other antiplatelet agents(excluding Aspirin)
• Statins
• Nitrates
• Other(non-statin) lipid lowering agents
Medications for heart failure/cardiovascular diseases at the start of OLE study drug will be 
summarized.
General medications newly added after the start of OLE study drug will be summarized.
Medications for heart failure/cardiovascular diseases newly added after the start of OLE study 
drug will be summarized.
Number and percentage of subjects treated with heart failure/cardiovascular medications upto 
month 18 in OLE epoch will be presented for total, and by the treatment arm in the double
blind treatment epoch and ATC class.
Surgical and medical procedures during OLE epoch by primary system organ class, preferred 
term will be summarized.
All concomitant medication, surgical and medical procedures will be summarized for cut-off 
data analysis at month 4.
2.5
Analysis of the primary objective
2.5.1
Efficacy endpoints
Below endpoints will be analyzed based on FAS-Ext poplulation.

NYHA classification

Echocardiographic parameters

Biomarkers

Association between NT-proBNP and echocardiographic parameters


Novartis
For business use only
Page 17
SAP
LCZ696B1301OLE
2.5.2
Statistical hypothesis, model, and method of analysis
NYHA classification
Change of NYHA functional class from OLE baseline will be grouped into 3 categories: 
improved, unchanged, or worsened. A shift table from OLE baseline to each post-baseline 
visit in NYHA class will be provided by the treatment arm in the double blind treatment 
epoch. FAS-Ext will be used. Number and percentage of subjects in each category will be 
provided. Same analysis will be repeated for  cut-off data analysis at month 4.
To assess the magnitude of change in NYHA class throughout the period from run-in epoch to 
OLE epoch, shift table will be provided for LCZ-Ext population, using Visit 101 as baseline.
Echocardiographic parameters
The echocardiogram will be performed at Visit 301 before administration of study medication 
and also at Visit 306. Cardiac parameters related to LV and LA structure, LV systolic and
diastolic function etc. (including LV end systolic and diastolic volume indices, LVEF, and LA
volume index) will be assessed. Summary statistics for change from OLE baseline of echo 
parameters will be presented. FAS-Ext will be used, and analyses will be done by the 
treatment arm in the double-blind treatment epoch.
Biomarkers
In the OLE epoch, biomarker measurements will be obtained from plasma and spot urine 
samples at Visits 301, 302, 303, 304, and 306 to determine effects of LCZ696 treatments on 
biomarkers. Descriptive summary statistics (mean, median, standard deviation, min, max, Q1, 
Q3, geometric mean, 95% CI for geometric mean) for the changes from OLE baseline to each 
post-baseline visit will be presented by treatment arm in the double blind treatment epoch for 
BNP, NT-proBNP, and urine cGMP. Same analysis will be repeated for  cut-off data analysis 
at month 4.
Descriptive summary statistics for NT-proBNP will be presentd for LCZ-Ext population, 
throughout the period from run-in epoch to OLE epoch using Visit 101 as baseline.
Graph for geometric mean and 95% confidence interval for total, and by treatment arm in the 
double blind treatment epoch  will be presented for BNP, NT-proBNP, and urine cGMP.
Association between NT-proBNP and echocardiographic parameters
Pearson’s and Spearman’s correlation coefficient and their two-sided 95% confidence interval 
between change in log transformed NT-proBNP and change in structural cardiac 
measurements (LV end systolic and diastolic volume indices, LVEF, and LA volume index) 
from OLE baseline to Month 12 will be analyzed. FAS-Ext will be used, and analyses will be 
done for total, and by the treatment arm in the double-blind treatment epoch.
2.5.3
Handling of missing values/censoring/discontinuations
No imputation for missing.
2.6
Analysis of the key secondary objective
No key secondary objectives are analyzed.


Novartis
For business use only
Page 18
SAP
LCZ696B1301OLE
2.7
Analysis of secondary efficacy objective(s)
No secondary efficacy objectives are analyzed.
2.8
Safety analyses
For AEs/SAEs, FAS-Ext will be used, and all analyses will be done for total, and by the
treatment arm in the double-blind treatment epoch. Additionally, all analyses will be repeated 
for LCZ-Ext population, throughout the period from run-in epoch to OLE epoch.
Change from baseline (Visit 301) of lab parameters, vital signs and ECG will be summarized. 
Shift from baseline of ECG data will be presented using shift table. FAS-Ext will be used, and 
all analyses will be done for total, and by the treatment arm in the double blind treatment 
epoch. Additionally, all analyses will be repeated for LCZ-Ext population, throughout the 
period from run-in epoch to OLE epoch using core baseline.
Proportion of patients reaching target dose level 3 of LCZ696 at Week 8 and maintained at
Month 4 will be presented. Additionally, proportion of patients in each dose level category 
upto month 12 will be presented.
2.8.1
Adverse events (AEs)
All AEs during OLE epoch including on-going AEs at Visit 301 will be recorded on the Adverse 
Event eCRF page. AEs starting on or after the first dose of OLE epoch study medication or
events present prior to the first dose of OLE epoch study medication but increased in severity 
based on preferred term will be classified as treatment-emergent AEs(TEAE).
The following rules are applied. 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.
Number and percentage of subjects reporting any treatment-emergent AE during OLE epoch, 
reporting an AE in each primary system organ class and reporting individual AE (preferred 
term) will be summarized for the followings.

all treatment-emergent AEs, all treatment-emergent SAEs

drug-related treatmentemergent AEs, drug-related treatment-emergent SAEs

most common treatment-emergent AEs (≥3% in total)

most common drug-related treatment-emergent AEs (≥2% in total)

treatment-emergent AEs requiring dose adjustment or temporary interruption

treatment-emergent AEs causing study drug discontinuation
Similarly, summaries for following will be presented for cut-off data analysis upto month 4.

treatment-emergent AEs, treatment-emergent SAEs upto month 4

drug-related treatment-emergent AEs, drug-related treatment-emergent SAEs upto 
month 4


Novartis
For business use only
Page 19
SAP
LCZ696B1301OLE

treatment-emergent AEs requiring dose adjustment or temporary interruption upto 
month 4

treatment-emergent AEs causing study drug discontinuation upto month 4
The most common adverse events reported will be presented in descending frequency of total.
Summaries will also be presented by severity for all treatment-emergent AEs in OLE epoch
and treatment-emergent AEs upto month 4 for cut-off data analysis.
Number and percentage of subjects reporting any AE throughout the period from run-in epoch 
to OLE epoch, reporting an AE in each primary system organ class and reporting individual 
AE (preferred term) for LCZ-Ext population will be summarized for the followings.

all AEs, all SAEs

drug-related AEs, drug-related SAEs

most common AEs (≥5%)

most common drug-related AEs (≥3%)

AEs requiring dose adjustment or temporary interruption

AEs causing study drug discontinuation
The most common adverse events reported will be presented in descending frequency.
Summaries will also be presented by severity for all AEs throughout the period from run-in 
epoch to OLE epoch for LCZ-Ext population.
2.8.1.1
Adverse events of special interest / grouping of AEs
AEs of special interest will also be summarized. AEs of special interest and their further 
specified events include the followings.
Hypotension

SBP <90 mmHg

SBP decline by ≥30 mmHg

Simultaneous SBP <90 mmHg and SBP decline by ≥30 mmHg
Hyperkalemia

serum potassium ≥5.5 mmol/L

serum potassium >6.0 mmol/L

serum potassium >6.5 mmol/L
Renal impairment

Serum creatinine level >176.8 μmol/L

Serum creatinine level >221.0 μmol/L

Serum creatinine level >265.2 μmol/L

Serum creatinine increase by >50%

eGFR decline by ≥25%

eGFR decline by ≥40%

eGFR decline by ≥50%
Angioedema (adjudicated)


Novartis
For business use only
Page 20
SAP
LCZ696B1301OLE

No treatment or antihistamines only

Treated with catecholamines or steroids

Hospitalized but no mechanical airway protection, without airway compromise

Hospitalized but no mechanical airway protection, with airway compromise

Mechanical airway protection or death from airway compromise
Drug-related hepatic disorders

all preferred terms listed in the Standardized Med-DRA Query(SMQ) module 
“drugrelated hepatic disorders – comprehensive search SMQ code 20000006 - broad 
search”
Cough
Summary tables that summarize the numbers and percentages of subjects experienced the
above events at least once during OLE epoch will be presented by event or SMQ (when drug-
related hepatic disorders). Same summary analysis will be repeated for cut-off data analysis at 
month 4. 
Summary tables that summarize the numbers and percentages of subjects experienced the
above events at least once throughout the period from run-in epoch to OLE epoch for LCZ-
Ext population will be presented by event or SMQ (when drug-related hepatic disorders).
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for 
hypotension, hyperkalaemia, renal impairment and cough are based on LCZ696 used in core 
part.
Numbers and percentages of subjects with adjudicated angioedema events with the
adjudicated maximum severity and angioedema-like (i.e. investigator-reported) events will be
presented in OLE epoch.
Numbers and percentages of subjects with adjudicated angioedema events with the
adjudicated maximum severity and angioedema-like (i.e. investigator-reported) events 
throughout the period from run-in epoch to OLE epoch for LCZ-Ext population will be 
presented.
2.8.2
Deaths
Summaries for death will be provided by the investigator-reported primary cause in OLE 
epoch. Summaries for death will also be presented for cut-off data analysis at month 4.
Additionaly, summaries for death will be provided by the investigator-reported primary cause
throughout the period from run-in epoch to OLE epoch for LCZ-Ext population.
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests.
Hematology

Hemoglobin


Novartis
For business use only
Page 21
SAP
LCZ696B1301OLE

Hematocrit

RBC count

WBC count

WBC differential

Platelet count
Biochemistry

Blood urea nitrogen (BUN)

Creatinine

Estimated glomerular filtration rate (eGFR)

Total bilirubin

AST (SGOT)

ALT (SGPT)

Alkaline phosphatase

Sodium

Potassium

Chloride

Calcium

Glucose

Total protein

Albumin

Uric acid

Total cholesterol

LDL

HDL

Triglycerides

Hemoglobin A1c
Urinalysis

Specific gravity

pH

Blood

Total protein

Bilirubin

Ketones

Leukocytes
Estimated GFR will only be calculated using the following formula for Japanese (Matsuo
2009):
eGFR (mL/min/1.73m2) = 194 × (serum creatinine in mg/dL)-1.094 × (age in years)-0.287
× (0.739 if female)
where serum creatinine is in μmol/L (SI unit) and age at the time of the laboratory sample in
years.


Novartis
For business use only
Page 22
SAP
LCZ696B1301OLE
For continuous laboratory parameters, descriptive summary statistics for the change from
OLE baseline to each post-baseline visit will be presented. These descriptive summaries will 
be presented by laboratory parameter. Change from baseline will only be summarized for
subjects with both baseline and post-baseline values and will be calculated as: change from
baseline = post-baseline value – OLE baseline value. Similarly, summary statistics for 
hematology and biochemistry lab parameters(including eGFR) will be presented for cut-off 
data analysis at month 4.
In addition, shift tables will be provided for all parameters to compare a subject’s OLE 
baseline laboratory evaluation relative to the visit’s observed value and the most extreme 
value. For the shift tables, the normal laboratory ranges will be used to evaluate whether a 
particular laboratory test value was normal, low, or high for each visit value relative to 
whether or not the OLE baseline value was normal, low, or high. These summaries will be 
presented by laboratory parameter and treatment arm in the double-blind treatment epoch.
The number and percentage of subjects with clinically notable laboratory results at each post
baseline visit will be presented by laboratory parameter. An additional section will be
included for abnormalities occurring at any visit. The denominator for each visit is based on
subjects with values at both OLE baseline and corresponding post-baseline visit; the 
denominator for any visit is based on subjects with values at both OLE baseline and any post-
baseline visit. Number and percentage of subjects with clinically notable laboratory results 
will also be presented for cut-off data analysis at month 4.
Clinically notable criteria, for those parameters where ranges are available, are given in 
appendix 5.3.
Specific gravity of urinalysis will be summarized by visit with standard summary statistics,
including change from baseline. Change from baseline will only be summarized for subjects
with both baseline and post-baseline values and will be calculated as: change from baseline =
post-baseline value – OLE baseline value.
Other categorical urinalysis laboratory parameters (blood, total protein, bilirubin, ketones,
Leukocytes, pH) will be described using frequency and percentage by visit and treatment arm 
in the double blind treatment epoch.
Liver function test data
Liver events and triggers, defined in Appendix 2 of protocol, should be based on central
laboratory results. The details of every liver event should be provided on Liver Event eCRF
pages.
To evaluate potential drug-induced liver injury, newly occurring or worsening liver enzyme
abnormalities at any time post-baseline will be summarized based on the event criteria given
below.

ALT or AST >3x upper limit of normal range (ULN)

ALT or AST >5x ULN

ALT or AST >8x ULN

ALT or AST >10x ULN

ALT or AST >20x ULN


Novartis
For business use only
Page 23
SAP
LCZ696B1301OLE

ALT or AST >3x ULN and TB >1.5x ULN

ALT or AST >3x ULN and TB >2x ULN

ALT or AST >5x ULN and TB >2x ULN

ALT or AST >8x ULN and TB >2x ULN

ALT or AST >10x ULN and TB >2x ULN

ALT or AST >20x ULN and TB >2x ULN

ALP >2x ULN

ALP >3x ULN

ALP >5x ULN

TBL >1.5x ULN

TBL >2x ULN

TBL >3x ULN

ALP >3x ULN and TBL >2x ULN

ALP >5x ULN and TBL >2x ULN

(AST or ALT >3x ULN) and (TBL >2x ULN) and (ALP ≤2x ULN)

(AST or ALT >3x ULN) and (TBL >2x ULN) and (ALP ≤2x ULN) or reported Hy’s 
Law case

(ALT or AST >3x ULN) and reported symptoms of (nausea or vomiting or fatigue or
malaise or abdominal pain or (rash and eosinophilia))

(TBL >3x ULN) and (AST or ALT ≤3x ULN) and (ALP ≤1.5x ULN)

(ALP >3x ULN) and (AST, ALT, TBL are within normal range)
Liver enzyme abnormalities will also be summarized for cut-off data analysis at month 4.
The event which combines lab information and signs/symptoms information is derived using
central laboratory results and the Liver Event eCRF. A case will be considered as newly 
occurring if a criterion is not met at baseline but is met thereafter.
All analyses in this section will be repeated for LCZ-Ext population, throughout the period 
from run-in epoch to OLE epoch using screening as baseline. As applicable, all visits will be 
presented.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Heart rate and QRS duration will be summarized. Descriptive summary statistics for the 
change from OLE baseline to each post-baseline visit will be presented. FAS-Ext will be used, 
and analyses will be done by the treatment arm in the double-blind treatment epoch.
In addition, shift tables comparing OLE baseline overall ECG interpretation (normal, 
clinically abnormal) will be provided for each post-baseline visit.
In the case where any new clinically significant abnormalities are present, more detailed
abnormalities should be specified: atrial fibrillation, atrial flutter, LBB block, RBB block,
pathological Q waves, left ventricular hypertrophy, paced rhythm. The numbers and
percentages of subjects with these specific abnormalities will be shown by visit.


Novartis
For business use only
Page 24
SAP
LCZ696B1301OLE
All analyses in this section will be repeated for LCZ-Ext population, throughout the period 
from run-in epoch to OLE epoch using screening visit as baseline. As applicable, all visits 
will be presented.
2.8.4.2
Vital signs
Sitting systolic blood pressure, sitting diastolic blood pressure, sitting pulse rate and body
weight will be summarized by post-baseline visit with standard summary statistics, including
changes from OLE baseline. Change from baseline will only be summarized for subjects with 
both baseline and post-baseline values and will be calculated as: change from baseline = post-
baseline value - baseline value. Same analysis will be repeated for cut-off data analysis at 
month 4.
Graphical mean plots with 95% CIs for these vital signs will also be provided. The number 
and percentage of subjects with clinically notable vital signs changes from baseline will be 
presented. Number and percentage of subjects with clinically notable vital signs change from 
baseline will also be presented for cut-off data analysis at month 4. The clinically notable 
criteria are provided in Table 2-2 below.
Table 2-2 Clinically notable changes in vital signs
Vital Sign (unit)
Clinically notable criteria
Weight (kg)
decrease > 7% from baseline
increase > 7% from baseline
Sitting systolic blood pressure 
(mmHg)
<90 and decrease from baseline of >20
>180 and increase from baseline of >20
Sitting diastolic blood pressure 
(mmHg)
<50 and decrease from baseline of >15
>105 and increase from baseline of >15
Pulse (bpm)
<50 and decrease from baseline of > 15
>120 and increase from baseline of >15
All analyses in this section will be repeated for LCZ-Ext population, throughout the period 
from run-in epoch to OLE epoch using Visit 101 as baseline. As applicable, all visits will be 
presented.
2.8.4.3
Patients reaching target dose level
Proportion of patients reaching target dose level 3 of LCZ696 at Week 8 and maintained at
Month 4 will be presented. FAS-Ext will be used, and analyses will be done for total, and by
the treatment arm in the double-blind treatment epoch. Proportions of patients by visit upto 
month 12 will be presented for dose levels of open-label LCZ696. FAS-Ext will be used, and 
analyses will be done for total, and by the treatment arm in the double-blind treatment epoch.
2.9
Pharmacokinetic endpoints
PK samples will not be collected during the OLE epoch.


Novartis
For business use only
Page 25
SAP
LCZ696B1301OLE
2.10
PD and PK/PD analyses
None.
2.11
Patient-reported outcomes
None.
2.12
Biomarkers
Described in section 2.5.2
2.13
Other Exploratory analyses
None.
2.14
Interim analysis
Not planned.
3
Sample size calculation
Sample size calculation is not done for open label extension epoch.
4
Change to protocol specified analyses
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
If medication stop date is unknown or is incomplete, the imputation rules are:
a) If only the day field of the drug stop is missing, then the missing date is imputed by using 
the 15th of the month;
b) If year and month are missing, then use the next scheduled visit date (using the protocol 
specified visit schedule) from the previous last non-missing visit date to replace the missing 
drug stop date;
c) If the drug stop date is completely missing, then:
a. If subject had fatal AEs (identified as either start or end date is equal to the
date of death and the AE is flagged as an SAE), handling rules are (in the
specified order):
i. AE end date is not missing: use the AE end date to replace the missing drug 
stop date;
ii. AE end date is completely missing but AE onset date not missing: use the 
AE onset date to replace the missing drug stop date;
iii. AE end date is partially missing (only day field is missing): use Novartis 
standard procedure to impute the AE end date, and then use the imputed AE 
end date to replace the missing drug stop date;


Novartis
For business use only
Page 26
SAP
LCZ696B1301OLE
iv. AE end date is completely missing and AE onset date is partial missing
(missing the day field only): impute the AE onset date using Novartis standard 
procedure, and then use the imputed AE onset date to replace the missing drug 
stop date;
v. If both the AE onset and end dates are completely missing, then use the last 
previous non-missing visit date plus 35 days to replace the missing drug stop 
date.
b. If subjects had no fatal AEs, handling rules are the same with the case that year and month 
are missing.
5.1.2
AE date imputation
If the start/stop date of an event is not known or is incomplete, the imputation rules are:
a) If the day of the event is unknown, then the 15th day of this month will be imputed for
a missing day;
b) If only the month is unknown, then July will be used for imputation of the missing;
c) If only the year of the event is known, then the 1st of July will be imputed for a missing day 
and month;
5.1.3
Concomitant medication date imputation
If the start/stop date of concomitant medication is not known or is incomplete, same imputation 
method as described above in section 5.1.1 will be used.
5.2
AEs coding/grading
AEs will be coded using MedDRA (Medical Dictionary for Regulatory Activities
Terminology). The MedDRA version used for reporting the study will be described in a
footnote.
5.3
Laboratory parameters derivations
Table 5-1 Clinical notable criteria for selected laboratory tests
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
Biochemistry
ALT (SGOT) 
>150% increase
AST (SGPT) 
>150% increase
BUN 
>50% increase
>14.28 mmol/L
Creatinine 
>50% increase
>136.8 μmol/L
Total bilirubin 
>100% increase
Alkaline phosphatase 
>100% increase


Novartis
For business use only
Page 27
SAP
LCZ696B1301OLE
Sodium 
>5% decrease
Potassium 
>20% increase, >20% decrease
≥6.0 mmol/L
≥5.5 mmol/L
<3.5 mmol/L
       Chloride 
>10% increase, >10% decrease
       Calcium 
>10% increase, >10% decrease
       Uric acid 
>50% increase
In the above table increase and decrease are defined as compared to the baseline value.
5.4
Statistical models
5.5
Rule of exclusion criteria of analysis sets 
Table 1
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analyses
INCL07
Informed consent missing
Excluded form EXT, FAS-Ext 
and LCZ-Ext analysis
Table 2
Subject Classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
EXT
INCL07
FAS-Ext
INCL07
No open-label study drug taken
LCZ-Ext
INCL07
Not in FAS-Ext
6
Reference