Clinical trial NCT02768298
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Keywords: LCZ696 sacubitril/valsartan VO2peak heart failure systolic heart failure heart failure with reduced ejection fraction exercise capacity
Sponsor: Novartis Pharmaceuticals
Start date: 2016-07-12; Completion date: 2019-11-25
Enrollment: 201 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to determine the effect of LCZ696 vs. enalapril on improvement of exercise capacity in patients with chronic heart failure with reduced ejection fraction.

Detailed description:
This study was a randomized, double-blind, double-dummy, parallel-group, active-controlled, two-arm trial to compare LCZ696 200 mg twice daily (bid) to enalapril 10 mg bid in improving exercise capacity, daily physical activity and quality of life in patients with stable chronic heart failure (New York Heart Association III) and reduced left ventricular ejection fraction (LVEF ≤ 40%).

The study consisted of a screening period of 2 weeks during which the subject's eligibility for the study was assessed followed by a double blind treatment period of 12 weeks. Eligible subjects were randomized 1:1 to receive either LCZ696 or enalapril during the double-blind period. Treatment was initiated with LCZ696 100 mg bid or enalapril 5 mg bid (enalapril 10 mg bid for patients at a stable daily dose of enalapril above 10 mg per day or corresponding doses of other angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) prior first screening visit), respectively. Dose was up-titrated after 2 weeks to the final dose of LCZ696 200 mg bid or enalapril 10 mg bid.

Patients continued to take their background medications for chronic heart failure during the study, with the exception of ACEI or ARBs which were replaced by investigational treatment and had to be discontinued before first dose of study drug.

The primary objective was to demonstrate the superiority of LCZ696 200 mg bid compared to enalapril 10 mg bid in improving exercise tolerance (peak respiratory oxygen uptake (VO2peak), adjusted to body weight) as assessed by cardio-pulmonary-exercise testing (CPET) in patients with stable chronic heart failure (NYHA III) and reduced ejection fraction (LVEF ≤ 40%) after 3 months treatment.

Arms: arm 1: LCZ696 100 mg oral twice daily (bid) for 2 weeks followed by LCZ696 200 mg oral bid for 10 weeks. arm 2: Enalapril 5 mg oral twice daily (bid) for 2 weeks followed by enalapril 10 mg oral bid for 10 weeks.

Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid.
Interventions: intervention 1: LCZ696 intervention 2: Enalapril intervention 3: Placebo matching enalapril intervention 4: Placebo matching LCZ696
Intervention descriptions: intervention 1: LCZ696 100 mg bid for 2 weeks followed by LCZ696 200 mg bid for 10 weeks. Treatment was administered as oral tablets. intervention 2: Enalapril 5 mg bid for 2 weeks followed by enalapril 10 mg bid for 10 weeks. Treatment was administered as oral tablets.

Patients who prior Screening were at a stable daily dose of enalapril above 10 mg per day (or corresponding doses of other ACEI/ARB) started the study at a dose of enalapril 10 mg bid. intervention 3: Patients randomized to LCZ696 arm also received placebo matching enalapril (enalapril 0 mg tablets) to ensure the blinding during the entire course of the study. intervention 4: Patients randomized to enalapril arm also received placebo matching LCZ696 (LCZ696 0 mg tablets) to ensure the blinding during the entire course of the study.

Protocol documents:
Prot_000.pdf: 
Clinical Development 
LCZ696B 
Clinical Trial Protocol CLCZ696BDE01 / NCT02768298
 A randomized, double-blind, active-controlled study to 
assess the effect of LCZ696 compared with enalapril to 
improve exercise capacity in patients with heart failure with 
reduced ejection fraction (HFrEF). 
Authors: 
 
Document type: 
Clinical Trial Protocol  
EUDRACT number: 
2015-004632-35  
Version number: 
v04  
Development phase: 
IV 
Release date: 
24-July-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 


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Table of contents 
 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Protocol synopsis ............................................................................................................... 11 
Amendment 4 ........................................................................................................................... 16 
Amendment 3 ........................................................................................................................... 18 
Amendment 2 ........................................................................................................................... 19 
Amendment 1 ........................................................................................................................... 20 
1 
Introduction ....................................................................................................................... 21 
1.1 
Background ............................................................................................................ 21 
1.2 
Purpose .................................................................................................................. 22 
2 
Study objectives ................................................................................................................. 22 
2.1 
Primary objectives ................................................................................................. 22 
2.2 
Secondary objectives ............................................................................................. 22 
 
 23 
3 
Investigational plan ........................................................................................................... 24 
3.1 
Study design .......................................................................................................... 24 
3.2 
Rationale of study design ...................................................................................... 30 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 30 
3.4 
Rationale for choice of comparator ....................................................................... 31 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 31 
3.6 
Risks and benefits .................................................................................................. 31 
4 
Population .......................................................................................................................... 32 
4.1 
Inclusion criteria .................................................................................................... 32 
4.2 
Exclusion criteria ................................................................................................... 33 
5 
Treatment ........................................................................................................................... 36 
5.1 
Protocol requested treatment ................................................................................. 36 
5.1.1 
Investigational treatment ....................................................................... 36 
5.1.2 
Additional study treatment .................................................................... 37 


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5.2 
Treatment arms ...................................................................................................... 37 
5.3 
Treatment assignment, randomization ................................................................... 37 
5.4 
Treatment blinding ................................................................................................ 37 
5.5 
Treating the patient ................................................................................................ 38 
5.5.1 
Patient numbering ................................................................................. 38 
5.5.2 
Dispensing the investigational treatment .............................................. 38 
5.5.3 
Handling of study treatment .................................................................. 38 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 39 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 40 
5.5.6 
Rescue medication ................................................................................ 42 
5.5.7 
Concomitant treatment .......................................................................... 42 
5.5.8 
Other concomitant treatment ................................................................. 42 
5.5.9 
Prohibited Treatment ............................................................................. 44 
5.5.10 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 44 
5.5.11 
Emergency breaking of treatment assignment ...................................... 46 
5.5.12 
Study completion and post-study treatment .......................................... 46 
5.5.13 
Early study termination ......................................................................... 46 
6 
Visit schedule and assessments ......................................................................................... 46 
6.1 
Information to be collected on screening failures .................................................. 51 
6.2 
Patient demographics/other baseline characteristics ............................................. 51 
6.3 
Treatment exposure and compliance ..................................................................... 51 
6.4 
Efficacy .................................................................................................................. 51 
6.4.1 
Peak respiratory oxygen uptake (VO2peak) ............................................ 51 
 
 52 
 
 53 
6.4.4 
Appropriateness of efficacy assessments .............................................. 53 
6.5 
Safety ..................................................................................................................... 53 
6.5.1 
Physical examination ............................................................................ 54 
6.5.2 
Vital signs.............................................................................................. 54 
6.5.3 
Height and weight and waist hip circumference ................................... 54 
6.5.4 
Laboratory evaluations .......................................................................... 54 


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6.5.5 
Electrocardiogram (ECG) ..................................................................... 57 
6.5.6 
Pregnancy and assessments of fertility ................................................. 57 
6.5.7 
Angioedema .......................................................................................... 57 
6.5.8 
Cognitive impairment ............................................................................ 58 
6.5.9 
Statin-related Events ............................................................................. 58 
6.5.10 
Appropriateness of safety measurements .............................................. 58 
6.6 
Other assessments .................................................................................................. 58 
 
 58 
6.6.2 
Blood pressure home measurements ..................................................... 59 
6.6.3 
Pharmacokinetics .................................................................................. 60 
6.6.4 
Pharmacogenetics/pharmacogenomics ................................................. 60 
6.6.5 
Other biomarkers ................................................................................... 60 
7 
Safety monitoring .............................................................................................................. 60 
7.1 
Adverse events ....................................................................................................... 60 
7.2 
Serious adverse event reporting ............................................................................. 62 
7.3 
Liver safety monitoring ......................................................................................... 63 
7.4 
Pregnancy reporting ............................................................................................... 63 
7.5 
Prospective suicidality assessment ........................................................................ 64 
8 
Data review and database management ............................................................................. 64 
8.1 
Site monitoring ...................................................................................................... 64 
8.2 
Data collection ....................................................................................................... 64 
8.3 
Database management and quality control ............................................................ 65 
8.4 
Data Monitoring Committee .................................................................................. 65 
8.5 
Adjudication Committee ........................................................................................ 65 
9 
Data analysis ...................................................................................................................... 66 
9.1 
Analysis sets .......................................................................................................... 66 
9.2 
Patient demographics and other baseline characteristics ....................................... 66 
9.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................ 66 
9.4 
Analysis of the primary and key secondary variable(s) ......................................... 67 
9.4.1 
Variable(s) ............................................................................................. 67 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 67 


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9.4.3 
Handling of missing values/censoring/discontinuations ....................... 67 
9.4.4 
Supportive analyses ............................................................................... 67 
9.5 
Analysis of secondary variables ............................................................................ 67 
9.5.1 
Efficacy variables .................................................................................. 67 
9.5.2 
Safety variables ..................................................................................... 68 
9.5.3 
Resource utilization ............................................................................... 69 
 
 69 
9.5.5 
Pharmacokinetics .................................................................................. 69 
9.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 69 
9.5.7 
Biomarkers ............................................................................................ 69 
9.5.8 
PK/PD ................................................................................................... 69 
9.6 
Interim analyses ..................................................................................................... 69 
9.7 
Sample size calculation.......................................................................................... 69 
10 Ethical considerations ........................................................................................................ 69 
10.1 
Regulatory and ethical compliance ........................................................................ 69 
10.2 
Informed consent procedures ................................................................................. 70 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 70 
10.4 
Publication of study protocol and results............................................................... 70 
11 Protocol adherence ............................................................................................................ 71 
11.1 
Protocol Amendments ........................................................................................... 71 
12 References ......................................................................................................................... 72 
13 Appendix 1: Clinically notable laboratory values ............................................................. 74 
14 Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than or 
equal to 5.3 mmol/L) ......................................................................................................... 75 
15 Appendix 3: Guidelines for the management of blood pressure ....................................... 76 
16 Appendix 4: Guidelines for the management of renal dysfunction ................................... 76 
 77 
 83 
19 Appendix 7: Liver event definitions and follow-up requirements .................................... 87 
 


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List of tables 
Table 1-1 Weber classification of CHF .................................................................................... 22 
Table 3-1 Minimum required pre-study daily doses of commonly prescribed ACEIs and ARBs
 .................................................................................................................................................. 26 
Table 3-2 Safety monitoring criteria that must be met at Visit 1 (screening) and Visit 3 
(randomization) ........................................................................................................................ 26 
Table 5-1 Study drug dispensed during the double-blind period ............................................. 40 
Table 5-2 Prohibited treatment ................................................................................................. 44 
Table 6-1 Assessment schedule ................................................................................................ 48 
Table 6-2 Routine laboratory examination ............................................................................... 56 
Table 19-1 Liver event definitions ........................................................................................... 87 
Table 19-2 Liver event follow up requirements ....................................................................... 88 
 
List of figures 
Figure 3-1 Study design ............................................................................................................ 24 
 


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List of abbreviations 
ACE 
angiotensin converting enzyme 
ACEI(s) 
angiotensin converting enzyme inhibitor(s) 
AE(s) 
adverse event(s) 
AF 
atrial fibrillation 
AHU377 
pro-drug that is metabolized to the active moiety LBQ657 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance model 
ANP 
atrial natriuretic peptide 
APP 
aminopeptidase P 
ARB(s) 
angiotensin receptor blocker(s) 
ARNi(s) 
angiotensin receptor neprilysin inhibitor(s) 
AST 
aspartate aminotransferase 
AT1 
angiotensin type 1 
AUC 
area under the curve 
bid 
twice a day 
BP 
blood pressure 
CCB 
Calcium channel blockers 
CHF 
chronic heart failure 
CPET 
cardiopulmonary exercise testing 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CRT-D 
cardiac resynchronization therapy defibrillator 
CRT-P 
cardiac resynchronization therapy pacemaker 
CSR 
Clinical Study Report 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DS&E 
Drug Safety and Epidemiology 
EC(s) 
Ethics Committee(s) 
ECG 
electrocardiogram 
eCRF 
electronic case report form 


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EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
 
 
ER 
emergency room 
ESRD 
end stage renal disease 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction  
 
 
IA 
interim analysis(es) 
ICD 
implantable cardioverter defibrillator 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IFCC 
International Federation of Clinical Chemistry and Laboratory Medicine 
IRB(s) 
Institutional Review Board(s) 
IRT 
Interactive Response Technology 
i.v. 
intravenous(ly) 
IVRS 
Interactive Voice Response System  
 
 
LBW 
Lean Body Weight  
LCZ696 
Novartis compound code 
LFT 
Liver function test 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MET  
metabolic equivalent of task 
mg 
milligram 
MI 
myocardial infarction 
mmHg 
millimeter mercury 
mph 
mile per hour 
MRI 
magnetic resonance imaging 


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MUGA 
multiple gate acquisition scan 
NEP 
neutral endopeptidase 
NODM 
new onset diabetes mellitus 
NP(s) 
natriuretic peptide(s) 
NYHA 
New York Heart Association 
o.d. 
once a day 
PK 
pharmacokinetic(s) 
p.o. 
oral(ly) 
PCI 
percutaneous coronary intervention 
PRA 
plasma renin activity 
RAAS 
renin angiotensin aldosterone system 
REB 
Research Ethics Board 
RER 
respiratory exchange ratio 
SAE(s) 
serious adverse event(s) 
SBP 
systolic blood pressure 
 
 
SHF 
systolic heart failure 
UACR 
urinary albumin to creatinine ratio 
ULN 
upper limit of normal 
V 
visit 
VAD 
ventricular assistance device 
VAT  
Ventilatory anaerobic threshold 
VO2 
respiratory oxygen uptake 
VO2max 
respiratory oxygen uptake (max.) 
VO2peak 
respiratory oxygen uptake (peak) 
WBC 
White blood cell  
 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Epoch  
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after treatment 
has ended. 
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a fixed 
combination.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage 
Medication number 
A unique identifier on the label of each investigational/study drug package 
in studies that dispense medication using an IRT system 
Subject Number  
A number assigned to each patient who enrolls into the study  
Part  
A subdivision of a single protocol into major design components. These 
parts often are independent of each other and have different populations 
or objectives. For example, a single dose design, a multiple dose design 
that are combined into one protocol, or the same design with different 
patient populations in each part. 
Period 
A subdivision of a cross-over study 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up) 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study/investigational treatment was discontinued whichever is later 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
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 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points 
 


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Protocol synopsis 
 
 Protocol number 
CLCZ696BDE01 
Title 
A randomized, double-blind, active-controlled study to assess the 
effect of LCZ696 compared with enalapril to improve exercise 
capacity in patients with heart failure with reduced ejection 
fraction (HFrEF). 
Brief title 
 
Exercise capacity study of LCZ696 vs. enalapril in patients with 
chronic heart failure and reduced ejection fraction  
Sponsor and Clinical 
Phase 
Novartis  
Phase IV 
Investigation type 
Drug  
Study type 
Interventional  
Purpose and rationale 
Patients with chronic heart failure (CHF) with impaired cardiac 
function and peripheral deconditioning experience a significantly 
reduced ability to exercise, reduced daily physical activity and a 
diminished quality of life. Current pharmacological treatment for 
CHF has so far substantially improved symptoms, hospitalization 
and clinical outcomes but most patients remain symptomatic 
experiencing shortness of breath during daily activity. Therefore, 
there is a demand for therapeutic interventions showing 
improvement in symptoms and exercise capacity with subsequent 
improvement of quality of life in CHF patients.  
Studies have demonstrated that cardiopulmonary exercise testing 
(CPET) could reliably evaluate the exercise tolerance of heart 
failure patients. In addition, parameters attained by CPET have 
shown to provide very reliable parameters for predicting prognosis. 
There is sound evidence including VO2peak in stratifying the risk in 
patients with CHF. In addition, exercise parameters assessed by 
CPET are not only associated with prognosis, but are all associated 
with the severity of CHF symptoms and quality of life in CHF 
patients. 
LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) 
being developed for the treatment of CHF. The clinical efficacy of 
LCZ696 in patients with heart failure with reduced ejection fraction 
(HFrEF) has been assessed previously and showed a significant 
benefit over enalapril in reducing cardiovascular death and 
hospitalizations due to HF. 
 
 
 We therefore hypothesize that LCZ696 
will also improve exercise capacity and daily physical activity in 


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Protocol No. CLCZ696BDE01 
HF patients, parameters of immediate relevance to patients 
suffering from HF. 
Primary Objective(s) 
and Key Secondary 
Objective 
To assess the effect of LCZ696 versus enalapril regarding 
improvement of exercise tolerance (VO2peak, adjusted to body 
weight) as assessed by cardiopulmonary exercise testing (CPET) in 
patients with chronic heart failure (NYHA class III, left ventricular 
ejection fraction (LVEF ≤40%). 
Key secondary objective: To assess the early effect (6 weeks) of 
LCZ696 versus enalapril regarding improvement of exercise 
tolerance (VO2peak, adjusted to body weight) as assessed by 
cardiopulmonary exercise testing (CPET) in patients with chronic 
heart failure (NYHA class III, LVEF ≤40%). 
Secondary Objectives 
 
To assess the long-term effect of LCZ696 versus enalapril on the 
following CPET parameters: 
 Change of VE/VCO2 slope after 6 weeks and 3 months  
 Change in exercise capacity (Watt) at ventilatory 
anaerobic threshold (VAT) after 6 weeks and 3 months  
 Change in rate of perceived exertion during exercise 
(Borg Scale) after 3 months  
Study design 
This is a randomized, double-blind, active-controlled parallel 
grouped study to assess the effect of LCZ696 compared with 
enalapril to improve exercise capacity, daily physical activity and 
quality of life in patients with stable chronic heart failure (NYHA 
class III) with reduced ejection fraction (LVEF ≤ 40 %), within a 
duration of 3 months. 
Population 
Patients with CHF (NYHA class III) and reduced ability to exercise, 
evidenced by VO2peak ≤ 18 ml/min per kg, aged 18 years or older 
with LVEF ≤ 40%. The target projected sample size is 200 patients 
(100 patients in each arm). It is estimated that approximately 400 
patients will be screened at up to approximately 40 study sites 
because a screen failure rate of approximately 50 % is anticipated 
based on previous experience. 
Inclusion criteria 
 Patients must give written informed consent before any 
assessment is performed and must be willing and capable to 
comply with all study procedures. 
 Outpatients ≥ 18 years of age, male or female. 
 Patients with a diagnosis of CHF NYHA class III and reduced 
ejection fraction (LVEF ≤ 40%) 
 Reduced ability to exercise, evidenced by VO2peak ≤ 18 ml/min 
per kg 


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Protocol No. CLCZ696BDE01 
 Patients must be on an ACEI or an ARB at a stable dose of at 
least enalapril 10 mg/d or equivalent for at least 4 weeks before 
Visit 1 
Exclusion criteria 
 History of hypersensitivity or allergy to any of the study drugs, 
drugs of similar chemical classes, ACEIs, ARBs, or NEP 
inhibitors as well as known or suspected contraindications to 
the study drugs 
 Previous history of intolerance to recommended target doses of 
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 at Visit 3 (randomization) 
 Estimated GFR < 30 mL/min/1.73m2 as measured by the 
simplified MDRD formula at Visit 1 (screening), or Visit 3 
(randomization)  
 Serum potassium > 5.2 mmol/L at Visit 1 (screening) or at Visit 
3 (randomization) 
 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 
 Patients with severe obesity (Adipositas permagna – BMI ≥ 40) 
 Pregnant or nursing (lactating) women 
Investigational and 
reference therapy 
 LCZ696 200 mg bid 
 Enalapril 10 mg bid 
Efficacy assessments 
Primary assessment: 
• change of VO2peak compared to baseline measurements 
(adjusted to body weight) after 3 months  
Secondary assessments: 
• change of VO2peak compared to baseline measurements 
(adjusted to body weight) after 6 weeks of treatment 


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• Change of VE/VCO2 slope after 6 weeks and 3 months of 
treatment 
• Change in exercise capacity (Watt) at ventilatory anaerobic 
threshold (VAT) after 6 weeks and 3 months of treatment 
• Change in rate of perceived exertion during exercise (Borg 
Scale) after 3 months of treatment 
Safety assessments 
• AEs and SAEs 
• Sitting systolic (SBP) and sitting diastolic BP (DBP)  
• Symptomatic hypotension 
• Angioedema 
• Laboratory values  
• Hyperkalemia 
• Renal dysfunction 
Other assessments 
 
Data analysis 
Conservatively assuming a standard deviation of 3 ml/min/kg and a 
two-sided alpha of 0.05, 86 patients per arm would confer a 90% 
power to detect a treatment difference of 1.5 ml/min/kg. Correcting 
for expected drop-out of patients, approximately 100 patients per 
treatment group (200 in total) will need to be enrolled in the trial.  


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Key words 
Heart failure, NYHA class III, VO2peak, Exercise capacity, 
ventilatory anaerobic threshold, VE/VCO2 slope, ergospirometry, 
cardiopulmonary exercise testing (CPET), 
 
 


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Amendment 4 
Amendment Rationale 
This amendment was implemented to improve comparability of the primary and secondary 
endpoints with other studies using cardiopulmonary exercise testing (CPET) as an outcome 
measure in heart failure trials (Keteyan et al., 2016; Akbulut et al., 2006; Arena and Sietsema, 
2011).  
1) Substituting “VO2peak adjusted by lean body weight (VO2peak/LBW)” by “VO2peak adjusted 
by whole body weight” (VO2peak/kg): 
  This amendment affects the primary endpoint “Change of VO2peak compared to baseline 
measurements (adjusted to body weight) after 3 months” and the secondary endpoint 
“Change of VO2peak compared to baseline measurements (adjusted to body weight) after 6 
weeks of treatment”. As most of the heart failure trials investigated VO2peak/kg instead of 
VO2peak/LBW, we changed this accordingly.   
 
 
 
 
 
 
  
3) Substituting RER = 1 by ventilatory anaerobic threshold (VAT): 
This amendment affects the secondary endpoint “Exercise capacity (Watt) at RER = 1 
(RER=VCO2/VO2)” 
 
. VAT is the gold standard of submaximal exercise capacity comparable 
to daily activities and therefore more valid and reliable than RER=1. Furthermore, it is a 
strong prognostic marker to identify patients at high risk for adverse events (Gitt et al. 2002).  
In addition, minor changes were made to correct inconsistencies within the study protocol.  
Changes to the protocol  
 The term “lean body weight” was changed to “body weight” throughout the protocol and 
therefore the primary (adjusted VO2peak after 3 months of treatment) and secondary endpoint 
(adjusted VO2peak after 6 weeks of treatment) are altered  
 RER=1 was exchanged to VAT for the secondary endpoint “Exercise capacity (Watt)” 
 
  
 
    
 Minor changes to other sections (pages 8, 12, 27, 29, 30, 31, 67 and 69)  


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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. 
References: 
 Keteyian SJ, Patel M, Kraus WE, et al. (2016). Variables Measured During 
Cardiopulmonary Exercise Testing as Predictors of Mortality in Chronic Systolic Heart 
Failure. J Am Coll Cardiol., 67(7):780–789. doi:10.1016/j.jacc.2015.11.050 
 Akbulut T, Akgöz H, Dayi ŞÜ, Çelik SE, Gürkan U, & Tayyareci G (2006). Evaluation of 
Enalapril+Losartan Treatment with Cardiopulmonary Exercise Test in Patients with Left 
Ventricular Dysfunction. Angiology, 57(2):181–186. 
 
https://doi.org/10.1177/000331970605700207 
 Arena R and Sietsema KE (2011). Cardiopulmonary Exercise Testing in the Clinical 
Evaluation of Patients With Heart and Lung Disease. Circulation, 123:668-680. 
https://doi.org/10.1161/CIRCULATIONAHA.109.914788 
 Gitt AK, Wasserman K, Kilkowski, C, Kleemann T, Kilkowksy A, Bangert M, Schneider 
S, Schwarz A & Senges J (2002). Exercise Anaerobic Threshold and Ventilatory Efficiency 
Identify Heart Failure Patients for High Risk of Early Death. Circulation, 103:3079-3084. 


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Protocol No. CLCZ696BDE01 
Amendment 3 
 
Amendment Rationale  
This Amendment was introduced as consequence of changes in the drug supply, so that enalapril 
5 mg and 10 mg tablets which were provided in blister packs, will be provided in HDPE bottles, 
as enalapril 2.5 mg tablets already were. There will be a transition time where both versions of 
packaging are possible, thus both versions are reflected in this protocol version. 
Changes to the protocol 
In section 5.1.1 ‘Investigational treatment’, the primary packaging of enalapril 5 mg and 10 mg 
tablets is updated.  
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. 


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Protocol No. CLCZ696BDE01 
Amendment 2 
Amendment Rationale  
This Amendment was introduced as consequence of experiences made during the recruitment 
period of the first patients. Recruitment of patients eligible for the study is slow and patients are 
hard to identify. The specific patients with more severe chronic heart failure (NYHA III) mostly 
have a number of comorbidities that fulfill exclusion criteria. Thus, all inclusion and exclusion 
criteria were reviewed.  
More symptomatic patients (NYHA III) tend to more often have a device (ICD/CRT) or are 
treated with amiodarone which both artificially prolong the QT interval without posing 
pathology or qualifying as true long QT syndrome. From the LCZ696 program it is known, that 
in a thorough QTc clinical study in healthy male subjects, single doses of 400 mg and 1200 mg 
LCZ696 had no effect on cardiac repolarization. Additionally, the SmPC of the marketed 
product does not include any specific effects or warnings of LCZ696 on QTc time. Therefore, 
the respective exclusion criterion was modified excluding only patients with long QT syndrome. 
Patients for whom a heart transplantation or a ventricular assist device implantation is planned 
are excluded, since this significant procedure would considerably impact the study endpoint. 
However, patients need only to be excluded if it is very likely that these procedures are 
necessary throughout the study. Since the study duration of 14 weeks (including screening 
period) is rather short this exclusion criterion was reworded to account for this.  
To assess the efficacy endpoints investigated in this study, it is necessary to evaluate the chronic 
HF patients and its baseline characteristics and to perform baseline assessments in a stable state 
of the chronic disease. Thus, all medications prescribed for treatment of HF are to be stable 4 
weeks prior to inclusion of the patient, more specifically, prior to the baseline assessments. 
Throughout the study, to evaluate the effect of LCZ696 vs. comparator, all other disease 
modifying agents should be kept on a stable dose, if possible. Thus, those medications have to 
be stable 4 weeks prior to the screening visit and until randomization visit. After randomization, 
all efforts should be made to keep the dose stable, This is clarified in the protocol. 
Additionally, minor changes are made to be consistent throughout the protocol.  
Changes to the protocol 
The described changes in the amendment rationale are implemented throughout the protocol: 
 Exclusion criterion 13 is adapted to clarify that only a planned transplantation of heart or 
VAD during the expected study duration of 14 weeks is excluded. 
 Exclusion criterion 31 is updated to only exclude a diagnosed long QT syndrome. 
 In Section 5.5.8 ‘Other concomitant medication’, it is explicitly stated that concomitant HF 
medication should be stable 4 weeks prior to screening Visit 1 and until randomization Visit 
3.  
 In Section 3, investigational plan, it is clarified, that 36 hour wash-out period is necessary 
for ACEI, but not for ARB. This is to be consistent throughout the protocol.  
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. 


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Protocol No. CLCZ696BDE01 
Amendment 1 
Amendment Rationale  
CLCZ696BDE01 Protocol Amendment 1 clarifies that if during the double-blind treatment 
period the initiation of prohibited concomitant medication is necessary, study drug has to be 
discontinued. Especially due to increased risk of angioedema, concomitant application of ACEI 
is strictly prohibited and an at least 36 hour wash-out period is mandatory. Thus, the protocol 
is amended to clearly define that as long as the discontinued study medication is blinded in any 
case the 36 hours washout with regard to contraindicated concomitant medication ACEI must 
be followed. It is clarified that for prohibited treatment ARBs study drug has to be discontinued 
but no additional wash-out period is necessary. This is now consistent throughout the protocol 
and in line with current safety data.  
Changes to the protocol 
The described changes in the amendment rationale are implemented throughout the protocol: 
 Section 5.5.8 Other concomitant treatment –ACEIs and ARBs – is reworded to clearly state 
that both ACEI and ARB are prohibited during treatment with double-blind study 
medication. If ACEI and/or ARB are initiated, study medication has to be discontinued. It 
is clarified, that 36 hour wash-out period is necessary for ACEI, but not for ARB.  
 In Section 5.5.10, the use of prohibited treatment during the study will now require to stop 
study medication. The mandatory wash-out period for ACEI is explicitly mentioned.  


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1 
Introduction 
1.1 
Background  
The prevalence of chronic heart failure (CHF) is steadily increasing and remains a major cause 
of morbidity and mortality in the Western world. Because of impaired cardiac function and 
peripheral deconditioning patients with CHF experience a significantly reduced ability to 
exercise, directly leading to reduced daily physical activity and a dramatically diminished 
quality of life. Long before clinical outcomes, patients with CHF experience inability to perform 
exercise without discomfort as one of the first clinical symptoms. It is often the initial reason 
for seeking medical care and a central target for treatment. Current pharmacological treatment 
for CHF has so far substantially improved symptoms, hospitalization and clinical outcomes. 
However, most patients remain symptomatic particularly experiencing shortness of breath 
during daily activity. This issue remains an urgent challenge in the development of future 
therapeutic strategies in these patients. Therefore, given this background, there is a definite and 
high demand for therapeutic interventions showing improvement in symptoms and exercise 
capacity with subsequent improvement of quality of life in these patients (Belardinelli et al. 
1999). 
Cardiopulmonary exercise testing (CPET) is an established method to reliably evaluate the 
exercise tolerance of heart failure patients by evaluating the cardio-pulmonary system using the 
measurement of respiratory gases during physical (exercise) stress. In addition, parameters 
attained by this test have shown to provide very reliable parameters for predicting prognosis. 
The most important measurements acquired during cardiopulmonary exercise testing are 
respiratory oxygen uptake (VO2), carbon dioxide production (VCO2), and ventilatory measures 
(Albouaini et al. 2007). Respiratory oxygen uptake reflects the cellular O2 demand up to a level 
that equates to maximal rate of O2 transport limited by cardiocirculatory, pulmonary and 
peripheral function. As response to increasing exercise load VO2 increases reaching a plateau, 
called VO2max. In a clinical setting, patients are often unable to reach this plateau because of 
symptom limitation. Then peak VO2max is termed VO2peak. There is sound evidence for VO2peak 
in stratifying the risk in patients with CHF and prognostic value for patients with CHF (Corrà 
et al. 2004; Mancini et al. 1991). An adjustment of VO2peak to body weight could provide an 
even better prognostic value in these patients (Osman et al. 2000). Moreover of significant 
prognostic value seem to be the ventilatory expired gas parameters, namely minute ventilation 
(VE) to carbon dioxide output slope (VE/VCO2). Likewise, various studies have demonstrated 
that an abnormally high VE/VCO2 ratio resembling the inability to eliminate CO2 by respiration 
is associated with a poor outcome in patients with CHF. In addition, these exercise parameters 
are not only associated with prognosis, but are all associated with the severity of CHF symptoms 
and quality of life in CHF patients. The Weber classification for CHF (Table 1-1) indicates 
increasing disease severity from Class A through Class D and correlates subjective symptom 
severity levels with the measure of oxygen consumption VO2max. Data suggest a moderate risk 
of cardiac events in patients with VO2peak between 10 and 18 mL/kg/min. 
CPET will be performed to assess VO2peak. The test protocol was selected according to the 
purpose of testing and the patient population in the current study. CPET is evaluated according 
to the modified Naughton protocol as recommended for treadmill exercise in patients with CHF 
(Fletcher et al. 2013) which provides a moderate increase in workload between stages and is 
thus a useful choice for elderly, deconditioned patients like patients with CHF and NYHA class 


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Protocol No. CLCZ696BDE01 
III. Based on this protocol, the workload will start at 10W and will be increased by 10W for 
each 1-minute stage. 
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for 
the treatment of patients with CHF. The clinical efficacy of LCZ696 in heart failure with 
reduced ejection fraction (HFrEF) patients has been assessed in the LCZ696B2314 
PARADIGM-HF study (McMurray et al. 2013). LCZ696 showed a significant benefit over 
enalapril in reducing cardiovascular death and hospitalizations due to HF as well as all-cause 
mortality (McMurray et al. 2014). 
 
 
 We therefore hypothesize that 
LCZ696 will also improve exercise capacity and daily physical activity in HF patients, 
parameters of immediate relevance to patients suffering from HF.  
Table 1-1 Weber classification of CHF 
Class 
Severity level 
VO2 max (ml/min/kg) 
Cl max (l/min/m2)  
A 
Mild/none 
>20 
>8 
B 
Mild to moderate 
16-20 
6-8 
C 
Moderate to severe 
10-16 
4-6 
D 
Severe 
6-10 
2-4 
E 
Very severe 
<6 
<2 
 
1.2 
Purpose  
The purpose of this study is to evaluate the effect of LCZ696 on daily physical activity and 
quality of life by improving exercise capacity in patients with stable CHF and reduced ejection 
fraction. Data from this study are intended to provide further understanding of the early impact 
of LCZ696 treatment on CHF patients with regard to other patient related outcomes. Data are 
also intended for publication. 
2 
Study objectives 
2.1 
Primary objectives 
The primary objective of this study is to demonstrate the superiority of LCZ696 200 mg bid 
compared to enalapril 10 mg bid in improving exercise tolerance (VO2peak, adjusted to body 
weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with stable chronic 
heart failure (NYHA class III) and reduced ejection fraction (LVEF ≤ 40%) after 3 months 
treatment. 
2.2 
Secondary objectives 
Secondary objectives of this study are 
 
To demonstrate the superiority LCZ696 versus enalapril regarding improvement of 
exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary 
exercise testing (CPET) in patients with chronic heart failure after 6 weeks treatment. 


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Protocol No. CLCZ696BDE01 
 
To compare LCZ696 versus enalapril on the following CPET parameters: 
 
Change of  VE/VCO2 slope after 6 weeks and 3 months  
 
Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months  
 
Rate of perceived exertion during exercise (Borg Scale) after 3 months  
 
To assess the safety and tolerability of LCZ696 in patients with stable chronic heart 
failure with NYHA class III and reduced ejection fraction (LVEF ≤ 40%)  


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3 
Investigational plan 
3.1 
Study design 
Figure 3-1 Study design 
 
This study is a randomized, double-blind, double-dummy, parallel-group, active-controlled, 
two-arm trial to compare LCZ696 200 mg bid to enalapril 10 mg bid in improving exercise 
capacity, daily physical activity and quality of life in patients with stable CHF (NYHA III) and 
reduced ejection fraction (LVEF ≤ 40%). 
Eligible patients at stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks 
before Visit 1 and LVEF ≤ 40% can be randomized at Visit 3. β-blocker, ivabradine and 
aldosterone antagonist therapy should be at a stable dose for 4 weeks prior to Visit 1. Please 
refer to Section 4 Population for a full list of inclusion and exclusion criteria.  
VO2peak inclusion criterion will only be checked after assessment of patients’ eligibility 
according to all other inclusion and exclusion criteria. Thus, ergospirometry will be performed 
on Visit 2 to get a complete assessment of CPET (for screening), 
 
  
Once patients’ eligibility has been ascertained, they will attend Visit 3 for randomization 
approximately two weeks after Visit 1 to start enalapril 5 mg bid versus LCZ 100 mg bid for 2 
weeks. All efficacy assessments collected at Visit 2 will be used as baseline values. 
Before dispensing of study treatment, a valid baseline efficacy assessment of CPET must be 
performed including central plausibility and quality check.  
At baseline, all eligible patients will be randomized to receive either LCZ696 or enalapril in a 
1:1 allocation during the double-blind period.  
Treatment will be initiated with enalapril 5 mg bid (enalapril 10 mg bid for patients with a dose 
above enalapril 10 mg/d or equivalent prior Visit 1) or LCZ696 100mg bid, respectively. Dose 


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will be up-titrated after 2 weeks to the final dose of enalapril 10mg bid or LCZ696 200mg bid. 
For allowed investigational treatment dose adjustments during double-blind period refer to 
Section 5.5.5. 
Patients should continue to take their background medications for CHF during the study, with 
the exception of ACEI or ARBs which are replaced by investigational treatment and must be 
discontinued before first application of study drug (washout period of 36 hours applies to ACEI, 
compare Section 5.5.8). First application of study drug is planned on the day after Visit 3; last 
intake of ACEI or ARB before study drug application thus will be in the evening prior to Visit 
3 (randomization) (If Visit 3 is scheduled for Wednesday e.g., last ACE or ARB medication 
should be taken by the patient on Tuesday evening. The patient will then start to take the first 
dose of LCZ696 or enalapril double blind medication on Thursday morning.).  
 
 
 
 
 
 
  
Tolerability to study treatment will be checked at every visit after randomization. Please refer 
to Section 5.5.5 for allowed study drug adjustments during the study. 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, if they are believed to be the 
cause of the AE such as hyperkalemia, hypotension, and renal dysfunction, in an attempt to 
allow patients to meet the safety criteria in Table 3-2. The dose of background disease 
modifying drugs, such as β-blockers, ivabradine and aldosterone antagonists, may be reduced 
to facilitate maintenance of study drug if they are believed to be the cause of the adverse effect 
in question. If necessary, in doubt patients will be titrated down to the next lower dose level of 
study medication twice a day as described in Section 5.5.5, at the investigator’s discretion, based 
on the defined safety and tolerability criteria (Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4). The reason for medication modification must be carefully documented in the 
appropriate eCRFs. 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. 
After randomization, temporary study drug discontinuation for any reason does not 
automatically constitute withdrawal from the study and should not lead to the patient being 
withdrawn from the study. Patients should be re-challenged to receive study treatment 
according to guidance in Section 5.5.5.  
Please refer to Table 6-1 for a detailed list of study procedures and assessment to be performed 
at each double-blind period visit. Regardless of the occurrence of any unscheduled visits, 
scheduled visits must occur within the timeframe of -3/+3 days to the visits outlined in Table 
6-1. 
Of note, all appointments shall be scheduled in the morning if possible. Otherwise all 
appointments at all study days shall be performed at about same time. 


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All laboratory evaluations for planned visits and also for unscheduled visits will be performed 
by the central laboratory. Thus, at Visit 3 and 4, patients should come to the site 3 to 4 days 
prior to the scheduled visit date for blood draw only so that results from central laboratory are 
available and enable a competent decision on randomization or up-titration at the respective 
visits. 
Visit 1 (Screening) 
At Visit 1 (day -14) patients will be checked for eligibility. Inclusion and exclusion criteria will 
be checked for all patients. Eligible patients at least at a stable dose of enalapril 10 mg (or 
equivalent ACE or ARBs according to Table 3-1) 4 weeks prior to Visit1 can be randomized at 
Visit 3 (day 1).  
Table 3-1 Minimum required pre-study daily doses of commonly prescribed ACEIs and ARBs 
ACEIs  
Minimum dose 
ARBs 
Minimum dose 
Enalapril  
10 mg 
Candesartan 
16 mg 
Benazepril 
20 mg 
Eprosartan 
400 mg 
Captopril 
100 mg 
Irbesartan 
150 mg 
Cilazapril 
2.5 mg 
Losartan 
50 mg 
Fosinopril 
20 mg 
Olmesartan 
10 mg 
Lisinopril 
10 mg 
Telmisartan 
40 mg 
Moexipril 
7.5 mg 
Valsartan 
160 mg 
Perindopril 
4 mg 
 
 
Quinapril 
20 mg 
 
 
Ramipril 
5 mg 
 
 
Trandolapril 
2 mg 
 
 
Zofenopril 
30 mg 
 
 
 
Table 3-2 Safety monitoring criteria that must be met at Visit 1 (screening) and Visit 3 (randomization) 
Parameter 
Visit 1 (screening) and Visit 3 (randomization) 
 
Potassium level 
K ≤ 5.2 mmol/L 
 
Kidney function 
eGFR ≥ 30 mL/min/1.73m2 
 
Blood pressure 
No symptomatic hypotension and SBP ≥ 100 mmHg 
 
Adverse events (AEs) or 
conditions 
No postural symptoms or any conditions that preclude 
continuation according to the investigator’s judgment 
 
Patients will be asked to sign an informed consent form prior to performing any study-related 
procedures. For a full list of inclusion and exclusion criteria see Section 4 Population.  
Complete physical examination is required at Visit 1. Any local measurement of LVEF made 
within the past 6 months using echocardiography, multiple-gated acquisition (MUGA), CT 
scanning, MRI or ventricular angiography will be acceptable, provided no subsequent 
measurement above 40%. If a patient has an implanted cardiac resynchronization therapy 
device, the LVEF values used to qualify for the study must be obtained after the implantation 
of that device by at least three months. Screening potassium levels and eGFR will be assessed 
by sending blood samples to the central laboratory and only patients with the required values 
per entry criteria will be eligible for entering the study. Since it may take up to 72 hours to 


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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 2 approximately 5 days after 
Visit 1 and Visit 3 approximately two weeks after Visit 1.  
Detailed HF history and other relevant CV medical history will be recorded on eCRFs 
separately from other medical history. 
Screening ECG performed within the 6 months before Visit 1 is accepted, otherwise ECG 
evaluation must be performed at Visit 1 for safety reasons. 
Visit 2 (-9 d) 
Visit 2 is performed to get a complete laboratory assessment by the central lab and assessment 
of CPET to verify inclusion criterion of VO2peak including a quality evaluation of CPET in time 
before randomization. All efficacy assessments will be collected at this visit as well to ascertain 
a similar schedule of all visits with efficacy assessments.  
Blood draw for lab assessments will be done.  
 
 
Ergospirometry will be performed at Visit 2 for assessment of eligibility of VO2peak according 
to provided separate manual. The details of the procedure will be outlined in a manual provided 
to all participating sites. Patients will be under continuous ECG and frequent blood pressure 
monitoring.  
 
 
 
Plausibility and quality checks of the ergospirometry data will be done by a reading center. If 
ergospirometry data acquisition fails for any reason, it may be repeated one day later. Study 
medication dispense at Visit 3 can only be done with a valid ergospirometry measurement. 
 
 
Patients should be reminded to come without taking their usual ACEI or ARB to Visit 3 to 
ascertain a wash-out period of 36 hours for ACEI before first application of investigational 
treatment. 
 
 
 
 
 
  
 
 


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Visit 3 (Randomization) 
At Visit 3 all patients who meet all entry criteria, including the required clinical laboratory 
values, and meet the safety criteria in Table 3-2, will be randomized to one of the two treatment 
arms enalapril bid or LCZ bid add on to their current heart failure therapy.  
Patients should have discontinued their ACE/ARB medical therapy in the evening before Visit 
3 in order to start study drug in the morning one day later. (If Visit 3 is scheduled for e.g. 
Wednesday, last ACE or ARB medication should be taken by the patient on Tuesday evening. 
The patient will then start to take the first dose of LCZ696 or enalapril double blind medication 
on Thursday morning.). If the patient continued to take their usual ACEI, the start of study drug 
has to be postponed to assure a 36 hour washout before first application of study drug. 
Patients will start study treatment at dose level 2 or 2a according to their ACE/ARB-treatment 
prior to study (refer to Section 5.5.4 for details) and must be stabilized on this dose for 2 weeks. 
To ascertain patient’s eligibility, study drug should not be dispensed unless laboratory 
assessments of potassium and eGFR are available and meet the safety criteria (see Table 3-2).  
Study medication dispense can only be done with a valid ergospirometry measurement. 
 
Visit 4 (+ 2 weeks; up-titration visit) 
After 2 weeks of treatment at Visit 4, patients will be checked for tolerability and will be up-
titrated to target dose level 3 (LCZ 200 mg bid; enalapril 10 mg bid). Therefore symptomatic 
hypotension, renal dysfunction and/or hyperkalemia are considered to be safety parameters and 
should be handled according to respective guidelines for management (Appendix 1, Appendix 
2 Appendix 3, and Appendix 4).  
Blood draw for lab assessments has to be done. In case of lab deviations an unscheduled visit 
may be scheduled at the discretion of the investigator to re-assess lab parameters and evaluate 
the efficacy of taken measures. Please refer to Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4, respectively, for guidance on handling hyperkalemia, hypotension, and renal 
dysfunction.  
Visit 5 (+4 weeks) 
After 2 weeks of treatment on level 3 study medication, patients will be checked for tolerability 
at Visit 5. Every attempt should be made to keep the patients stable on level 3 throughout the 
whole study in accordance with all safety parameters (e.g. symptomatic hypotension, renal 
dysfunction and /or hyperkalemia).  
 
  
 
 
 
Blood draw for lab assessments (abbreviated chemistry panel) has to be done. In case of lab 
deviations an unscheduled visit may be scheduled at the discretion of the investigator to re-


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assess lab parameters and evaluate the efficacy of taken measures. Please refer to Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4, respectively, for guidance on handling hyperkalemia, 
hypotension, and renal dysfunction.  
Visit 6 (+6 weeks) 
After 6 weeks of treatment, patients will be checked for tolerability at Visit 6. Every attempt 
should be made to keep the patients stable on level 3 in accordance with all safety parameters 
(e.g. symptomatic hypotension, renal dysfunction and /or hyperkalemia).  
 
  
  
 
 
 
 
 
Ergospirometry will be performed at Visit 6 (according to a separate manual). Patients will be 
under continuous ECG and frequent blood pressure monitoring.  
 
 
Plausibility and quality checks of the ergospirometry data will be done by a reading center. If 
ergospirometry data acquisition fails for any reason, it may be repeated one day later.  
 
 
Blood draw for lab assessments (abbreviated chemistry panel) has to be done. In case of lab 
deviations an unscheduled visit may be scheduled at the discretion of the investigator to re-
assess lab parameters and evaluate the efficacy of taken measures. Please refer to Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4, respectively, for guidance on handling hyperkalemia, 
hypotension, and renal dysfunction.  
Visit 7 (+3 months; EOS) 
After 3 months of treatment, a final assessment of patients for tolerability at Visit 7 is 
performed.  
 
  
  
Ergospirometry will be performed at Visit 7 (according to separate manual). Patients will be 
under continuous ECG and frequent blood pressure monitoring.  


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Plausibility and quality checks of the ergospirometry data will be done by a reading center. If 
ergospirometry data acquisition fails for any reason, it may be repeated one day later. 
 
 
Blood draw for final laboratory assessments has to be done. 
Unscheduled visits 
In addition to the protocol-required visits, patients may be seen at any time throughout the study 
at the discretion of the investigator to follow any new lab abnormalities or AEs. All randomized 
patients, including any patient who has experienced a health event, should continue to receive 
double-blind treatment until the trial is completed. Unscheduled visits may also be performed 
throughout the study at the discretion of the investigator for up-titration of the study medication. 
3.2 
Rationale of study design 
There is a general agreement that apart from reducing the major fatal and non-fatal 
consequences of HF with a reduced LVEF, i.e., CV death and hospitalization for worsening HF, 
improving exercise capacity, daily physical activity and quality of life is crucial in patients with 
CHF. Thus, measurement of VO2peak (adjusted to body weight) as assessed by cardiopulmonary 
exercise testing (CPET) in patients with chronic heart failure will be the primary endpoint of 
this study. This endpoint is established for assessing activity levels of patients. Moreover, the 
study design is reasonable and adapted from recent studies in treatment of patients with CHF in 
terms of investigational treatment, duration of assessment period and the comparator is 
established as standard of care in those patients. The study design is also in line with all required 
safety assessments and follow-ups for patients with CHF and for the treatment with LCZ696 
and in compliance with the effective risk management plan for the product. Thus, events of 
angioedema, liver events, statin related events, and events of cognitive impairment are followed 
up by targeted questionnaires. Pregnancies during the study are also followed to capture 
outcome. Please refer to Section 6.5 (safety assessments) for further details. Known risks of 
hypotension, renal impairment, and hyperkalemia are closely monitored to prevent severe 
events and are subject to separate guidance should such events occur. Please refer to Sections 
6.5.2 and 6.5.4 for assessments of blood pressure and laboratory assessments, respectively; and 
to Sections 14, 15, and 16 for guidance to manage these risks.  
3.3 
Rationale of dose/regimen, route of administration and duration of 
treatment 
A strong rationale from the PARADIGM data (McMurray et al. 2014) exists for the selection 
of LCZ696 200 mg bid as the target dose. Importantly, a dose of LCZ696 200 mg bid delivers 
similar exposures of valsartan (assessed by AUC) as Diovan® 160 mg bid, the maximal 
approved Diovan® dose for HF and the dose recommended in international guidelines for the 
treatment of HF.  


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In addition, biomarker analysis (increase in ANP and cGMP) indicates that this dose delivers 
approximately 90% of its maximal NEP inhibition. The biomarker data are also consistent with 
results obtained in a dose ranging study in hypertension, which demonstrated additive effects 
of the ARB moiety and the NEPi moiety with LCZ696 400 mg and 200 mg once daily, with a 
minimal incremental BP reduction from LCZ696 200 mg/d to LCZ696 400 mg/d. LCZ696 400 
mg/d and 200 mg/d were well tolerated in this study. 
LCZ696 will be dosed at 200 mg twice daily to ensure sustained NEP inhibition over 24 hours, 
which is thought to be critical for patients with HF. Furthermore, twice daily dosing will also 
mitigate the likelihood of hypotension, particularly in those with more severe HF impairment 
(NYHA class III as chosen in this study). 
The dose regimen is also in accordance with the label of LCZ696.  
With the purpose of this study to demonstrate the superiority of LCZ696 compared to enalapril 
in improving exercise capacity, daily physical activity and quality of life, in patients with CHF 
(NYHA class III) and LVEF ≤ 40 %, we assume an measurable effect of VO2peak (adjusted to 
body weight) after 3 months of treatment. 
3.4 
Rationale for choice of comparator 
Major clinical trials have established ACEI treatment as the standard of care for RAAS blockade 
and to date, treatment guidelines recommend ACEI as the treatment of choice for all patients 
with CHF and reduced LVEF, unless ACEI-intolerant. Since LCZ696 is tested in this study 
according to its label in treatment of patients with CHF, a standard-of-care comparator is 
thought to be most appropriate. 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 OVERTURE (Packer et al. 2002), CONSENSUS (CONSENSUS Trial Study 
Group 1987), SOLVD-Treatment (SOLVD Investigators 1991), and SOLVD-Prevention 
(SOLVD Investigators 1992). 
An enalapril dose of 10 mg bid 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 (SOLVD Investigators 1991).  
The comparator is standard of care in HF indication with established efficacy and safety profile. 
Dose for comparator is according to label and established treatment practice. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
3.6 
Risks and benefits  
Both treatments LCZ696 and Enalapril are approved in the indication investigated within this 
study. Please refer to the corresponding Summary of Product Characteristics (SmPC) of the 
corresponding products as well as the Investigator’s Brochure (IB) for LCZ696 for known 
adverse reactions, or special precautions on both IMPs (provided to all participating sites).  
Patients will be instructed to discontinue any RAAS blockade medications (ACEI or ARB) with 
a 36 hours washout for ACEI before study start treatment with study drug to avoid excess RAAS 


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blockade. The risk of discontinuation of concomitant ACEIs or ARBs will be minimal as it will 
be reflective of the typical dosing schedule of most ACEIs and ARBs.  
All patients will be allowed to continue receiving their other background CV medications.  
The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
close clinical monitoring.  
In women of child-bearing potential, a possible risk of developmental toxicity cannot be 
excluded. Women of child-bearing potential should therefore use a highly effective method of 
contraception during dosing and for 7 days off study medication as described under Section 4.2 
on page 35.  
If there is any question that the patient will not reliably comply, they should not be entered in 
the study. Participating patients will benefit from careful monitoring and follow-up during the 
entire study duration. 
4 
Population 
This is an outpatients multi-center clinical study to be conducted in Germany. It is expected that 
400 patients will be screened in order to randomize 200 patients in about 40 centers in Germany. 
The study population will consist of a representative group of patients with NYHA class III and 
LVEF ≤ 40%. Eligible patients should be on a stable dose of an ACEI or an ARB for at least 4 
weeks before entering into the study. The required minimum doses of pre-study ACEIs and 
ARBs are listed in Table 3-1. 
Patients from up to approximately 40 research sites in Germany will be randomized in a 1:1 
ratio to either LCZ696 200 mg bid or enalapril 10 mg bid. 
The investigator must ensure that all patients who meet the inclusion criteria and do not fulfill 
any of the exclusion criteria are offered enrollment in the study. No additional parameter can 
be applied by the investigator. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Patients must give written informed consent before any assessment is performed and 
must be willing and capable to comply with all study procedures. 
2. Outpatients ≥ 18 years of age, male or female. 
3. Patients with a diagnosis of CHF NYHA class III and reduced ejection fraction: 
 LVEF ≤ 40% at Visit 1 (any local measurement, made within the past 6 months 
using echocardiography, MUGA, CT scanning, MRI or ventricular angiography 
is acceptable, provided no subsequent measurement above 40%) 
4. Reduced ability to exercise, evidenced by VO2peak ≤ 18 ml/min per kg 
5. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or 
equivalent for at least 4 weeks before Visit 1, which have to be discontinued before 
randomization.  


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 For this protocol doses of other ACEIs considered to be equivalent to enalapril 
10 mg/d include benazepril 20 mg/d, captopril 100 mg/d, cilazapril 2.5 mg/d, 
fosinopril 20 mg/d, lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, 
quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d. 
 For this protocol doses of ARBs considered to be equivalent to enalapril 10 mg/d 
include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 
50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d. 
6. Patients must be treated for CHF according to local guideline recommendations and 
should be stable on treatment and dose for at least 4 weeks prior to Visit 1. Treatment 
according to guideline should include:  
 A β-blocker, unless contraindicated or not tolerated, (reason should be 
documented for patients not on CHF target doses per local guidelines, or in 
absence of that medication).  
 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.  
 Ivabradine should also be considered in all patients with heart rates above 70 
beats per minute. If given, the dose of ivabradine should be optimized according 
to guideline recommendations and patient tolerability.  
 Other evidence-based therapy for heart failure should also be considered e.g. 
cardiac resynchronization therapy and an implantable cardioverter-defibrillator 
in selected patients, as recommended by guidelines. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:  
1. Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half-
lives of enrolment, whichever is longer 
2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical 
classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected 
contraindications to the study drugs 
3. Previous history of intolerance to recommended target doses of ACEIs or ARBs 
4. Known history of angioedema 
5. Requirement of treatment with a dual RAAS blockade, e.g. a treatment with both ACEIs 
and ARBs or concomitant treatment with aliskiren 
6. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy) 
7. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening) or at Visit 
3 (randomization) 


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8. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at 
Visit 1 (screening), or Visit 3 (randomization)  
9. Serum potassium > 5.2 mmol/L at Visit 1 (screening) or Visit 3 (randomization) 
10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other 
major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty 
within the 3 months prior to Visit 1 
11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 6 months after Visit 1. 
12. 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 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. 
13. Heart transplant or ventricular assistance device (VAD) or intent to transplant within 
the 14 week study duration (on transplant list with high urgency (HU) status) or to 
implant a VAD. 
14. History or current diagnosis of severe pulmonary disease, including chronic obstructive 
pulmonary disease (COPD). 
15. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 
months prior to Visit 1 
16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 
months prior to Visit 1 
17. Symptomatic bradycardia or second or third degree heart block without a pacemaker 
18. Presence of hemodynamically significant mitral and/or aortic valve disease, except 
mitral regurgitation secondary to left ventricular dilatation 
19. Presence of other hemodynamically significant obstructive lesions of left ventricular 
outflow tract, including aortic and sub-aortic stenosis 
20. 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 
21. Evidence of hepatic disease as determined by any one of the following: AST or ALT 
values exceeding 2 x ULN at Visit 1, severe hepatic insufficiency (classification Child-
Pugh C), biliary cirrhosis, cholestasis (current or anamnestic evidence), history of 
hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt 
22. Active treatment with cholestyramine or colestipol resins 


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23. Presence of any other disease with a life expectancy of < 5 years 
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 (> 5 mIU/mL) 
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 further 7 days. Highly effective contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment.  
In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the sole partner for that 
subject 
 Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository 
 In case of use of hormonal contraception (oral, injected, implanted or IUS) 
women should have been stabile on the same treatment for a minimum of 3 
months before taking study treatment. 
 Women are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six 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.  
26. Presence of bilateral renal artery stenosis. 
27. Patients with thyroidal dysfunction which have not been on a stable dosing of L-thyroxin 
within the last 3 months  
28. Patients with Basedow disease 
29. Patients with severe adipositas (Adipositas permagna – BMI ≥ 40)  


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30. Based on the judgement of the investigator unable to undergo a CPET 
31. Long QT syndrome.  
32. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Double blind treatment 
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 as this will be replaced 
by investigational treatment. The use of an ACEI or an ARB in addition to investigational 
treatment 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) 
 LCZ696 100 mg film-coated tablets (LCZ696 dose level 2; dose level 2a) 
 Placebo to match LCZ696 100 mg film-coated tablets (placebo matching LCZ696 dose level 
2; dose level 2a) 
 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 film-coated tablets (enalapril dose level 1) 
 Placebo to match enalapril 2.5 mg tablets (placebo matching enalapril dose level 1) 
 Enalapril 5 mg film-coated tablets (enalapril dose level 2) 
 Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2) 
 Enalapril 10 mg film-coated tablets (enalapril dose level 3; dose level 2a) 
 Placebo to match enalapril 10 mg tablets (placebo matching enalapril dose level 3, dose 
level 2a) 
Target doses: LCZ696 200 mg bid and enalapril 10 mg bid 
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. 


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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 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 either blister packs or HDPE bottles.  
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
Patients who are eligible for randomization at Visit 3 will be assigned to one of the following 
two treatment arms in a 1:1 ratio bid: 
 LCZ696 bid and placebo to match enalapril bid 
 Enalapril bid and placebo to match LCZ696 bid  
5.3 
Treatment assignment, randomization  
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 randomization list will be produced by or under the responsibility of Novartis Randomization 
Office using a validated system ensuring assignment of treatment arms to randomization 
numbers in the specified ratio.  
At Visit 3, 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 under the supervision of the Novartis Randomization Office 
who provides the Novartis IRT (NIRT) using a validated system. The IRT 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).  
5.4 
Treatment blinding  
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 


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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 study drugs that are all identical in packaging, 
labeling, schedule of administration, appearance, and odor. Unblinding will only occur in the 
case of patient emergencies (see Section 5.5.11) and at the conclusion of the study.  
A double-dummy design is used because the identity of the investigational treatment cannot be 
disguised due to their different forms. 
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number (XXXXYYY). The center number is assigned by Novartis to the investigative 
site. Upon signing the informed consent form, the patient is assigned a sequential number by 
the investigator. At each site the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g., the second patient is assigned patient number 
2, the third patient is assigned patient number 3).  
The investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. 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 
Study Disposition CRF. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with study drug in identically-appearing packaging 
for each medication (LCZ696 or enalapril). 
The investigational treatment packaging has a 2-part label. A unique medication number is 
printed on each part of this label which corresponds to a specific material type. Investigator 
staff will identify the investigational treatment package(s) to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing the 
package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
subject number.  
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all investigational treatment should be stored according 
to the instructions specified on the labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. 


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Medication labels will be in German and comply with the legal requirements of Germany. They 
will include storage conditions for the investigational treatment but no information about the 
patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the study 
or at the time of discontinuation of investigational treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
Novartis will supply the investigators with all 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 study, patients will be required to take a total of two tablets (one tablet 
from the LCZ696/LCZ696 matching placebo pack and one tablet from the enalapril/enalapril 
matching placebo pack) twice a day for the duration of the study. Table 5-1 summarizes the 
study drug that will be taken during the double-blind period. 
Patients will begin treatment with dose level 2 or 2a for 2 weeks. Patients at a stable daily dose 
of enalapril 10 mg (or equivalent ACE or ARBs according to Table 3-1) 4 weeks prior to 
Visit1will start treatment at dose level 2. Patients at a stable daily dose of enalapril above 10 
mg once daily (or equivalent ACE or ARBs according to Table 3-1) 4 weeks prior to Visit1will 
start treatment at dose level 2a. Dose level 2a is for initial up-titration only and will not be 
available for down-titration for safety reasons during the course of the study. 
At Visit 4, patients will be up-titrated to dose level 3 unless safety monitoring criteria (Table 
3-2) prevent up-titration.  
 
 
 
 
 
 


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Table 5-1 Study drug dispensed during the double-blind period 
Study visit 
Dose level 
LCZ696 
Enalapril 
Visit 4 and all 
subsequent visits 
3* 
200 mg or matching placebo bid 
10 mg or matching placebo bid 
Available for Visit 3 
and any visit after 
Visit 3 
2§ 
100 mg or matching placebo bid 
5 mg or matching placebo bid 
Available for Visit 3  
2a$ 
100 mg or matching placebo bid 
10 mg or matching placebo bid 
Available for any 
visit after Visit 3 
1& 
50 mg or matching placebo bid 
2.5 mg or matching placebo bid 
* 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. 
§ Available for Visit 3 and thereafter, if dose level 3 is not tolerated despite modification of other non-disease-modifying HF 
medications. See also Section 5.5.5 
$ Available for up-titration (Visit 3) only. If dose level 3 is not tolerated despite modification of other non-disease-modifying HF 
medications, down-titration to dose level 2 is to be done. 
&. Only if dose levels 3 and 2 are not tolerated despite modification of other non-disease-modifying HF medications. 
Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 
AM) and their evening study drug doses at approximately 19:00 (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 on the Dosage Administration Record eCRF. 
All kits of investigational treatment assigned by the IRT will be recorded/databased in the IRT. 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable to take the study treatment as prescribed for any reason. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
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, the investigator should consider 
whether non-disease-modifying medication (e.g., CCBs, diuretics, nitrates, α-blockers) can be 
reduced 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 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 investigational treatment if necessary. 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, 


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the goal is to keep the patient on the highest study drug dose possible 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 1, Appendix 2, Appendix 3, and 
Appendix 4 for treatment guidelines for hyperkalemia, management of BP, and renal 
dysfunction, respectively). 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose adjustments 
and interruptions of study treatment are permitted in order to keep the patient on study drug. 
The following guidelines should be followed:  
Adjustment of study drug dose level 
If despite adjustment of concomitant medications per the guidance provided above the situation 
is not rectified, the investigator may consider adjusting the study medication according the 
following instructions. 
During the double-blind treatment period down-titration of the study drug at any time will be 
allowed based on the safety and tolerability criteria defined in Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4. If down-titration is necessary, the patient should be down-titrated 
to the next dose level (see Table 5-1; Dose level 2a is for initial up-titration only and will not 
be available for down-titration for safety reasons.). The patient may continue receiving the 
lower dose level for a recommended period of 1 to 2 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 2 
weeks. Then, he/she should be re-challenged with up-titration back to dose level 3. 
If the tolerability issues are not alleviated, the investigator may lower the study drug dose further 
to the next lower level for 1 to 2 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 2 weeks in an attempt to bring back the patient gradually to the target study drug 
dose level (dose level 3). The investigator may choose the next dose level for down- or up-
titration according to his or her judgment (Table 5-1).  
In some cases, according to the safety and tolerability criteria and the investigator’s judgment, 
dose level 2 could be maintained if he/she considers that the patient’s condition would not allow 
an 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 2 (or lower), to assure treatment with the higher dose level 
tolerated by the patient. 
Study drug restart after temporary treatment interruption 
Study drug should be reintroduced after 1-2 weeks in those who temporarily discontinue 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 


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and tolerability criteria in Appendix 1, Appendix 2, Appendix 3, and Appendix 4 the patient 
should be up-titrated to the next dose level (up to dose level 3) every 1 to 2 weeks, as per the 
investigator’s judgment. Dose level 2a is for initial up-titration only and will not be available 
for down-titration for safety reasons during the course of the study.  
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. Up-titration or 
reintroducing the study drug could be considered by the investigator as soon as medically 
justified in his/her medical judgment. 
Study visits should occur as close as possible to the time points indicated in Table 6-1. The 
timeframe between the regular visits should be maintained as scheduled, irrespective of the 
number of unscheduled visits that may be performed in between, according to the visit and time 
schedule described in Table 6-1.  
Any changes in the study drug dose level, including temporary/permanent withdrawal or re-
start of the study drug, must be recorded on the Dosage Administration Record CRF. 
In case of pregnancy discovered during the double-blind treatment period, the patient should be 
instructed to stop taking the study drug immediately. The patient should be followed until birth 
according to guidelines for pregnancies and reporting in Section 7.4. 
5.5.6 
Rescue medication 
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in Appendix 1, Appendix 2, Appendix 3, and Appendix 4 respectively. Patients 
may receive open-label ACEIs and/or ARBs during the study ONLY if the study medication 
has been discontinued either temporarily or permanently. A 36 hours washout phase of study 
drug is needed before start of an ACEI. 
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies Record in the CRF. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded. 
5.5.8 
Other concomitant treatment 
The investigator should instruct the patient to notify the study site staff of any changes in 
concomitant medications (new medications or changes in dose regimens of existing 
medications). All concomitant medications and significant non-drug therapies (including 
physical therapy and blood transfusions) administered after the patient starts treatment with the 
study medication must be listed on the Concomitant Medications/Significant Non-Drug 
Therapies eCRF. 


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ACEIs and ARBs 
Patients’ pre-study ACEIs/ARBs will be replaced by the study medications. 
The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient 
is receiving study medication. If the investigator believes that addition of an ACEI or ARB is 
necessary, then study drug must be discontinued. Study medication should be stopped 36 
hours prior to addition of open-label ACEI. If not already treated with an aldosterone 
antagonist, consideration should be given to adding this therapy rather than an ACEI or ARB.  
Similarly, if study medication is to be restarted, the open-label ACEI should be discontinued 36 
hours prior to resuming study medication.  
Heart failure medications and other cardiovascular medications  
The patient should be on an optimal medical regimen of background HF medications which 
have to be stable 4 weeks prior to screening at Visit 1 and during the screening period until 
randomization at Visit 3. Background HF medication must include an individually optimized 
dose of a β-blocker (i.e., maximally tolerated dose) at a stable dose for at least 4 weeks prior to 
study entry, unless contraindicated or not tolerated. This also includes the use of ivabradine 
according to guideline recommendations. Use of an aldosterone antagonist should be 
considered in patients eligible for this study. In self-identified black patients, the use of 
isosorbide dinitrate/hydralazine hydrochloride (e.g., BiDil®) should be considered with 
caution.  
Diuretics may be used and may be adjusted throughout the length of the study at the discretion 
of the investigator.  
Every effort should be made to keep the dose level of these background disease-modifying HF 
medications stable throughout the entire study including screening period. 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.  
If a patient experiences any AEs that may be contributed to the study drug, other HF medication, 
or other CV medications, the investigator should adjust non-disease-modifying medications 
(e.g., CCBs, nitrates, α-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. 
Concomitant administration of renin inhibitors, such as aliskiren, is prohibited. 
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. 


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Neseritide and intravenous nitrates 
Nesiritide and intravenous nitrates should only be used as the last choice as vasodilators 
are known to modulate VO2max. The concomitant administration of LCZ696 with neseritide 
and intravenous (i.v.) nitrates has not been studied. In the event a study patient requires the 
concomitant administration of neseritide and/or 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.  
Statins 
Caution should be exercised upon co-administration of LCZ696 and statins such as atorvastatin, 
simvastatin, pravastatin, and/or pitavastatin. The co-administration of LCZ696 increased the 
Cmax (maximum plasma concentration) of atorvastatin and its metabolites by 68% -108%, 
although the AUC was not significantly changed (<34%). 
L-thyroxin 
The patient should be on an optimal medical regimen of L-thyroxin medication in case of 
thyroidal dysfunction. This must include an individually optimized dose at a stable dose for at 
least 3 months prior to study entry. All changes administered after the patient starts treatment 
with the study medication must be listed on the Concomitant Medications/Significant Non-Drug 
Therapies eCRF. 
Other medications 
Bile acid sequestering agents, such as cholestyramine and colestipol, are prohibited to avoid 
interference with study drug absorption.  
5.5.9 
Prohibited Treatment 
Use of the treatments displayed in Table 5-2 is NOT allowed after the start of investigational 
treatment. Treatment with an investigational drug other than study treatment is also prohibited. 
Table 5-2 Prohibited treatment 
Medication 
Action to be taken 
Any ACEI 
Discontinue study drug. The open label ACEI 
must be stopped for ≥36 hours prior to re-initiation 
of study drug 
Any ARB 
Discontinue study drug. The open label ARB must 
be stopped prior to re-initiation of study drug and 
stop ARB 
Renin inhibitors (confounding safety: increased 
likelihood of occurrence of hyperkalemia)  
Discontinue study drug. The open label renin 
inhibitor must be stopped prior to re-initiation of 
study drug 
bile acid sequestering agents (cholestyramine, 
colestipol; potential interference with study drug 
absorption) 
none 
5.5.10 
Discontinuation of study treatment and premature patient withdrawal 
The emergence of the following circumstances will require study drug discontinuation: 


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 Withdrawal of informed consent 
 Pregnancy (see Section 7.4 Pregnancy reporting) 
 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 and constitute a 
reason for temporary or permanent discontinuation of study treatment. 
 Use of prohibited treatment as per Table 5-2. In case of initiation of open-label ACEI during 
the double blind treatment period, study medication must be stopped for ≥36 hours prior to 
initiation of open-label ACEI. The open label ACEI must be stopped for ≥36 hours prior to 
re-initiation of study drug. 
Study medication may be discontinued at the investigator’s discretion if any of the following 
occurs: 
 Any severe suspected drug related AE 
 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 2, Appendix 3, and Appendix 4 for treatment guidelines for hyperkalemia, 
hypotension, or renal dysfunction, respectively. 
 Any other protocol deviation that results in a significant risk to the patient’s safety 
In the case of study drug discontinuation, the patient should continue to complete all scheduled 
study visits and procedures. If the patient refuses, he/she should be contacted by telephone in 
place of protocol-specified visits unless the patient expressly refuses such contacts. 
The investigator must also record it on the drug administration form of the eCRF. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information. 
The investigator should discontinue study treatment for a given patient and/or withdraw the 
patient from study if, on balance, he/she believes that continuation would be detrimental to the 
patient’s well-being. 
Patients who discontinue study drug before completing the study or who prematurely withdraw 
from the study for any reason, should be scheduled for a visit as soon as possible at which time 
all (safety) assessments listed for the final end of study visit (EOS) will be performed. 
The investigator must also contact the IRT to register the patient’s discontinuation from 
investigational treatment. For patients who are lost to follow-up (i.e. those 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 documenting in the source documents steps 
taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 


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Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients. 
5.5.11 
Emergency breaking of treatment assignment 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, 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. The system will automatically inform 
the Novartis monitor for the site and the Clinical Trial Head (CTH) 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 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. 
5.5.12 
Study completion and post-study treatment 
The study will be considered completed when the patient completes the EOS visit (Visit 7). 
Patients will be asked to return the remaining study drug. The study as a whole will be 
considered completed when the last visit of last subject occurred.  
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. 
5.5.13 
Early study termination 
The study can be terminated at any time for any reason specified in the clinical trial study 
contract, by Novartis. Should this be necessary, the patient should be seen as soon as possible 
and treated for a prematurely withdrawn patient. The sponsor will be responsible for informing 
IRBs and/or ECs of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” which assessments are performed 
at each visit. 
Patients should be seen for all visits on the designated day with an allowed “visit window” of 
“+/-3” days. 


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Patients who discontinue study drug before completing the study or who prematurely withdraw 
from the study for any reason, should be scheduled for a visit as soon as possible at which time 
all (safety) assessments, listed for the final EOS visit will be performed. 
These patients should return for the assessments indicated by three asterisks (***) in Table 6-1. 
If they refuse to return for these assessments or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone. Documentation of attempts to 
contact the patient should be recorded in the patient’s record. 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit or following the last administration of study 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.  
All data obtained from the assessments listed in Table 6-1 and described in detail in the 
subsections below must be supported in the patient’s source documentation (e.g., medical charts 
or patient notes). Table 6-1 indicates which data remain in source documents only (S), or may 
be entered directly into the database (D; i.e., these data are considered source documentation 
and do not require separate source documentation), or are entered into the database from 
separate source documents (DS). Assessments that generate data for database entry and are 
recorded on eCRFs are listed using the eCRF name.  
If one visit is postponed or brought forward, it should not result in the next visit being postponed 
or brought forward (except Visit 2 must be repeated for ergospirometry). The next visit, if at all 
possible and with the latter mentioned exceptions, should adhere to the original time schedule.  
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.  
 
 


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Table 6-1 Assessment schedule 
Phase 
  
Screening 
Double blind treatment** 
Visit 
D/S* 
1 
2** 
3** 
4** 
5** 
6** 
7/EOS*** 
Days(D)/ 
  
D-16 to -12 
D-9 
D1 
D14 
D28 
D42 
D84 
Weeks (W) 
  
W-2 
  
  
W2 
W4 
W6 
W12 
Screening log 
DS 
x 
  
 
  
  
  
  
Informed consent form 
DS 
x 
  
 
  
  
  
  
Inclusion/Exclusion criteria 
DS 
x 
x 
x 
  
  
  
  
Demography 
DS 
x 
  
 
  
  
  
  
Medical history (including alcohol 
and smoking history) 
DS 
x 
  
 
  
  
  
  
Heart Failure History 
DS 
x 
  
 
  
  
  
  
Cardiovascular disease History 
DS 
x 
  
 
  
  
  
  
NYHA Classification (HF signs and 
symptoms) 
DS 
x 
x 
x 
x 
x 
x 
x*** 
Heart Failure and CV Medications 
DS 
x 
x 
x 
x 
x 
x 
x*** 
Concomitant Medications 
DS 
x 
x 
x 
x 
x 
x 
x*** 
Randomization 
DS 
  
  
x 
  
  
  
  
Physical Exam1 
S 
x 
x 
x 
x 
x 
x 
x*** 
Height (H) / Weight (W) 
DS 
H / W 
W 
W 
W 
W 
W 
W*** 
Vital signs 
DS 
x 
x 
x 
x 
x 
x 
x*** 
Waist/hip circumference 
DS 
  
x 
 
  
  
  
x*** 
Echocardiography2 
DS 
x 
  
 
  
  
  
  
Serum Pregnancy tests3 
DS 
x 
  
 
  
  
  
x*** 
Urine Pregnancy tests3 
DS 
  
x 
 
  
  
  
x*** 
AEs / SAEs 
DS 
x 
x 
x 
x 
x 
x 
x*** 
Complete laboratory assessments 
DS 
x 
x 
 
  
  
  
x*** 
Abbreviated chemistry panel4 
DS 
  
  
x9 
x9 
x 
x 
  


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Phase 
  
Screening 
Double blind treatment** 
Visit 
D/S* 
1 
2** 
3** 
4** 
5** 
6** 
7/EOS*** 
Days(D)/ 
  
D-16 to -12 
D-9 
D1 
D14 
D28 
D42 
D84 
Weeks (W) 
  
W-2 
  
  
W2 
W4 
W6 
W12 
12-lead ECG evaluation 
S 
x5 
  
 
  
  
  
  
Ergospirometry 
DS 
  
x 
 
  
  
x 
x 
Borg Scale documentation  
DS 
  
x 
 
  
  
x 
x 
Double blind medication dispense 
DS 
  
  
x 
x 
x 
x 
  
Contact IRT 
S 
x 
  
x 
x 
x 
x 
x 
Drug accountability 
S 
  
  
x 
x 
x 
x 
x 
Treatment completion form 
DS 
  
  
 
  
  
  
x**** 
Study completion form 
DS 
  
  
 
  
  
  
x*** 
* DS: assessment to be documented in the clinical database, S: assessment to be recorded in the source data 
** Visits marked with ** can be followed by unscheduled visits that may be performed at the investigator’s discretion due to chemistry panel evaluation or up-titration. 
*** Patients who prematurely discontinue study treatment should also return for the end of study (EOS) to collect at least safety assessments indicated by three asterisks (***). 
**** To be documented at Visit 7 or at the time of premature discontinuation 
1 Complete physical examination required at Visits 1, 2 and 7 (end-of-study visit). Short physical exam is sufficient at Visit 3 -6. 
2 Qualifying LVEF measurements/documentation of structural heart disease will be based on obtained measurements (e.g. echocardiograms (echo)) performed ≤ 6 months prior to Visit 1. If an 
assessment performed ≤6 months prior to Visit 1 is not available, an echo must be performed during the screening epoch. 
3 Women of childbearing potential only. At Visit 1 and 7 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 2 and 7 and every time this is clinically indicated or a contraception gap has been reported. 
4 Abbreviated chemistry panel including potassium, BUN, and serum creatinine will be measured at interim visits at the central laboratory. 
5 Screening ECG performed within the 6 months before Visit 1 is accepted. 
 


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Phase 
  
Screening 
Double blind treatment** 
Visit 
D/S* 
1 
2** 
3** 
4** 
5** 
6** 
7/EOS*** 
Days(D)/ 
  
D-16 to -12 
D-9 
D1 
D14 
D28 
D42 
D84 
Weeks (W) 
  
W-2 
  
  
W2 
W4 
W6 
W12 
 
9 At Visit 3 and 4, patients should come to the site 3 to 4 days prior to the scheduled visit date for blood draw only so that results from central laboratory are available and enable a competent 
decision on randomization or up-titration at the respective visits.  
 
 


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6.1 
Information to be collected on screening failures 
Patients may discontinue from the study prior to randomization from Visit 3, prior to any 
double-blind medication being administered.  
Patients discontinuing at Visit 1, Visit 2 or Visit 3 (were never randomized and never received 
active study drug) are considered screening failures  
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
SAE data collected. Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. 
Re-screening  
If a patient is not eligible to enter the double blind treatment period (Visit 3) 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 
assessments. 
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 source of patient referral. Relevant medical history/current medical 
condition data includes data until the start of study drug. 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. 
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 period. The investigator and/or study personnel will counsel the patient if 
compliance is below 80%. Study drug accountability will also be determined by the site monitor 
while performing routine site visits and at the completion of the study. 
Duration of double-blind study drug exposure will be calculated based upon the start and stop 
dates recorded in the eCRF.  
6.4 
Efficacy 
6.4.1 
Peak respiratory oxygen uptake (VO2peak)  
Cardio-pulmonary-exercise testing (CPET) is an examination of the cardio-pulmonary system 
using the measurement of respiratory gases during exercise stress. The result provides an 
overview of cardiopulmonary function, including the measurement of peak oxygen uptake (VO2 
peak). 


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CPET to assess VO2peak will be performed at a cycle ergometer during screening (Visit 2) and 
after 6 weeks and 3 months (Visit 6 and Visit 7). It will be evaluated by the modified Naughton 
protocol as recommended for treadmill exercise in patients with CHF. The workload will start 
at 10W and will be increased by 10W for each 1-minute stage. Patients will be under continuous 
ECG and frequent blood pressure monitoring. During ergospirometry, a physician should be 
available in case of an emergency situation where immediate medical intervention is necessary.  
 
 
 
 
 
 
 
The details of the procedure will be outlined in a manual provided to all participating sites.  
The primary endpoint is change of VO2peak compared to baseline measurements (adjusted to 
body weight) after 3 months of treatment.  
Further efficacy parameters assessed during CPET are  
 
Change in VO2peak (adjusted to body weight) after 6 weeks of treatment  
 
Change in VO2peak (unadjusted) after 6 weeks and 3 months  
 
Change of VE/VCO2 slope after 6 weeks and 3 months  
 
 
 
 
Change in exercise capacity (Watt) at VAT after 6 weeks and 3 month  
 
Change in rate of perceived exertion during exercise (Borg Scale) after 6 weeks 
and 3 months  
 
 
 


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6.4.4 
Appropriateness of efficacy assessments  
VO2max is the peak oxygen uptake achieved during the performance of dynamic exercise 
involving a large part of total muscle mass. It is considered the best measure of cardiovascular 
fitness and exercise capacity (Fletcher et al. 2013). Patients with CHF usually cannot achieve 
this plateau due to limiting factors caused by the presence of heart disease, LV dysfunction, 
myocardial ischemia, and associated symptomatology. Thus, it is common to refer to assessed 
VO2max as the VO2peak attained during volitional incremental exercise. Method and protocol for 
the assessment of VO2peak is defined as recommended in current guidelines (Fletcher et al. 
2013). 
 
 
6.5 
Safety 
The Sponsor may request additional information on specific adverse events or laboratory events of 
interest and may make requests to perform additional diagnostic tests to further assess the safety 
profile of LCZ696. Such information may include diagnostic procedure reports, discharge 
summaries, autopsy reports, and other relevant information that may help in assessing the reported 
adverse event. All additional information will be de-identified prior to collection by Novartis or its 
agents. 


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6.5.1 
Physical examination 
A complete physical examination will be performed at visit 1, 2 and 7. It will include the 
examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic exams 
will be performed.  
A short physical exam will include the examination of general appearance and vital signs (BP 
and pulse). A short physical exam will be at all visits starting from Visit 3 to 6 and at all 
unscheduled visits, except where a complete physical exam is required (see above).  
Information about the all physical examinations must be present in the source documentation at 
the study site. Significant findings that are present prior to the start of study drug must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings made after the start of study drug which meet the definition of an 
AE must be recorded on the AE screen of the patient’s eCRF. 
6.5.2 
Vital signs 
Vital signs will be assessed at every visit. This will include BP and pulse measurements. BP 
will be measured by using a standard sphygmomanometer with an appropriate size cuff and the 
non-dominant arm in the sitting position after 5 minutes of rest. During ergospirometry patients 
will be under frequent blood pressure monitoring. 
Guidelines for the management of BP are provided in Section 15 Appendix 3. 
6.5.3 
Height and weight and waist hip circumference 
Height in centimeters (cm) will be measured at Visit 1. 
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing without shoes) will be 
measured at all visits, until the EOS visit. 
Waist/hip circumference (to the nearest centimeter [cm] in indoor clothing) will be measured at 
Visit 2 and at the EOS visit. 
6.5.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all collected specimens. Details on the 
collections, shipment of samples and reporting of results by the central laboratory will be 
provided to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
Full laboratory evaluations (hematology, blood chemistry, and urine for pregnancy assessment 
in child-bearing women; Table 6-2) for the assessment of safety in this study will be performed 
at Visits 1, 2 and 7. Electrolyte laboratory evaluations will be included in the abbreviated 
laboratory assessments at Visits 4 to 6. 
The investigator or his/her designee should review the central laboratory results as soon as they 
become available to decide on whether any adjustments in the patient’s study drug or non-study 


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drug regimen are needed. Therefore unscheduled visit are possible based on investigator’s 
discretion. 
All central laboratory results will be communicated to the investigators 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 Comments screen of the patient's eCRF and additional 
laboratory evaluations should be performed, as judged appropriate by the investigator. If the 
laboratory abnormality induces clinical signs or symptoms, or requires therapeutic intervention, 
then the diagnosis or medical condition must be entered on the AEs screen of the patient's 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. Likewise, if the laboratory abnormality leads to discontinuation 
from the study drug (temporarily or permanently), the patient must be followed until the 
abnormality resolves or until it is judged to be permanent. 


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Table 6-2 Routine laboratory examination 
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) ** 
Creatine kinase (CK) 
Creatinine ** 
Total Bilirubin 
Aspartate amino-transferase (AST) 
Alanine amino-transferase (ALT) 
Alkaline phosphatase 
Total protein 
Albumin 
Uric Acid 
Serum Pregnancy Testa 
Lipid profile (total cholesterol, LDL, 
HDL, and triglycerides) 
Hemoglobin A1C 
Thyroid-stimulating hormone (TSH)b 
Urine pregnancy test at Visit 2 
and 7 and when clinically 
indicated or a contraception 
gap has been reported 
 
* List of laboratory assessments performed at Visits 1, 2 and 7(EOS) 
** Laboratory assessments for the abbreviated biochemistry test performed at visits where the complete laboratory 
test is not performed.  
a. Serum pregnancy test is performed at Visit 1, 7, and in case of positive urine pregnancy test only. 
b. TSH is assessed at Visit 1 only.  
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured at Visits 1, 2, and 7 (Table 6-2). 
6.5.4.2 
Clinical chemistry 
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, 2, and 7. 
BUN, serum potassium, and serum creatinine value for eGFR calculation will be obtained from 
patients at every visit when a complete laboratory test is not done (i.e., Visits 3-5). 
The latter is true for all unscheduled visits done with up-titration intention.  
6.5.4.3 
Urinalysis 
Urine pregnancy measurement is performed as dipstick measurement at Visit 2, and 7. 


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6.5.5 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed at screening (Visit 1, unless an ECG performed 
within the last 6 months is available) to assess the eligibility of patients regarding inclusion and 
exclusion criteria. Interpretation of the tracing must be made by a qualified physician. Each 
ECG tracing should be labeled with the study number, patient number, and date and kept in the 
source documents at the study site. Clinically significant abnormalities according to the 
judgment of the investigator should also be recorded on the relevant medical history/current 
medical conditions or AE eCRF page.  
During ergospirometry, patients will be under continuous ECG evaluation. 
6.5.6 
Pregnancy and assessments of fertility 
All female patients of childbearing potential will have a serum pregnancy test performed at 
Visit 1 and Visit 7. Additionally, at Visit 2 and 7 a urine pregnancy test will be performed, and 
whenever this is clinically indicated or a contraception gap has been reported.  
If during the study, the patient provides information which suggests that contraception might 
be impaired (e.g. due to of diarrhea and/or vomiting), the investigator should perform an 
additional urine pregnancy test to assure that the patient is not pregnant.  
In case of a positive urine pregnancy result, a confirmatory serum pregnancy test has to be 
performed at the central laboratory, and the study drug should be temporarily withdrawn until 
the result confirms no pregnancy.  
See Section 5.5.5 and 7.4 for details on pregnancies. 
6.5.7 
Angioedema 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise. 
Although, the mechanism is not fully understood, bradykinin has been implicated as the putative 
mediator. Therefore, medications that raise the levels of endogenous bradykinin by inhibiting 
the enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and NEP, may 
result in this potentially dangerous side effect.  
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 be also be contacted by Novartis regarding AEs that may resemble an 
angioedema-like event. A list of terms that are considered “angioedema-like” (e.g., periorbital 
swelling) will be provided to sites in a manual. The investigator or his/her delegated staff must 


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complete the required forms and provide the required medical records for all such events, 
regardless of whether the investigator views the event in question as angioedema or not.  
All angioedema reports will be forwarded to an Angioedema Adjudication Committee by 
Novartis for assessment. Information regarding this committee is outlined in Section 8.5. 
Details on the procedures for reporting angioedema events will be provided to investigators in 
a manual.  
6.5.8 
Cognitive impairment 
Angiotensin receptor blockade has been suggested to improve cognitive function, as might 
overall improvement in cardiac and vascular function. Thus, improvements in cardiac function 
and cerebral blood flow by LCZ696 are hypothesized to potentially improve vascular effects 
and, thereby, cognition. However, neprilysin is one of multiple enzymes involved in the 
breakdown of amyloid β, a peptide linked to cognitive impairment. Thus, cognitive function 
resulting from combined angiotensin receptor blockade and neprilysin inhibition with LCZ696 
is subject to standardized follow-up.  
It is important that the investigator pays attention to any events of cognitive impairment or 
related events that may be reported by patients. If such an event occurs that meets criteria for 
serious adverse event, the investigator will complete a separate questionnaire for a Dementia-
related Event form (provided by Novartis) to summarize the event, its further diagnostic tests 
performed, and its related information. A list of terms that are considered “dementia-like” (e.g., 
presenile dementia, memory impairment) will be provided to sites in a manual. 
6.5.9 
Statin-related Events 
Statin-related events are subject to additional safety assessments and thus are followed with a 
standardized questionnaire. A list of terms that are considered “statin-related” (e.g., 
rhabdomyolysis, acute pancreatitis, myalgia and muscle spasm) will be provided to sites in a 
manual.  
If such an event occurs that meets criteria for serious adverse event, the investigator will 
complete a separate questionnaire for a Hepatotoxicity and Statin-related Event form (provided 
by Novartis) to summarize the event, its further diagnostic tests performed, and its related 
information. 
6.5.10 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 


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6.6.2 
Blood pressure home measurements 
Additionally to the assessment of vital signs at each visit, blood pressure will be self-monitored 
by the patient via home-measurement.  
Therefore, at Visit 3, the use of a home blood pressure monitor should be explained. A home 
blood pressure monitor will be provided with all appropriate supplies. Blood pressure should 
be measured  
 once daily until Visit 5 
 each time the patient experiences symptoms which may be suggestive of hypotension, 
as well as other time points which may be recommended by the investigator 
The review of the Standard Patient Diary should be done at every visit after Visit 3. Any time 
the patient experiences symptoms which he/she suspects are related to hypotension, the patient 
should be instructed to take a blood pressure measurement. Patients should record the event in 
the Standard Patient Diary, including: 
 the blood pressure value. Any symptomatic blood pressure < 100 mmHg should be 
recorded in the Standard Patient Diary and the patient should be instructed to contact 
the study investigator directly  
 any relevant associated information. 


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 time of occurrence in relation to the last medication. 
Additionally, if a patient performs routine measurements of blood pressure, any asymptomatic 
blood pressure ≤ 95 mmHg should be recorded in the Standard Patient Diary and the patient 
should be instructed to contact the study investigator directly.  
The patient should return the study diary at each next scheduled visit. 
The home blood pressure monitor and Standard Patient Diary should be given to the patient at 
Visit 3. 
6.6.3 
Pharmacokinetics 
Not applicable 
6.6.4 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
6.6.5 
Other biomarkers 
Not applicable. 
7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 


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Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
 the severity grade  
 mild: usually transient in nature and generally not interfering with normal activities 
 moderate: sufficiently discomforting to interfere with normal activities 
 severe: prevents normal activities 
 its relationship to the study treatment (no/yes),  
 its duration (start and end dates) or if the event is ongoing an outcome of not recovered/not 
resolved should be reported. 
 whether it constitutes a serious adverse event (SAE)  
 action taken regarding study treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
An SAE is any 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 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent  
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); investigational treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 


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medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF.  
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 treatment, 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 event 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. 
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 Directive 2001/20/EC or as per national regulatory requirements 
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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.  
Hepatotoxicity-related events are subject to additional safety assessments and thus are followed 
with a standardized questionnaire. A list of terms that are considered “hepatotoxicity-related” 
(e.g., cholaemia, ascites, liver disorder) will be provided to sites in a manual.  
If such an event occurs that meets criteria for serious adverse event, the investigator will 
complete a separate questionnaire for a Hepatotoxicity and Statin-related Event form (provided 
by Novartis) to summarize the event, its further diagnostic tests performed, and its related 
information. 
Liver events are divided into two categories: 
 Liver events of special interest (AESI) which consist of liver function tests (LFTs) 
elevations 
 Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events. 
Please refer to Table 19-1 in Appendix 7 for complete definitions of liver events.  
Any liver event which meets the criteria for “medically significant” event as outlined in Table 
19-1 of Appendix 7 should follow the standard procedures for SAE reporting as described 
in Section 7.2.  
Every liver event as defined in Table 19-1 of Appendix 7 should be followed up by the 
investigator or designated personal at the trial site as summarized below. Detailed information 
is outlined in Table 19-2 in Appendix 7. 
 Repeating the LFT to confirm elevation as appropriate 
 Discontinuation of the investigational drug if appropriate 
 Hospitalization of the patient if appropriate 
 A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
 An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 
7.4 
Pregnancy reporting 
In case a patient becomes pregnant, or plans to become pregnant, the study drug must be 
interrupted before contraception is discontinued (or, from the date the pregnancy becomes 
known) for the entire duration of the pregnancy and lactation period (or, for the entire duration 
that contraception is discontinued). To ensure patient safety, each pregnancy in a patient on 
study drug 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 


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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 DS&E Department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the Novartis 
study drug of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form. 
7.5 
Prospective suicidality assessment 
Not applicable. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the 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 


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the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff, or CRO staff working on behalf of Novartis, review the data entered into the 
eCRFs by investigational staff for completeness and accuracy and instruct the site personnel to 
make any required corrections or additions. Obvious errors are corrected by Novartis personnel 
or CRO staff working on behalf of Novartis. 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 who 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. 
Medical history/current medical conditions and AEs will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
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 Novartis, who will also manage the database.  
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused supplies to Novartis. The 
occurrence of relevant protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made after written agreement by Trial Statistician 
and Statistical Reporting and the Clinical Trial Leader. 
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 
8.4 
 Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Angioedema Adjudication Committee 
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis). Details 
on the process of reporting angioedema and angioedema like events are outlined in a manual 
provided to investigators. 


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Submission of an angioedema report is not a substitution for the submission of an AE or SAE 
report. If an angioedema-like event satisfies the definition of an AE or SAE, the investigator 
must submit an AE or SAE report according to the respective processes in addition to the 
Adjudication Questionnaire for an Angioedema-like Event.  
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites.  
9 
Data analysis 
9.1 
Analysis sets 
The following populations will be used for the statistical analyses: 
The full analysis set (FAS) will consist of all randomized patients who have received at least 
one dose of study drug. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment to which they were assigned at randomization. Efficacy variables 
will be analyzed based on the FAS as the primary population. 
The Safety Population (SAF) will consist of all randomized patients who received at least one 
dose of study drug. Patients will be analyzed according to the treatment actually received. The 
safety population will be used for the analyses of safety variables.  
9.2 
Patient demographics and other baseline characteristics 
Baseline value is defined as the last non-missing assessment prior to the first dose of 
randomized study medication unless specified otherwise.  
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (<65 years vs. ≥65 years), sex, race, weight, height, 
body mass index (BMI), category of prior CHF medication, prior HF hospitalization, NYHA 
class, 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 FAS will be the patient population for the above analyses. 
9.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
The overall duration on the double-blind study drug will be summarized by treatment group 
using mean, standard deviation, median, minimum, and maximum. Additionally, the number 
and percentage of patients will be summarized by treatment group for duration category.  
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.  


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The number and percentage of patients on different CHF background medications (aldosterone 
antagonists, β-blockers, ivabradine, diuretics, digoxin) will be tabulated by treatment at baseline 
and during the double-blind stage. 
The FAS will be used for the above analyses. 
9.4 
Analysis of the primary and key secondary variable(s) 
9.4.1 
Variable(s) 
The primary efficacy variable is the change from baseline in VO2peak (adjusted to body weight) 
at month 3. 
The key secondary variable is the change from baseline in VO2peak (adjusted to body weight) at 
week 6. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The trial aims to establish the (alternative) hypotheses of superiority of LCZ696 vs enalapril. 
The primary analysis will be performed comparing treatments with respect to the primary 
efficacy variable in an analysis of covariance (ANCOVA) model with the factors treatment and 
center and baseline VO2peak as a covariate. The raw- as well as the adjusted (LS) group means 
will be presented. Additionally, a 95% confidence interval and a p-value will be given for the 
treatment contrast.  
The key secondary endpoint, the change from baseline in VO2peak (adjusted to body weight) at 
week 6 will be analyzed using the same model. The significance level will not be adjusted for 
multiplicity, the result of the test for week 6 will be regarded as providing confirmatory 
evidence, only if the test of the primary hypothesis (month 3) is also significant (a-priori ordered 
hypotheses). 
9.4.3 
 Handling of missing values/censoring/discontinuations 
Missing values of VO2peak will be replaced with the last observed value (LOCF). Since the trial 
aims to estimate which improvements are achievable under the respective treatment regimens, 
LOCF seems to provide meaningful estimates for this purpose. 
9.4.4 
Supportive analyses 
In case of serious deviations from the normality assumptions, treatments may additionally be 
compared by a non-parametric test (Mann-Whitney-U-test). In case of a substantial rate of 
missing data (>15%) or strong imbalances between treatment groups, Multiple Imputation (MI) 
may be considered as a sensitivity analysis. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Secondary efficacy variables are: 
 
Change in VE/VCO2 slope after 6 weeks and 3 months  


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 
Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months  
 
Change in rate of perceived exertion during exercise (Borg Scale) after 6 weeks and 3 
months  
Secondary efficacy variables will be analyzed using ANCOVA models analogous to the 
analyses of the primary endpoint. 
9.5.2 
 Safety variables 
Safety assessments will be based mainly on the frequency of adverse events. Adverse events 
will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). An adverse event related to study drug is 
defined as one considered by the investigator to have a suspected relationship with the study 
drug. The adverse events will be summarized by the number and percentage of patients in each 
primary system organ class and preferred term. For summaries by severity of event, the most 
severe occurrence for a particular preferred term will be used for a given patient. Summary 
tables of adverse events by treatment and severity will be provided. 
Multiple occurrences of the same AE or SAE in the same patient will be counted only once, 
using the worst severity and drug relationship. 
In the data listings of adverse events, the severity of an AE, whether or not an AE is study drug 
related, and whether or not it is a serious AE, will be indicated. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms or require therapy. 


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Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values (means, medians, standard deviations, ranges) and by presenting number 
and percentage of patients with notable laboratory abnormalities according to Appendix 1.  
Data from other tests (vital signs) will be listed, notable values will be flagged, and any other 
information collected will be listed as appropriate. 
9.5.3 
Resource utilization 
Not required. 
9.5.4 
Health-related Quality of Life 
See under ‘secondary/ 
 endpoints’ above. 
9.5.5 
Pharmacokinetics 
Not applicable. 
9.5.6 
Pharmacogenetics/pharmacogenomics 
Not applicable 
9.5.7 
Biomarkers 
Not applicable 
9.5.8 
PK/PD 
Not applicable 
9.6 
Interim analyses 
Not applicable. 
9.7 
Sample size calculation 
Existing data suggest that the difference between LCZ696 and enalapril in VO2peak at month 3 
may be about 1.5 mL kg−1 min−1 with a (common) SD of 3 (Guazzi et al. 1999; Lewis et al. 
2007). Under these assumptions, 86 patients per treatment arm would be required to achieve 
90% power on a 2-sided, 5% significance level. To compensate for some drop-out and other 
protocol deviations, 100 patients per treatment group (200 in total) will need to be enrolled into 
this trial. The above mentioned literature suggests that the treatment effect for the key secondary 
endpoint, VO2peak after 6 weeks, might be of a similar magnitude, therefore, the sample size 
calculation above applies also for the key secondary endpoint.  
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 


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regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents.  
Novartis will provide to investigators in a separate document an informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.  
10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the informed consent form must be reviewed and approved by a properly 
constituted Institutional Review Board/Independent Ethics Committee/Research Ethics Board 
(IRB/IEC) before study start. A signed and dated statement that the protocol and informed 
consent have been approved by the IRB/IEC must be given to Novartis before study initiation. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 


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11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the trial 
to request approval of a protocol deviation, as requests to approve deviations will not be granted. 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants.  Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed within 10 
working days or less, if required by local regulations. 


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12 
References 
Albouaini, K. et al., 2007. Cardiopulmonary exercise testing and its application. Postgraduate medical journal, 
83(985), 
pp.675–82. 
Available 
at: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2734442&tool=pmcentrez&rendertype=abstrac
t [Accessed September 28, 2015]. 
Belardinelli, R. et al., 1999. Randomized, controlled trial of long-term moderate exercise training in chronic heart 
failure: effects on functional capacity, quality of life, and clinical outcome. Circulation, 99(9), pp.1173–82. 
Available at: http://www.ncbi.nlm.nih.gov/pubmed/10069785 [Accessed September 28, 2015]. 
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. The New England journal of medicine, 316(23), pp.1429–35. Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/2883575 [Accessed May 27, 2015]. 
Corrà, U. et al., 2004. Cardiopulmonary exercise testing and prognosis in chronic heart failure: a prognosticating 
algorithm 
for 
the 
individual 
patient. 
Chest, 
126(3), 
pp.942–50. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/15364777 [Accessed November 10, 2015]. 
Fletcher, G.F. et al., 2013. Exercise standards for testing and training: a scientific statement from the American 
Heart 
Association. 
Circulation, 
128(8), 
pp.873–934. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/23877260 [Accessed July 10, 2014]. 
Green, C.P. et al., 2000. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new 
health status measure for heart failure. Journal of the American College of Cardiology, 35(5), pp.1245–55. 
Available at: http://www.ncbi.nlm.nih.gov/pubmed/10758967 [Accessed October 20, 2015]. 
Guazzi, M. et al., 1999. Synergistic efficacy of enalapril and losartan on exercise performance and oxygen 
consumption at peak exercise in congestive heart failure. The American journal of cardiology, 84(9), 
pp.1038–43. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10569660 [Accessed October 20, 2015]. 
Lewis, G.D. et al., 2007. Sildenafil improves exercise capacity and quality of life in patients with systolic heart 
failure and secondary pulmonary hypertension. Circulation, 116(14), pp.1555–62. Available at: 
http://circ.ahajournals.org/cgi/doi/10.1161/CIRCULATIONAHA.107.716373 
[Accessed 
October 
20, 
2015]. 
Mancini, D.M. et al., 1991. Value of peak exercise oxygen consumption for optimal timing of cardiac 
transplantation in ambulatory patients with heart failure. Circulation, 83(3), pp.778–86. Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/1999029 [Accessed September 2, 2015]. 
McMurray, J.J. V et al., 2014. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England 
journal 
of 
medicine, 
371(11), 
pp.993–1004. 
Available 
at: 
http://www.nejm.org/doi/abs/10.1056/NEJMoa1409077 [Accessed July 10, 2015]. 
McMurray, J.J. V et al., 2013. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-
converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the 
Prospective comparison of ARNI with ACEI to Determine Impact. European journal of heart failure, 15(9), 
pp.1062–73. 
Available 
at: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3746839&tool=pmcentrez&rendertype=abstrac
t [Accessed September 8, 2015]. 
Osman, A.F. et al., 2000. The incremental prognostic importance of body fat adjusted peak oxygen consumption 
in chronic heart failure. Journal of the American College of Cardiology, 36(7), pp.2126–31. Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/11127451 [Accessed September 28, 2015]. 


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Packer, M. et al., 2002. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the 
Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation, 
106(8), pp.920–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12186794 [Accessed October 1, 
2015]. 
SOLVD Investigators, 1992. Effect of enalapril on mortality and the development of heart failure in asymptomatic 
patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. The New England 
journal of medicine, 327(10), pp.685–91. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1463530 
[Accessed September 13, 2015]. 
SOLVD Investigators, 1991. Effect of enalapril on survival in patients with reduced left ventricular ejection 
fractions and congestive heart failure. The SOLVD Investigators. The New England journal of medicine, 
325(5), pp.293–302. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2057034 [Accessed January 14, 
2015]. 


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13 
Appendix 1: Clinically notable laboratory values 
 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
RBC count 
 
>50% increase, >20% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit 
 
>50% increase, >20% decrease 
WBC count 
 
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Blood Chemistry 
ALT (SGPT)  
>150% increase 
AST (SGOT)  
>150% increase 
BUN  
 
>50% increase 
Creatinine 
 
>50% increase 
Total bilirubin  
>100% increase 
CPK 
 
 
>300% increase 
Alkaline phosphatase >100% increase 
Potassium 
 
>20% increase, >20% decrease 
Chloride 
 
>10% increase, >10% decrease 
Calcium 
 
>10% increase, >10% decrease 
Uric acid 
 
>50% increase 


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Appendix 2: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.3 mmol/L)  
General principles 
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken. 
Any patient with a serum potassium ≥ 5.3 mmol/L after enrollment into the study requires 
regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) 
until it is clear that the potassium concentration is stable and not rising into the range of concern 
(≥ 5.5 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L).  
Patients with 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 
 Confirm potassium concentration in a non-hemolyzed sample 
 Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.)  
 Review medical regimen (including dietary supplements and over-the-counter 
medications) for agents known to cause hyperkalemia. Consider reduction in dose or 
discontinuation of these agents: 
 Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 
 Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics  
 Potassium supplements, e.g., potassium chloride 
 Salt substitutes  
 Non-steroidal anti-inflammatory drugs (NSAIDs) 
 Cyclo-oxygenase-2 (COX-2) inhibitors 
 Trimethoprim and trimethoprim-containing combination products, such as 
trimethoprim/sulfamethoxazole fixed combinations 
 Herbal Supplements:  
 For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily 
of the valley, Siberian ginseng, hawthorn berries 
 Repeat serum potassium measurement within 3 to 5 days 
 If serum potassium remains ≥ 5.3 and ≤ 5.5 mmol/L, regularly monitor serum potassium 
levels to ensure stability (suggested once monthly) 
 Consider down-titration of study medication, according to investigator’s medical 
judgment. 


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Serum potassium > 5.5 and < 6.0 mmol/L  
 Confirm potassium concentration in a non-hemolyzed sample  
 Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment.  
 Apply all measures outlined for serum potassium ≥ 5.3 and ≤ 5.5 mmol/L 
 Repeat serum potassium measurement after 2-3 days 
 If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days 
Serum potassium greater than or equal to 6.0 mmol/L 
 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 
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee. 
15 
Appendix 3: 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. 
16 
Appendix 4: Guidelines for the management of renal 
dysfunction  
General principles: 
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, renal 
dysfunction may develop or may deteriorate in some patients after study drug administration. 
These recommendations have been developed to guide the investigators in managing patients 
with renal dysfunction after randomization. 


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Two types of response to serum creatinine increase are described: 
Surveillance situation  
If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (Visit 2) (or if 
serum creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will check 
for potentially reversible causes of renal dysfunction such as: 
 Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia 
 Volume decrease, including that resulting from excessive dosing of diuretics 
 Urinary infection 
 Urinary tract obstruction 
 Study medication 
Action situation  
If a patient eGFR decreases by ≥ 40% from baseline (Visit 2) (or if serum creatinine 
concentration rises above 3 mg/dL (265 µmol/L)), the investigator will check for potentially 
reversible causes of renal dysfunction (see above). 
If the investigator judges that study medication has to be stopped, he/she 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. 
 


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19 
Appendix 
7: 
Liver 
event 
definitions 
and 
follow-up 
requirements 
Table 19-1 Liver event definitions 
 
Definition/ threshold 
Adverse 
event 
of 
special 
interest 
 
Laboratory values 
ALT or AST > 3 x ULN 
 
ALP > 2 x ULN 
 
TBL > 1.5 x ULN 
Medically 
significant 
event 
(SAE) 
 
Laboratory values 
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction]) 
 
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction]) 
 
TBL > 3 x ULN 
 
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and TBL 
> 2 x ULN [mainly conjugated fraction] without notable increase in 
ALP to > 2 x ULN) 
Adverse events 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; 
the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms 
 
 
 


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Table 19-2 Liver event follow up requirements 
Criteria 
Event type 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
Medically 
significant 
Discontinue 
the 
study 
drug 
immediately 
Hospitalize, 
if 
clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
ALT or AST 
> 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize 
if 
clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists for more than 
2 weeks, discontinue the study 
drug 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 x ULN 
accompanied by 
symptomsb 
Medically 
significant 
Discontinue 
the 
study 
drug 
immediately 
Hospitalize 
if 
clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 x ULN  
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
week 
If elevation persists, establish 
causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 3 x ULN  
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
ALP (isolated) 
> 5 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, report to 
Novartis as an SAE 
Establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
> 2 to ≤5 x ULN  
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
week. 
If 
elevation 
persists, 
establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 2 x ULN  
N/A 
Repeat LFT at next visit 
 


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Criteria 
Event type 
Actions required 
Follow-up monitoring 
(patient is 
asymptomatic) 
TBL (isolated) 
> 3 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize 
if 
clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, 
haptoglobin, 
unconjugated 
[indirect] 
bilirubin) 
> 1.5 to ≤ 3 x ULN 
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Novartis 
Repeat LFT once or twice in the 
week 
If elevation persists, establish 
causality 
investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 1.5 x ULN 
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
Preferred terms 
Jaundice 
Medically 
significant 
Discontinue 
the 
study 
drug 
immediately 
Hospitalize the patient 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
“Drug-related 
hepatic 
disorders - severe 
events only” SMQ 
AE 
Medically 
significant 
Discontinue the study drug  
hospitalization 
if 
clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Investigator discretion 
a Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN 
b General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia 
c 
Resolution is defined as an outcome of one of the following: return to baseline values, stable 
values at three subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a 
maximum of 6 months, liver transplantation, and death. 
 

SAP_001.pdf: 
Clinical Development 
LCZ696B 
CLCZ696BDE01 / NCT02768298
A randomized, double-blind, active-controlled study to 
assess the effect of LCZ696 compared with enalapril to 
improve exercise capacity, daily physical activity and 
quality of life in patients with heart failure with reduced 
ejection fraction (HFrEF) 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
; Lead Statistician, 
 
 
Document type: 
SAP Documentation 
Document status: 
Amendment 1.0 
Release date: 
10-Feb-2020
Number of pages: 
38 
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 
 
LCZ696BDE01 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
27-Feb-2019 
Prior to 
DBL 
First 1.0 
CTT to review 
NA 
10-Feb-2020 
Prior to 
DBL 
Amendment 1.0 
As per protocol 
amendment. 
Changes in primary and 
secondary objective 
Section 1.2.2 
Section 1.2.3 
Section 2.5.1 
Section 2.6.1 
Section 2.7.1 
Section 2.20 
Section 4 
 
 


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SAP 
 
LCZ696BDE01 
 
Table of contents 
Table of contents ............................................................................................................. 3 
List of abbreviations ........................................................................................................ 5 
1 
Introduction .................................................................................................................... 6 
1.1 
Study design ........................................................................................................ 6 
1.2 
Study objectives and endpoints ............................................................................ 7 
1.2.1 
Primary objectives ............................................................................... 7 
1.2.2 
Secondary objectives ........................................................................... 7 
 
 7 
2 
Statistical methods .......................................................................................................... 8 
2.1 
Data analysis general information ........................................................................ 8 
2.1.1 
General definitions ............................................................................... 8 
2.2 
Analysis sets ........................................................................................................ 9 
2.2.1 
Subgroup of interest ............................................................................. 9 
2.3 
Patient disposition, demographics and other baseline characteristics .................... 9 
2.3.1 
Patient disposition .............................................................................. 10 
2.3.2 
Demographic characteristics .............................................................. 10 
2.3.3 
Medical History ................................................................................. 11 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ....................................................................................................... 12 
2.4.1 
Study treatment / compliance ............................................................. 12 
2.4.2 
Prior, concomitant and post therapies ................................................. 12 
2.5 
Analysis of the primary objective ....................................................................... 14 
2.5.1 
Primary endpoint ............................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis ......................... 15 
2.5.3 
Handling of missing values/censoring/discontinuations ...................... 15 
2.5.4 
Supportive analyses ........................................................................... 15 
2.6 
Analysis of the key secondary objective ............................................................. 15 
2.6.1 
Key secondary endpoint ..................................................................... 15 
2.6.2 
Statistical hypothesis, model, and method of analysis ......................... 15 
2.7 
Analysis of secondary efficacy objective(s)........................................................ 15 
2.7.1 
Secondary endpoints .......................................................................... 15 
2.7.2 
Statistical hypothesis, model, and method of analysis ......................... 16 
2.7.3 
Handling of missing values/censoring/discontinuations ...................... 16 
2.8 
Safety analyses .................................................................................................. 16 
2.8.1 
Adverse events (AEs) ........................................................................ 16 
2.8.2 
Deaths................................................................................................ 17 


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SAP 
 
LCZ696BDE01 
 
2.8.3 
Laboratory data .................................................................................. 17 
2.8.4 
Other safety data ................................................................................ 19 
2.9 
Pharmacokinetic endpoints ................................................................................ 20 
2.10 
PD and PK/PD analyses ..................................................................................... 20 
2.11 
Ergospirometry analysis ..................................................................................... 20 
 
 21 
2.13 
Borg scale analysis ............................................................................................ 21 
 
 21 
 
 22 
 
 22 
 
 25 
 
 25 
2.19 
Biomarkers ........................................................................................................ 25 
 
 25 
2.21 
Interim analysis ................................................................................................. 26 
3 
Sample size calculation ................................................................................................. 26 
4 
Change to protocol specified analyses ........................................................................... 26 
5 
Appendix ...................................................................................................................... 27 
Appendix 1: Clinically notable laboratory values .......................................................... 27 
Appendix 2: Liver event definitions and follow-up requirements ................................... 27 
Appendix 3: Guidelines for the management of renal dysfunction ................................. 30 
Appendix 4: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.3 mmol/L) ..................................................................................... 31 
5.1 
Imputation rules ................................................................................................. 32 
5.1.1 
Study drug ......................................................................................... 32 
5.1.2 
AE date imputation ............................................................................ 32 
5.1.3 
Concomitant medication date imputation ........................................... 35 
5.2 
AEs coding/grading ........................................................................................... 37 
5.3 
Laboratory parameters derivations ..................................................................... 37 
5.4 
Statistical models ............................................................................................... 37 
5.4.1 
Primary analysis ................................................................................ 37 
5.4.2 
Key secondary analysis ...................................................................... 37 
5.5 
Rule of exclusion criteria of analysis sets ........................................................... 38 
6 
Reference ...................................................................................................................... 38 


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LCZ696BDE01 
 
List of abbreviations 
ACE 
angiotensin converting enzyme 
ACEI(s) 
angiotensin converting enzyme inhibitor(s) 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance model 
ARB(s) 
angiotensin receptor blocker(s) 
AST 
aspartate aminotransferase 
bid 
twice a day 
BP 
blood pressure 
CCB 
Calcium channel blockers 
CHF 
chronic heart failure 
CPET 
cardiopulmonary exercise testing 
CRF 
Case Report/Record Form 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DBP 
diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
 
 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction  
 
 
IA 
interim analysis(es) 
ICD 
implanatable cardioverter defibrillator 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
i.v. 
intravenous(ly) 
 
 
LCZ696 
Novartis compound code 
LFT 
Liver function test 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MET  
metabolic equivalent of task 
mg 
Milligram 
MI 
myocardial infarction 
mmHg 
millimeter mercury 
mph 
mile per hour 
MRI 
magnetic resonance imaging 
NYHA 
New York Heart Association 
 
 


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PK 
pharmacokinetic(s) 
PCI 
percutaneous coronary intervention 
RER 
respiratory exchange ratio 
SAE(s) 
serious adverse event(s) 
SBP 
systolic blood pressure 
 
 
ULN 
upper limit of normal 
VAT  
Ventilatory anaerobic threshold 
VO2 
respiratory oxygen uptake 
VO2max 
respiratory oxygen uptake (max.) 
VO2peak 
respiratory oxygen uptake (peak) 
WBC 
White blood cell  
1 
Introduction 
The purpose of this document is to provide summary of the statistical methodology that will be 
used for this clinical study; this includes a detailed description of data summaries. Analysis 
plans in this document refer to the related statistical analysis sections in clinical study reports.   
This Statistical Analysis Plan (SAP) module describes the statistical analysis according to 
Section 9 of the study protocol along with any additional analyses, specifications or deviations 
planned. 
Data will be analyzed according to the data analysis section 9 of the study protocol which will 
be available in Appendix 16.1.1 of the CSR.  Important information is given in the following 
sections 2.7 (Analysis of secondary efficacy), 2.8 (Safety evaluation), 2.14 (Interim analysis) 
and 3 (Sample size calculation). 
1.1 
Study design 
 


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This study is a randomized, double-blind, double-dummy, parallel-group, active-controlled, 
two-arm, long-term trial to compare LCZ696 200 mg bid to enalapril 10 mg bid in improving 
exercise capacity, daily physical activity and quality of life in patients with stable CHF (NYHA 
III) and reduced ejection fraction (LVEF ≤ 40%). 
Eligible patients at stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks 
before Visit 1 and LVEF ≤ 40% can be randomized at Visit 3.  
VO2peak inclusion criterion will only be checked after assessment of patients’ eligibility 
according to all other inclusion and exclusion criteria. Thus, ergospirometry will be performed 
on Visit 2 to get a complete assessment of CPET (for screening), 
  
Once patients’ eligibility has been ascertained, they will attend Visit 3 for randomization 
approximately two weeks after Visit 1 to start enalapril 5 mg bid versus LCZ 100 mg bid for 2 
weeks.  
At baseline, all eligible patients will be randomized to receive either LCZ696 or enalapril in a 
1:1 allocation during the double-blind period.  
1.2 
Study objectives and endpoints 
1.2.1 
Primary objectives 
The primary objective of this study is to demonstrate the superiority of LCZ696 200 mg bid 
compared to enalapril 10 mg bid in improving exercise tolerance (VO2peak, adjusted to body 
weight) as assessed by cardiopulmonary exercise testing (CPET) in patients with stable chronic 
heart failure (NYHA class III) and reduced ejection fraction (LVEF ≤ 40%) after 3 months 
treatment. 
1.2.2 
Secondary objectives 
Secondary objectives are: 
• 
To demonstrate the superiority LCZ696 versus enalapril regarding improvement of 
exercise tolerance (VO2peak, adjusted to body weight) as assessed by cardiopulmonary 
exercise testing (CPET) in patients with chronic heart failure after 6 weeks treatment. 
• 
To compare LCZ696 versus enalapril on the following CPET parameters: 
• 
Change of VE/VCO2 slope after 6 weeks and 3 months 
• 
Change in exercise capacity (Watt) at ventilatory anaerobic threshold (VAT) 
after 6 weeks and 3 months 
• 
Change in rate of perceived exertion during exercise (Borg Scale) after 3 month 
• 
To assess the safety and tolerability of LCZ696 in patients with stable chronic 
heart failure with NYHA class III and reduced ejection fraction (LVEF ≤ 40%)  


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2 
Statistical methods 
Descriptive statistics will be provided for all study variables. The descriptive statistics will 
include mean, median, SD, minimum, maximum, and 95% confidence interval of the mean, as 
needed for continuous scale variables and frequency distributions for categorical variables. 
For categorical data, percentages will be rounded up to 1 decimal place. For continuous data, 
mean, and median will be rounded up to 1 additional decimal place compared to the original 
data. Standard deviation will be rounded up to 2 additional decimal places. Minimum and 
maximum will be displayed with the same accuracy as in the original data. Wherever changes 
from baseline will be used, change will be calculated as “post-baseline value – baseline value”. 
The number of decimal places for the “change from baseline” variables will be the same as for 
the original measurement. 
2.1 
Data analysis general information 
Statistical Analysis System (SAS) version 9.4 or higher will be used to perform all the statistical 
analyses in the report. 
2.1.1 
General definitions  
Patients who are eligible for randomization at Visit 3 will be assigned to one of the following 
two treatment arms in a 1:1 ratio. 
• LCZ696 bid and placebo to match enalapril bid 
• Enalapril bid and placebo to match LCZ696 bid  
All randomized patients will receive either LCZ696 100mg or enalapril 5mg in a 1:1 allocation 
during the double-blind period at visit 3. Dose will be up-titrated after 2 weeks (Visit 4) to the 
final dose of enalapril 10mg bid or LCZ696 200mg bid. For allowed investigational treatment 
dose adjustments during double-blind period refer to Section 5.5.5 in the protocol. 


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Baseline: Baseline value is defined as the last non-missing assessment prior to the first dose of 
randomized study medication unless specified otherwise. 
Post baseline: Any measurements taken after baseline will be considered as post-baseline 
measurements. 
Change from baseline: Post baseline value – baseline value 
Last contact: last contact will be the last time a patient’s study record has been taken. For a 
patient who is still alive and in study the last contact will be his/her last clinical contact. For 
patient who died or is determined to be lost to follow-up before the analysis cut-off date, the 
last contact will be his/her death/lost-to-follow-up day. 
Final Visit: Final visit will be the last time a patient’s study record has been taken. For a patient 
who is still alive and in the study the final visit will be his/her last clinical visit. For a patient 
who died or is determined to be lost to follow-up before the analysis cut-off date, the final visit 
will be his/her death/lost-to-follow-up day. For a patient who is alive but no longer has regularly 
scheduled clinic visits and whose study records only can be obtained by telephone or indirect 
contact, the final visit will be the day the study records being taken. 
2.2 
Analysis sets 
The following analysis sets will be defined for statistical analysis: 
• Screened set (SCR) – All patients who signed the informed consent. The screened set 
includes patients based on their patient IDs assigned at each screening visit. 
• Randomized set (RAN) - All patients who received a randomization number, regardless 
of receiving trial medication. 
• Full analysis set (FAS) - The full analysis set (FAS) will consist of all randomized 
patients who have received at least one dose of study drug. Efficacy variables will be 
analyzed based on the FAS as the primary population. 
• Safety set  (SAF) - The Safety Set (SAF) will consist of all randomized patients who 
received at least one dose of study drug. The safety Set will be used for the analyses of 
safety variables. 
2.2.1 
Subgroup of interest 
Not applicable. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Patient demographic and baseline characteristic data will be summarized based on FAS. Patient 
demographic and baseline characteristics include age, sex, and race. Relevant medical 
history/current medical condition, includes data until the start of study drug will be summarized. 
HF medications and other CV medications will be  summarized separately from other 
medications. Likewise, detailed HF history and other relevant CV medical history will be 
summarized separately from other medical history. 


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2.3.1 
Patient disposition 
The number and percentage of patients enrolled, completed, and discontinued in the study and 
reason for the discontinuation will be summarized by treatment group. The reasons for screen 
failure will also be provided. All data will be listed. The analysis set will be FAS.  
The number and percentage of the patients with protocol deviations as well as the criteria 
leading to exclusion from analysis sets will be presented for the FAS. 
2.3.2 
Demographic characteristics  
Summary statistics will be provided based on FAS by treatment group for demographics and 
baseline characteristics, including age, age group (<65 years, >= 65 and < 85 Years, and ≥85 
years), sex, race, weight, height, body mass index (BMI), category of prior CHF medication, 
prior HF hospitalization, NYHA class, and vital signs. BMI will be calculated as weight (kg) / 
(height (m))2 collected 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 following demographic variables will be analyzed: 
• Age (years) 
• Age group (<65 years, >= 65 and < 85 Years, and ≥85) 
• Gender (Male, Female) 
• Race (Caucasian, Black, Asian, Other) 
The following baseline characteristic variables will be analyzed: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• NYHA Class 
• LVEF (%) 
• Smoking History (Yes / No) 
• Alcohol History (Yes / No) 
• SBP 
• DBP 
• eGFR 
• Prior CHF medication 
 


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2.3.3 
Medical History 
Any condition entered on the relevant medical history / current medical conditions CRF will be 
coded using the MedDRA dictionary. HF history and other CV medical history will be 
summarized. 
The number and percentage of subjects with each medical condition will be provided by 
preferred term and system of organ class for the FAS. 
The above medical conditions will also be listed. 
Medical history possibly contributing to liver dysfunction and medical history possible related 
to statin will be summarized and listed seperatly based on FAS. 
• Heart failure History 
Heart failure history will be summarized by number and percent for following categories: 
o  Primary HF etiology (Ischemic /Non ischemic ) 
o If Non ischemic: 
 Hypertensive (Yes/No) 
 Diabetic (Yes/No) 
 Alcoholic (Yes/No) 
 Viral cardiomyopathy (Yes/No) 
 Infectious cardiomyopathy (Yes/No) 
 Peripartum (Yes/No) 
 Drug induced (Yes/No) 
 Hypertrophic cardiomyopathy (Yes/No) 
 Idiopathic (yes/No) 
 Unknown (Yes/No) 
 Vitium (Yes/No) 
                                                     - If Yes, hemodynamically significant? (Yes/No) 
o Prior heart failure hospitalization(yes/no) 
o Number of hospitalization in the last 12 months 
o Ejection Fraction (%) in last 6 months 
The heart failure history will also be listed for FAS. 
• Cardiovascular Medical history 
Cardiovascular history will be summarized by number and percent for following categories: 
o Prior myocardial infection (Yes/No) 
o Prior angina pectoris (Yes/No) 


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- 
If Yes, precise Angina Class (Class I, Class II, Class III, Class IV) 
o Did the subject have any prior PCIs? (Yes/No) 
o Did the subject have any prior CABGs (Yes/No) 
o Does the subject have a pacemaker? (Yes/No) 
o Does the subject have an ICD (Yes/No) 
The cardiovascular history will also be listed for FAS. 
Smoking history and alcohol history will be summarized in the separate tables based on FAS 
and will also be listed. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The overall duration on the double-blind study drug will be summarized by treatment group 
using n, mean, standard deviation, median, minimum, and maximum. Additionally, the number 
and percentage of patients will be summarized by treatment group for duration category. The 
analysis will be based on the SAF. 
Dose levels  
Exposition to the different dose levels will be analyzed as patient numbers on the specified dose 
levels on visit 4, visit 6 and visit 7.  
Doses and dose levels in the double blind phase as defined in the clinical study protocol are: 
LCZ696: dose level 1 = 50 mg bid, dose level 2 = 100 mg bid, dose level 2a = 100 mg bid and 
dose level 3 = 200 mg bid. 
Enalapril: dose level 1 =  2.5 mg bid, dose level 2 = 5 mg bid, dose level 2a = 10 mg bid, 
and dose level 3 = 10 mg bid. 
Duration of double-blind study drug exposure will be calculated based upon the start and stop 
dates recorded in the eCRF.  
• 
  Last date of study drug – start date of study drug+ 1 
2.4.2 
Prior, concomitant and post therapies 
Medications will be identified using Novartis Drug and Therapy Dictionary, NovDTD which is 
a modified Novartis internal version of Q3 2004 WHO Drug Reference List (DRL) including 
Anatomical Therapeutic Chemical (ATC) code. 
The concomitant medication information for the double blind phase will be summarized based 
on the SAF. 
Concomitant medications, significant non-drug therapies and surgical and medical procedures, 
prior to and after the randomization date respectively, will be summarized by treatment group 
based on the latest version of dictionary. Medications will be presented in alphabetical order, 
by ATC codes and grouped by anatomical main group (the 1st level of the ATC codes). Table 


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will also show the overall number and percentage of subjects receiving at least one drug of 
particular ATC code and at least one drug in a particular anatomical main group.   
As before, concomitant medication will be identified based on recorded or imputed start and 
end dates of medication taking. The rules for imputing incomplete (start and end) dates are 
described in Section 5.1.3. 
Concomitant heart failure and CV medications administered during double blind period will be 
summarized separately, in the same way. More specifically, the following classes of medication 
will be summarized separately. 
• 
Aldosterone antagonists 
• 
β- blockers 
• 
Ivabradine 
• 
Diuretics 
• 
Digoxin 
• 
Other 
• 
Statin 
• 
ACEI 
• 
ARBs 
Below ATCs will be used to present ATC specific table for during and/or prior to study period: 
ATC codes  
Sub group  
Sub sub group  
Period 
C 
CARDIOVASCULAR 
SYSTEM  
C01 CARDIAC THERAPY 
C01A CARDIAC GLYCOSIDES  
Prior, During 
  
  
C01B ANTIARRHYTHMICS, CLASS I AND III  
Prior, During 
  
  
C01C CARDIAC STIMULANTS EXCL. CARDIAC 
GLYCOSIDES  
Prior, During 
  
  
C01D VASODILATORS USED IN CARDIAC 
DISEASES  
Prior, During 
  
  
C01E OTHER CARDIAC PREPARATIONS  
Prior, During 
  
C02 
ANTIHYPERTENSIVES 
C02A ANTIADRENERGIC AGENTS, CENTRALLY 
ACTING  
Prior, During 
  
  
C02B ANTIADRENERGIC AGENTS, GANGLION-
BLOCKING  
Prior, During 
  
  
C02C ANTIADRENERGIC AGENTS, 
PERIPHERALLY ACTING  
Prior, During 
  
  
C02D ARTERIOLAR SMOOTH MUSCLE, 
AGENTS ACTING ON  
Prior, During 
  
  
C02K OTHER ANTIHYPERTENSIVES  
Prior, During 
  
  
C02L ANTIHYPERTENSIVES AND DIURETICS IN 
COMBINATION  
Prior, During 
  
  
C02N COMBINATIONS OF 
ANTIHYPERTENSIVES IN ATC-GR. C02  
Prior, During 
  
C03 DIURETICS 
C03A LOW-CEILING DIURETICS, THIAZIDES  
Prior, During 
  
  
C03B LOW-CEILING DIURETICS, EXCL. 
THIAZIDES  
Prior, During 
  
  
C03C HIGH-CEILING DIURETICS  
Prior, During 


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C03D POTASSIUM-SPARING AGENTS  
Prior, During 
  
  
C03E DIURETICS AND POTASSIUM-SPARING 
AGENTS IN COMBINATION  
Prior, During 
  
  
C03X OTHER DIURETICS  
Prior, During 
  
C04 PERIPHERAL 
VASODILATORS 
  
Prior, During 
  
C05 VASOPROTECTIVES 
  
Prior, During 
  
C07 BETA BLOCKING 
AGENTS 
C07A BETA BLOCKING AGENTS  
Prior, During 
  
  
C07B BETA BLOCKING AGENTS AND 
THIAZIDES  
Prior, During 
  
  
C07C BETA BLOCKING AGENTS AND OTHER 
DIURETICS  
Prior, During 
  
  
C07D BETA BLOCKING AGENTS, THIAZIDES 
AND OTHER DIURETICS  
Prior, During 
  
  
C07E BETA BLOCKING AGENTS AND 
VASODILATORS  
Prior, During 
  
  
C07F BETA BLOCKING AGENTS, OTHER 
COMBINATIONS  
Prior, During 
  
C08 CALCIUM CHANNEL 
BLOCKERS 
C08C SELECTIVE CALCIUM CHANNEL 
BLOCKERS WITH MAINLY VASCULAR EFFECTS  
Prior, During 
  
  
C08D SELECTIVE CALCIUM CHANNEL 
BLOCKERS WITH DIRECT CARDIAC EFFECTS  
Prior, During 
  
  
C08E NON-SELECTIVE CALCIUM CHANNEL 
BLOCKERS  
Prior, During 
  
  
C08G CALCIUM CHANNEL BLOCKERS AND 
DIURETICS  
Prior, During 
  
C10 LIPID MODIFYING 
AGENTS 
C10A LIPID MODIFYING AGENTS, PLAIN  
Prior, During 
  
  
C10B LIPID MODIFYING AGENTS, 
COMBINATIONS  
Prior, During 
 
C09 AGENTS ACTING ON 
THE RENIN-
ANGIOTENSIN SYSTEM 
 
C09A ACE INHIBITORS, PLAIN 
Prior 
 
 
C09B ACE INHIBITORS, COMBINATIONS 
Prior 
 
 
C09C ANGIOTENSIN II RECEPTOR BLOCKERS 
(ARBs), PLAIN 
Prior 
 
 
C09D ANGIOTENSIN II RECEPTOR BLOCKERS 
(ARBs), COMBINATIONS 
Prior 
 
 
C09X OTHER AGENTS ACTING ON THE RENIN-
ANGIOTENSIN SYSTEM 
Prior 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is change of VO2peak compared to baseline measurements (adjusted to 
body weight) after 3 months of treatment. 
As per the protocol amendement, the primary variable changed from “VO2peak adjusted to lean 
body weight” to “VO2peak adjusted to body weight”. Furthermore, VO2peak adjusted will be 
derived programatically as follows for the analysis: 
 


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VO2peak (unadjusted) 
VO2peak (adjusted) = ________________________ 
                   Body weight  
VO2peak (adjusted) will be calculated at visit 2, 6 and 7 based on the every visit’s VO2peak 
(unadjusted) and weight data. 
Efficacy analysis will be summarized based on FAS. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis will be performed using analysis of covariance (ANCOVA) model with 
treatment and center as factors and baseline VO2peak as a covariate. The raw as well as the 
adjusted (LS) group means will be presented. Additionally, a 95% confidence interval and p-
value will be presented for the treatment contrast.  
Listing will be based on dervied VO2peak data. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing values of VO2peak will be replaced with the last observed value (LOCF). Since the trial 
aims to estimate which improvements are achievable under the respective treatment regiments, 
LOCF seems to provide meaningful estimates for this purpose. 
2.5.4 
Supportive analyses 
In case of deviations from the normality assumptions, treatments may additionally be compared 
by a non-parametric test (Mann-Whitney-U-test). In case of a substantial rate of missing data 
(>15%) or strong imbalances between treatment groups, Multiple Imputation (MI) may be 
considered as a sensitivity analysis. 
2.6 
Analysis of the key secondary objective 
2.6.1 
Key secondary endpoint 
The key secondary endpoint is change of VO2peak compared to baseline measurements (adjusted 
to body weight) at week 6. Efficacy analysis will be summarized based on FAS. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
The key secondary endpoint, the change from baseline in VO2peak (adjusted to body weight) at week 
6 will be analyzed similarly to the primary endpoint. The significance level will not be adjusted for 
multiplicity, the result of the test for week 6 will be regarded as providing confirmatory evidence, 
only if the test of the primary hypothesis (month 3) is also significant (a-priori ordered hypotheses). 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The following secondary endpoints will be analyzed: 


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• Change from in VE/VCO2 slope after 6 weeks  and 3 months  
• Change in exercise capacity (Watt) at VAT after 6 weeks and 3 months 
• Change  in rate of perceived exertion (Borg Scale) during exercise after 6 weeks and 3 
months 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Secondary efficacy variables will be analyzed using ANCOVA models analogous to the 
analyses of the primary endpoint. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing values will not be imputed and will be considered missing at that particular visit. 
2.8 
Safety analyses 
Safety assessments will be based mainly on the frequency of adverse events. Adverse events 
will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). An adverse event related to study drug is 
defined as one considered by the investigator to have a suspected relationship with the study 
drug. The adverse events will be summarized by the number and percentage of patients in each 
primary system organ class and preferred term. For summaries by severity of event, the most 
severe occurrence for a particular preferred term will be used for a given patient. Summary 
tables of adverse events by treatment and severity will be provided. 
Multiple occurrences of the same AE or SAE in the same patient will be counted only once, 
using the worst severity and drug relationship. 
In the data listings of adverse events, the severity of an AE, whether or not an AE is study drug 
related, and whether or not it is a serious AE, will be indicated. 
Abnormal laboratory values or test results constitute adverse events only if they induce clinical 
signs or symptoms or require therapy. 
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values (means, medians, standard deviations, ranges) and by presenting number 
and percentage of patients with notable laboratory abnormalities according to Appendix 1.  
Data from other tests (vital signs) will be listed, notable values will be flagged, and any other 
information collected will be listed as appropriate. 
All safety analysis will be based on SAF. 
2.8.1 
Adverse events (AEs) 
Any AE occurred during the study period will be included in AE summary tables, i.e. AEs 
occurred in screening phase and double blind period and SAE up to 30 days after the study 
completion.  
The MedDRA version used for reporting the study will be described in a footnote. 


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Within each reporting phase, the following rules are applicable. If a subject reported more than 
one adverse event with the same preferred term, the adverse event with the greatest severity 
will be presented. If a subject reported more than one adverse event within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the system 
organ class level, where applicable. Statistical analyses, which will only be performed for the 
double blind or later phase, will include all post-baseline AEs up to and including the analysis 
cut-off (AEs up to the final visit and SAEs up to 30 days after the final visit for each patient) 
irrespective of how long after the last day of study treatment they occurred. 
The number and percentage of subjects reporting any adverse event during reporting will be 
summarized by primary system organ class, preferred term and treatment. The most common 
adverse events reported (≥ 1 % in any group for each preferred term in the SOC-PT table) will 
be presented in descending frequency according to its incidence in the LCZ696 group starting 
from the most common event.  
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to study discontinuation and adverse 
events leading to dose adjustment. 
The following summaries will be generated for AEs during the double blind period: 
• 
All adverse events 
• 
Serious adverse events 
• 
Adverse event by severity grade 
• 
Adverse events causing study drug discontinuation 
• 
Adverse events requiring dose adjustment or study-drug interruption 
• 
Investigator reported causes of deaths by primary system organ class and preferred 
       Term 
The above information also be listed. Analysis will be based on SAF.  
2.8.1.1 
Adverse events of special interest / grouping of AEs 
AEs of special interest will be summarized separately in addition to the above analysis. The 
following are the AEs of special interest: angioedema events and angioedema-like events, dementia-
related events, hepatotoxicity (drug related hepatic disorders) and statin-related events (only 
rhabdomyolysis, acute pancreatitis, myalgia and muscle spasm). The information will also be listed. 
Analysis will be based on SAF. 
2.8.2 
Deaths 
Death will be summarized by number and percentage of patients in each primary system organ class 
and preferred term based on SAF. 
2.8.3 
Laboratory data 
Laboratory data will be summarized for double blind period based on the SAF and also be listed. 
Laboratory data for hematology (including hemoglobin, hematocrit, red blood cell count(RBC), 
white blood cell count with differential (WBC), and platelet count), and blood chemistry 
(including Blood urea nitrogen (BUN), glucose, creatinine, total bilirubin, AST (SGOT), ALT 


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(SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, HbA1C, total protein, 
albumin, uric acid, and lipid profile, estimated glomerular filtration rate (eGFR)) will be 
summarized by treatment.  
The eGFR is calculated according to the formula: 
eGFR (mL/min/1.73 m2) = 175 x (Serum creatinine/88.4)-1.154 x (Age)-0.203  
                                                         x (0.742 if female) x (1.212 if black), 
where serum creatinine is in μmol/L (SI unit) and age is non-rounded at the time of the 
laboratory sample in years. 
Descriptive summary statistics (mean, median, standard deviation, min and max) for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post-baseline values and will be calculated as 
defined in section 2.1.1. 
The number and percentage of subjects with clinically notable laboratory results after baseline 
will be presented. Clinically notable laboratory results, for those parameters where ranges are 
available, are given in appendix 1 below. For the calculation the denominator are based on the 
evaluable post-baseline subjects who did not have the notable abnormality at baseline from the 
central laboratory. 
2.8.3.1 
Hematology 
Hematology tests performed may include the following: 
• Hemoglobin 
• Hematocrit 
• RBC 
• WBC count with differential 
• Platelet  
The above tests will be analysed at visit 1 and 7. 
2.8.3.2 
Clinical chemistry 
Blood Chemistry tests performed may include the following: 
• Blood urea nitrogen (BUN) 
• Creatine kinase (CK)  
• Glucose 
• Creatinine  
• Total bilirubin (TBL) 
• AST (SGOT) 
• ALT (SGPT) 


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• Alkaline phosphatase (ALP) 
• Sodium 
• Potassium 
• Potassium 
• Calcium 
• Hemoglobin A1C 
• Total protein 
• Albumin 
• Uric acid 
• Lipid profile 
The above tests will be analysed at visit 1 and 7. 
• Thyroid-stimulating hormone (TSH) will be assessed at Visit 1 only. 
BUN, serum potassium, and serum creatinine value for eGFR calculation will be obtained from 
patients at every visit when a complete laboratory test is not done (i.e., Visits 3-5). 
2.8.3.3 
Liver event  
Liver event data of sign and symptoms will be summarized and listed based on data collected 
on eCRF. Analysis will be based on SAF.  
Liver events –imaging will be listed based on SAF. 
2.8.3.4 
Specific laboratory data 
Liver function test (LFT) data will be analyzed according to what specified in hepatotoxicity in 
appendix 2 in section 5. 
Laboratory data related to renal dysfunction (serum creatinine, eGFR) will be analyzed 
according to what specified in renal dysfunction in appendix 3 in section 5. 
Laboratory data related to hyperkalemia (serum potassium greater than or equal to 5.3 mmol/L) 
will be analyzed according what specified in appendix 4 in section 5. 
 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable. 
2.8.4.2 
Vital signs 
Sitting systolic blood pressure (SSBP), sitting diastolic blood pressure (SDBP), sitting pulse 
rate and body weight will be summarized by treatment group and visit, including changes from 


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baseline. Summary statistics will be based on SAF. Where the baseline is defined as visit 2 and 
double blind period is from visit 3 to visit 7.  
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as defined in section 2.1.1. 
2.8.4.3 
Height and Weight and waist hip circumference 
Height (cm), Body weight (kg), Waist/hip circumference (cm) will be summarized by treatment 
group and visit, including changes from baseline using SAF.   
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as defined in section 2.1.1. 
2.8.4.4 
NYHA Class assessment 
Patients’ NYHA class will be assessed at baseline and post-baseline. At baseline, only patients 
with heart failure NYHA class III can be enrolled in the study. The total number and percentage 
of patient with each NYHA class will be provided by treatment group and visits based on SAF. 
The change in NYHA class at every post-baseline visit compared to baseline will be 
summarized by frequency distribution. 
2.9 
Pharmacokinetic endpoints   
Not applicable. 
2.10 
PD and PK/PD analyses 
Not applicable. 
2.11 
Ergospirometry analysis 
Ergospirometry data will be summarized for visit 2 (baseline), visit 6 and visit 7.  
The data will be collected for the below parameters: 
• VO2peak adjusted 
• 
 
 
• VE/VCO2 
• Exercise capacity (Watt) at VAT  
• 
 
• 
  
• 
 
 
Descriptive summary statistics (mean, median, standard deviation, min and max) for baseline 
(visit 2) and change from the baseline to visit 6 and visit 7 will be presented. The descriptive 
summaries will be presented by ergospirometry parameters and treatment group based on FAS. 
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as defined in section 2.1.1. 


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Reason for termination will also be summarized seperatly based on FAS.  
 
 
 
 
 
 
 
 
 
 
2.13 
Borg scale analysis 
Borg scale data will be summarized for visit 2 (baseline), visit 6 and visit 7.  
Descriptive summary statistics (mean, median, standard deviation, min and max) for the 
baseline and change from the baseline to visit 6 and visit 7 will be presented. The descriptive 
summaries will be presented by treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post-baseline values and will be calculated as 
defined in section 2.1.1. Maximum value among the timepoints at every visit will be used for 
the analysis. In case of multiple maximum values at the same visit, the most recent timepoint 
will be considered in the analysis. Listings will be provided with all the timepoint values at all 
visits. 


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2.19 
Biomarkers 
Not applicable. 


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2.21 
Interim analysis 
Not applicable. 
3 
Sample size calculation 
Existing data suggest that the difference between LCZ696 and enalapril in VO2peak at month 3 
may be about 1.5 mL kg−1 min−1 with a (common) SD of 3 (Guazzi et al. 1999; Lewis et al. 
2007). Under these assumptions, 86 patients per treatment arm would be required to achieve 
90% power on a 2-sided, 5% significance level. To compensate for some drop-out and other 
protocol deviation 100 patients per treatment group (200 in total) will need to be enrolled into 
this trial. The above mentioned literature suggests that the treatment effect for the key secondary 
endpoint, VO2peak after 6 weeks, might be of a similar magnitude, therefore, the sample size 
calculation above applies also for the key secondary endpoint.  
4 
Change to protocol specified analyses 
VO2peak adjusted to body weight will be calculated as follows for the analysis: 
VO2peak (unadjusted) 
VO2peak (adjusted) = ________________________ 
                   Body weight  
VO2peak (adjusted) will be calculated at visit 2, 6 and 7 based on the visit’s VO2peak (unadjusted) 
and body weight data. 
Note1: The collected data of VO2peak adjusted will remain as it is in source data.  
 


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Note2: Patient 
 was unblinded at site on 
 for safety purpose. However, as 
confirmed by CTT, the patient would not be excluded from the analyses.  
5 
Appendix 
Appendix 1: Clinically notable laboratory values  
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:  
Hematology  
RBC count >50% increase, >20% decrease  
Hemoglobin >50% increase, >20% decrease  
Hematocrit >50% increase, >20% decrease  
WBC count >50% increase, >50% decrease  
Platelet count >75% increase, >50% decrease  
Blood Chemistry  
ALT (SGPT) >150% increase  
AST (SGOT) >150% increase  
BUN >50% increase  
Creatinine >50% increase  
Total bilirubin >100% increase  
CPK >300% increase  
Alkaline phosphatase >100% increase  
Potassium >20% increase, >20% decrease  
Chloride >10% increase, >10% decrease  
Calcium >10% increase, >10% decrease  
Uric acid >50% increase 
Appendix 2: Liver event definitions and follow-up requirements 
 
  Table 19-1 Liver event definitions                                                                                                                              
 
Definition/ 
Adverse    event    of    
special interest 
Laboratory values 
ALT or AST > 3 x ULN 
ALP 
TBL > 


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Medically    significant    event 
(SAE) 
Laboratory values 
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN 
[mainly conjugated fraction]) 
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction]) 
TBL 
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN 
and TBL 
> 2 x ULN [mainly conjugated fraction] without notable 
Adverse events 
Any clinical event of jaundice (or equivalent term) 
ALT or AST > 3 x ULN accompanied by general 
malaise, fatigue, abdominal pain, nausea, or vomiting, or 
Any event that links to a preferred term (PT) in the 
MedDRA dictionary falling under the SMQ sub-module 
“Drug-related hepatic disorders – severe events only”* or 
* 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 
 
  Table 19-2 Liver event follow up requirements                                                                                                        
 
Criteria 
Event 
Actions required 
Follow-up monitoring 
Potential Hy’s 
Law 
case
a 
Medicall
y 
significa
nt 
Discontinue    the    study    
drug immediately 
Hospitalize,         if         
clinically appropriate 
Report to Novartis as an 
SAE Establish causality
ALT,  AST,  TBL,  Alb, 
PT, ALP      and      γGT 
until 
resolutionc  
(frequency 
 
 
 
at 
investigator discretion) 
ALT or AST 
> 8 x ULN 
Medicall
y 
significa
nt 
Repeat LFT within 48 hours 
If elevation persists, 
discontinue the study drug 
immediately 
Hospitalize         if         
clinically appropriate 
Report to Novartis as an 
ALT,  AST,  TBL,  Alb, 
PT, ALP      and      γGT 
until 
resolutionc  
(frequency 
 
 
 
at 
investigator discretion) 
> 5 to ≤ 8 x ULN 
Medicall
y 
significa
nt 
Repeat LFT within 48 
hours 
If  elevation  persists  for  
more than  2  weeks, 
discontinue  the study drug 
Report to Novartis as an 
ALT,  AST,  TBL,  Alb, 
PT, ALP      and      γGT 
until 
resolutionc  
(frequency 
 
 
 
at 
investigator discretion) 
> 3 x ULN 
accompanied 
by 
symptomsb 
Medicall
y 
significa
nt 
Discontinue    the    study    
drug immediately 
Hospitalize         if         
clinically appropriate 
Report to Novartis as an 
SAE Establish causality
ALT,  AST,  TBL,  Alb, 
PT, ALP      and      γGT 
until 
resolutionc  
(frequency 
 
 
 
at 
investigator discretion) 


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> 3 to ≤ 5 x 
ULN (patient 
is 
asymptomati
c) 
AESI 
Central  laboratory  to  
report  to 
Investigator & Novartis 
Repeat LFT once or twice 
in the week 
If elevation persists,
Investigator discretion 
Monitor  LFT  within  1  
to  4 weeks or at next 
visit 
≤ 3 x ULN 
(patient is 
asymptoma
N/A 
Repeat LFT at next visit 
ALP (isolated) 
> 5 x ULN 
Medicall
y 
significa
nt 
Repeat LFT within 48 hours 
If  elevation  persists,  report
to 
Novartis as an SAE 
Investigator discretion 
Monitor  LFT  within  1  
to  4 weeks or at next 
visit 
> 2 to ≤5 x ULN 
(patient is 
asymptomatic) 
AESI 
Central  laboratory  to  
report  to 
Investigator & Novartis 
Repeat LFT once or twice in 
the week. If elevation 
Investigator discretion 
Monitor  LFT  within  1  
to  4 
Weeks or at next visit 
≤ 2 x ULN  
(patient is 
asymptomatic)  
N/A 
Repeat LFT at next visit  
 
 
TBL (isolated)  
 
> 3 x ULN  
Medically 
significant  
 
Repeat LFT within 48 hours  
If elevation persists, 
discontinue the study drug 
immediately  
Hospitalize if clinically 
appropriate  
Report to Novartis as an SAE  
Establish causality  
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)  
Test for hemolysis (e.g., 
reticulocytes, 
haptoglobin, 
unconjugated [indirect] 
bilirubin)  
 
> 1.5 to ≤ 3 x 
ULN  
(patient is 
asymptomatic)  
AESI  
 
 
Central laboratory to report to 
Novartis  
Repeat LFT once or twice in 
the week  
If elevation persists, establish 
causality  
investigator discretion  
Monitor LFT within 1 to 4 
weeks or at next visit  
≤ 1.5 x ULN  
(patient is 
asymptomatic)  
N/A  
 
Repeat LFT at next visit  
 
 
Preferred terms  


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Jaundice  
 
Medically 
significant  
 
Discontinue the study drug 
immediately  
Hospitalize the patient  
Report to Novartis as an SAE  
Establish causality  
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc  (frequency at 
investigator discretion)  
 
“Drug-related 
hepatic disorders - 
severe events 
only” SMQ AE  
 
Medically 
significant  
 
Discontinue the study drug  
hospitalization if clinically 
appropriate  
Report to Novartis as an SAE  
Establish causality  
Investigator discretion  
 
a     Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to     
     > 2 x ULN  
b     General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia  
c   Resolution is defined as an outcome of one of the following: return to baseline values,    
    stable values at three subsequent monitoring visits at least 2 weeks apart, remain at elevated         
    level after a maximum of 6 months, liver transplantation, and death. 
 
Appendix 3: Guidelines for the management of renal dysfunction  
General principles:  
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, renal 
dysfunction may develop or may deteriorate in some patients after study drug administration. 
These recommendations have been developed to guide the investigators in managing patients 
with renal dysfunction after randomization.  
Two types of response to serum creatinine increase are described:  
Surveillance situation  
If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (Visit 2) (or if 
serum creatinine concentration increase to 2.5 mg/dL [221 μmol/L]), the investigator will check 
for potentially reversible causes of renal dysfunction such as:  
• 
Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia  
• 
Volume decrease, including that resulting from excessive dosing of diuretics  
• 
Urinary infection  
• 
Urinary tract obstruction  
• 
Study medication  
Action situation  
If a patient eGFR decreases by ≥ 40% from baseline (Visit 2) (or if serum creatinine 
concentration rises above 3 mg/dL (265 μmol/L)), the investigator will check for potentially 
reversible causes of renal dysfunction (see above).  


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If the investigator judges that study medication has to be stopped, he/she will have to contact 
the Novartis medical monitor or his/her designee. Thereafter, serum creatinine assessments will 
have to be repeated at least each week until levels return to acceptable values. If study 
medication was stopped, every effort will be done to restart it again, according to clinical 
conditions. 
Appendix 4: Treatment guidelines for hyperkalemia (serum potassium 
greater than or equal to 5.3 mmol/L)  
General principles  
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken.  
Any patient with a serum potassium ≥ 5.3 mmol/L after enrollment into the study requires 
regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) 
until it is clear that the potassium concentration is stable and not rising into the range of concern 
(≥ 5.5 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L).  
Patients with 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  
• Confirm potassium concentration in a non-hemolyzed sample  
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.)  
• Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents:  
• 
Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia)  
• 
Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics  
• 
Potassium supplements, e.g., potassium chloride  
• 
Salt substitutes  
• 
Non-steroidal anti-inflammatory drugs (NSAIDs)  
• 
Cyclo-oxygenase-2 (COX-2) inhibitors  
• 
Trimethoprim 
and 
trimethoprim-containing 
combination 
products, 
such 
as 
trimethoprim/sulfamethoxazole fixed combinations  
• 
Herbal Supplements:  


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o For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of 
the valley, Siberian ginseng, hawthorn berries  
• Repeat serum potassium measurement within 3 to 5 days  
• If serum potassium remains ≥ 5.3 and ≤ 5.5 mmol/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  
• Confirm potassium concentration in a non-hemolyzed sample  
• Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment.  
• Apply all measures outlined for serum potassium ≥ 5.3 and ≤ 5.5 mmol/L  
• Repeat serum potassium measurement after 2-3 days  
• If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days  
 
Serum potassium greater than or equal to 6.0 mmol/L  
• 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  
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee. 
 
5.1 
Imputation rules 
5.1.1 
Study drug 
Not applicable. 
5.1.2 
AE date imputation 
Date imputation for AEs will be imputed according to Novartis conventions described in [RAP 
Module 8]. 
AE Start Date Imputation (#IMPUTAEV) 


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This algorithm is expressed in the Variable Source Derivation column as #IMPUTAEV (event) 
where event is the partial date of the adverse event. 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date(TRTSTD) 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
 
 
MON 
MISSING 
MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
NC 
Uncertain 
YYYY<TRTM 
( D ) 
Before Treatment 
Start 
( C ) 
Before Treatment 
Start 
( C ) 
Before Treatment 
Start 
( C ) 
Before Treatment 
Start 
YYYY=TRTM 
(B) 
Uncertain 
( C ) 
Before Treatment 
Start 
(A) 
Uncertain 
(A) 
After Treatment Start 
YYYY>TRTM 
(E) 
After Treatment Start 
(A) 
After Treatment Start 
(A) 
After Treatment Start 
(A) 
After Treatment Start 
The following table is the legend to the logic matrix. 
If AE end date is complete and AE end date < Treatment start date or AE end date is partial and 
AE imputed end date < Treatment start date, then AE start reference = min (informed consent 
date, earliest visit date from SV) 
Else if AE end date is partial, AE end date ≥ Treatment start date or AE is ongoing , then AE 
start reference = treatment start date. 
 
Relationship 
 
 
Before AE Start reference 
Partial date indicates AE start 
date prior to AE start reference 
 
After AE Start reference 
Partial date indicates AE start 
date after AE start reference 
 
Uncertain 
 
Partial date insufficient to 
determine relationship of AE 
start date 
to AE start reference 
 
Imputation Calculation 
 
 
 
NC/Blank 
No convention 
 


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(A) 
MAX( 01MONYYYY, AE start 
reference+1 day) 
 
(B) 
AE start reference+1 
 
(C) 
15MONYYYY 
 
(D) 
01JULYYYY 
 
 
(E) 
01JANYYYY 
 
Complete date 
No date imputation 
If time is captured for 
the study: 
Case 1. if AE start date 
is not 
equal to AE start 
reference 
then do the following: 
if minutes missing then 
AESTMF = M and time 
is 
imputed to hh:00 
if time missing then 
AESTMF = H and time 
is 
imputed to 00:00 
Case 2: if AE start 
date = AE 
start reference then 
AESTMF =  
H and time is imputed to 
treatment start time + 1 
hour 
Adverse Event End Date Imputation 
Imputed date = date part of original date, if complete date 
Imputed date = min (visit 299 date, DEC 31, date of death), if month is missing, 
Imputed date = min (visit 299 date, last day of the Month, date of death), if day is missing. 
Adverse Event End Time Imputation 
If the AE end date is complete and time is captured in the study then: 
Case 1. if AE end date is not equal to Treatment end date, then do the following: 
if minutes missing then time is imputed to hh:00 
if time missing then time is imputed to 00:00 


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Case 2: if AE end date = treatment end date then time is imputed to treatment end time 
If the AE end date is partial then end time is imputed to 00:00. 
Imputed Date Flag 
If year of the imputed date is not equal to YYYY then date flag = Y 
else if month of the imputed date is not equal to MON then date flag = M 
else if day of the imputed date is not equal to day of original date then date_flag = D 
else date flag = null 
Imputed Time Flag 
If hours of the imputed time is not equal to hours of original time then time flag = H 
else if minutes of the imputed time is not equal to minutes of original time then time flag = M 
else time flag = null 
5.1.3 
Concomitant medication date imputation 
Date imputation for concomitant medications will be imputed according to Novartis 
conventions described in [RAP Module 8]. 
Concomitant medication(CMD) start date imputation (#IMPUTMED) 
Rules for imputing the CMD start date: 
This algorithm is used when event is the partial start date of the concomitant medication, non-
drug therapy/procedure, or prior anti-neoplastic therapy. 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
 
Day 
Month 
Year 
Partial CM Start Date 
Not used 
MON 
YYYY 
Treatment Start Date(TRTSDT)    
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
 
 
MON 
MISSING 
MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
(C2) 
Uncertain 
(C1) 
Uncertain 
(C1) 
Uncertain 
(C1) 
Uncertain 


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YYYY<TRTY 
(D) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
(A) 
Before Treatment 
Start 
YYYY=TRTY 
(C2) 
Uncertain 
(A) 
Before Treatment 
Start 
(C1) 
Uncertain 
(B) 
After Treatment Start 
YYYY>TRTY 
(E) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
(B) 
After Treatment Start 
 
The following table is the legend to the logic matrix. 
Relationship 
 
Before Treatment Start 
Partial date indicates CMD start date prior to 
Treatment Start Date 
After Treatment Start 
Partial date indicates CMD start date after 
Treatment Start Date 
Uncertain 
Partial date insufficient to determine 
relationship of CMD start date relative to 
Treatment 
Start Date 
Imputation Calculation 
 
(A) 
15MONYYYY 
(B) 
01MONYYYY 
(C1 or C2) 
IF relative reference start = before treatment 
start THEN TRTSDT-1 
ELSE IF relative reference start = ‘ ’ THEN 
TRTSDT+1 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
Concomitant medication end date imputation 
If not ongoing then - 
Imputed date = date part of CMENDTC, if complete date 
Imputed date = min(visit 299 date, DEC 31) , if month is missing, (C2, D, E) 
Imputed date = min(visit 299 date, last day of the Month) , if day is missing. (A, B, C1) 
Concomitant medication date flag 
If not a complete date then 
Y - If year of the imputed date is not equal to YYYY else 


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M – If month of the imputed date is not equal to MON else 
D 
5.1.3.1 
Prior therapies date imputation 
Not applicable. 
5.1.3.2 
Post therapies date imputation 
Not applicable. 
5.1.3.3 
Other imputations 
5.2 
AEs coding/grading 
Not applicable. 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
For ANCOVA model 
proc mixed data = a; 
  class TRTN CENTRE; 
  model Estimate = TRTN CENTRE BSL_VO2peak; 
  lsmeans TRTN/om; 
  estimate 'LCZ696 - Enalapril' trtn 1 -1 /cl;  
run; 
For Mann-Whitney-U-test 
In case of deviations from the normality assumptions, treatments will additionally be compared 
by a non-parametric test (Mann-Whitney-U-test). 
 
proc NPAR1WAY data=a wilcoxon; 
 class TRTN CENTRE; 
 var VO2peak; 
 exact wilcoxon; 
run; 
here VO2peak variable contains change from baseline to Week X. 
 
5.4.2 
Key secondary analysis 
Key secondary endpoint will be analyzed similarly to the primary endpoint. 
 
 


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5.5 
Rule of exclusion criteria of analysis sets  
The following protocol deviations will be considered as major and will lead to exclusion of 
subjects from the respective analysis set: 
Category 
Description of Protocol 
Deviation 
Inclusion / Exclusion 
in 
analyses 
Severity code 
Study treatment Patient was misrandomized 
(patient randomized in error and no DB 
study 
medication taken). 
Excluded from 
FAS, SAF 
3 
Inclusion 
criteria 
Informed consent missing 
Excluded from 
FAS, SAF 
3 
General 
All other PDs 
Include in FAS, SAF 
0 
 
6 
Reference 
Same as protocol. 
Benjamin Waschki, Anne Kirsten, Olaf Holz, Kai-Christian Müller, Thorsten Meyer, Henrik 
Watz and Helgo Magnussen 
Chest; Prepublished online January 27, 2011; OI 10.1378 
http://chestjournal.chestpubs.org/content/early/2011/01/18/chest.10-2521