Conditions: Hearth Failure With Reduced Ejection Fraction (HFrEF)
Keywords: HFrEF, ACEi, ACE inhibitor, ARBs, systolic heart failure, chronic heart failure, CHF, reduced EF, Ejection Fraction
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 302
Healthy volunteers: no

Brief summary:
The primary purpose of the study was to describe the tolerability of treatment with the optimal dose of LCZ696 (97 mg sacubitril / 103 mg valsartan bid), over six (6) months, in patients with heart failure with reduced ejection fraction (HFrEF) in Canada.

The study was also to describe the overall tolerability, effectiveness and safety of LCZ696 for the management of HFrEF over 12 months of treatment, as well as describe the patterns of LCZ696 up and down dose titrations occurring during the management of patients with HFrEF.

Detailed description:

Arms:
arm 1: All patients were initiated on either LCZ696 at 24 mg sacubitril / 26 mg valsartan or LCZ696 at 49 mg sacubitril / 51 mg valsartan bid for 2-4 weeks and were up-titrated to the next higher dose for another 2 - 4 weeks as applicable.

Interventions: intervention 1: LCZ696 (sacubitril/valsartan)
Intervention descriptions: intervention 1: All patients were treated with the LCZ696 (sacubitril and valsartan) tablets

Protocol document:
Prot_001.pdf: 
Clinical Development 
LCZ696 
Clinical Trial Protocol CLCZ696BCA02 / NCT02690974 
PARASAIL - Prospective, multi-center, open lAbel, post-
appRovAl Study AImed at characterizing the use of LCZ696 at 
97 mg sacubitril / 103 mg valsartan bid in patients with HFrEF 
Authors: 
 
Document type: 
Clinical Trial Amended Protocol 
EUDRACT number: 
Not Applicable 
Version number: 
0.1 (Amendment 1) 
Development phase: 
IV 
Release date: 
12-Sep-2016
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 ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................ 8 
Amendment 1 ............................................................................................................................. 9 
Protocol synopsis .............................................................................................................. 11 
 
Introduction ....................................................................................................................... 16 
 
Background ........................................................................................................... 16 
 
Purpose .................................................................................................................. 18 
 
Study objectives ................................................................................................................ 19 
 
Primary .................................................................................................................. 19 
 
Secondary objectives ............................................................................................. 19 
19 
 
Investigational plan ........................................................................................................... 19 
 
Study design .......................................................................................................... 19 
 
Rationale of study design ...................................................................................... 20 
 
Rationale of dose/regimen, route of administration and duration of treatment..... 21 
 
Rationale for choice of comparator ....................................................................... 21 
 
Purpose and timing of interim analyses/design adaptations .................................. 21 
 
Risks and benefits .................................................................................................. 21 
 
Population ......................................................................................................................... 22 
 
Inclusion criteria .................................................................................................... 22 
 
Exclusion criteria ................................................................................................... 22 
 
Treatment .......................................................................................................................... 24 
 
Protocol requested treatment ................................................................................. 24 
 
Investigational treatment....................................................................... 24 
 
Additional study treatment.................................................................... 24 
 
Treatment arms ...................................................................................................... 24 
 
Treatment assignment, randomization .................................................................. 24 
 
Treatment blinding ................................................................................................ 25 
 
Treating the patient ................................................................................................ 25 
 
Patient numbering ................................................................................. 25 
 
Dispensing the investigational treatment .............................................. 25 
 
Handling of study treatment ................................................................. 25 


 
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Handling of other study treatment ........................................................ 26 
 
Instructions for prescribing and taking study treatment ....................... 26 
 
Permitted dose adjustments and interruptions of study treatment ........ 26 
 
Rescue medication ................................................................................ 27 
 
Concomitant treatment .......................................................................... 27 
 
Prohibited Treatment ............................................................................ 27 
 
Discontinuation of study treatment and premature patient withdrawal 27 
 
Emergency breaking of treatment assignment ...................................... 28 
 
Study completion and post-study treatment.......................................... 28 
 
Early study termination ......................................................................... 28 
 
Visit schedule and assessments ......................................................................................... 29 
 
Information to be collected on screening failures ................................................. 30 
 
Patient demographics/other baseline characteristics ............................................. 31 
 
Treatment exposure and compliance ..................................................................... 31 
 
Efficacy ................................................................................................................. 32 
 
Primary Efficacy Outcome ................................................................... 32 
 
Secondary Efficacy Outcomes .............................................................. 32 
32 
 
Appropriateness of efficacy assessments .............................................................. 33 
 
Safety ..................................................................................................................... 33 
 
Physical examination ............................................................................ 34 
 
Vital signs ............................................................................................. 34 
 
Height and weight ................................................................................. 34 
 
NYHA Class assessment ...................................................................... 34 
 
Laboratory evaluations ......................................................................... 34 
 
Pregnancy and assessments of fertility ................................................. 35 
 
Appropriateness of safety measurements ............................................. 35 
 
Other assessments.................................................................................................. 35 
 
Resource utilization .............................................................................. 35 
 35 
 
Pharmacokinetics .................................................................................. 36 
 
Pharmacogenetics/pharmacogenomics ................................................. 36 
 
Other biomarkers .................................................................................. 36 
 
Safety monitoring .............................................................................................................. 36 
 
Adverse events ...................................................................................................... 36 
 
Serious adverse event reporting ............................................................................ 38 


 
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Liver safety monitoring ......................................................................................... 39 
 
Pregnancy reporting .............................................................................................. 40 
 
Prospective suicidality assessment ........................................................................ 40 
 
Unusual Lack of Efficacy ...................................................................................... 40 
 
Data review and database management ............................................................................ 41 
 
Site monitoring ...................................................................................................... 41 
 
Data collection ....................................................................................................... 42 
 
Database management and quality control ............................................................ 42 
 
Data Monitoring Committee ................................................................................. 42 
 
Adjudication Committee ....................................................................................... 42 
 
Data analysis ..................................................................................................................... 42 
 
Analysis sets .......................................................................................................... 42 
 
Patient demographics and other baseline characteristics ...................................... 43 
 
Treatments ............................................................................................................. 43 
 
Analysis of the primary and key secondary variable(s) ........................................ 43 
 
Variable(s) ............................................................................................ 43 
 
Statistical model, hypothesis, and method of analysis.......................... 44 
 
Primary Efficacy Analysis .................................................................... 44 
 
Secondary Efficacy Analyses ............................................................... 44 
 44 
 
Handling of missing values/censoring/discontinuations ...................... 44 
 
Supportive analyses .............................................................................. 45 
 
Analysis of secondary variables ............................................................................ 45 
 
Efficacy variables ................................................................................. 45 
 
Safety variables ..................................................................................... 45 
 
Resource utilization .............................................................................. 45 
 
Symptoms ............................................................................................. 45 
 
Pharmacokinetics .................................................................................. 45 
 
Pharmacogenetics/pharmacogenomics ................................................. 46 
 
Biomarkers ............................................................................................ 46 
 
PK/PD ................................................................................................... 46 
 
Sample size calculation ......................................................................................... 46 
 Ethical considerations ....................................................................................................... 46 
 
Regulatory and ethical compliance ....................................................................... 46 
 
Informed consent procedures ................................................................................ 46 
 
Responsibilities of the investigator and IRB/IEC ................................................. 47 


 
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Publication of study protocol and results .............................................................. 47 
 Protocol adherence ............................................................................................................ 47 
 
Protocol Amendments ........................................................................................... 48 
 References ......................................................................................................................... 48 
 Appendix 1: Clinically notable laboratory values and vital signs..................................... 50 
 Appendix 2: Liver event definitions and follow-up requirements .................................... 51 
 Appendix 3: Study Assessments and Questionnaires ....................................................... 54 
 
Six Minute Walk Test............................................................................................ 54 
58 
60 
63 
 
List of tables 
Table 6-1 
Assessment schedule .......................................................................... 30 
Table 14.1 
Liver Event Definitions ...................................................................... 51 
Table 14-2 
Liver Event Follow Up Requirements ............................................... 52 
 
List of figures 
Figure 3-1 
Study design ........................................................................................ 20 
 


 
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List of abbreviations 
ACE 
angiotensin converting enzyme 
ACEI(s) 
angiotensin converting enzyme inhibitor(s) 
AE 
adverse event 
ALT 
alanine aminotransferase 
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 1bid 
twice a day 
BP 
blood pressure 
CHF 
chronic heart failure 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical Study Report 
CRO 
Contract Research Organization 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety & Epidemiology 
EC(s) 
Ethics Committee(s) 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
 
 
HF 
Hearth Failure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 


 
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IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization TechnologyLCZ696 
Novartis compound 
code 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
mg 
milligram 
NP(s) 
natriuretic peptide(s) 
NYHA 
New York Heart Association 
o.d. 
once a day 
p.o. 
oral 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
ULN 
upper limit of normal 
 
 
 


 
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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the 
study 
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) 
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  
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) 
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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Amendment 1  
 
Amendment Rationale 
 
ENTRESTOTM (sacubitril/valsartan) is indicated for the treatment of heart failure with 
reduced ejection fraction (HFrEF) in patients with NYHA Class II or III, to reduce the 
incidence of cardiovascular death and heart failure. The NYHA classification consists of a 
Functional Classification that helps assess the severity of the Heart Failure-related 
symptoms. In order to assess how these symptoms evolve during the subjects’ participation 
to the study, NYHA assessment will be performed by the investigator at every visit and 
reported in the eCRF.  
Since the NYHA assessment needs to be performed at every visit by the investigator, visit 4 
(month 3) has now to be performed on site and is no longer optional.  
The ENTRESTOTM Product Monograph has been updated in order to use rounded dosage 
strengths. Therefore, the ENTRESTOTM dosage descriptions in the protocol have been 
updated accordingly.  
According to the American Thoracic Society Guidelines, the Six Minutes Walk Test can be 
performed once or twice during the same visit, with the first test being used as a practice 
test. However, the practice test is not mandatory to ensure the reliability of the test. 
Therefore, the instructions related to the Six Minutes Walk Test have been updated to allow 
the centers to perform it either once or twice based on their routine practice. 
 
Changes to the protocol  
 
The described changes in the aforementioned amendment rationale are implemented 
throughout the protocol:  
 
• In Section 6.6.4 and table 6.1, NYHA class assessment will be performed by the 
Investigator at baseline (visit 1), month 3 (visit 4), month 6 (visit 5) and month 12 (visit 
6).  
• Table 6.1, the Visit 4 (month 3) is no longer optional and needs to be performed on site. 
• Across all applicable sections in the protocol, the initial dosage strengths descriptions, 
24.3 mg sacubitril / 25.7 mg valsartan, 48.6 mg sacubitril / 51.4 mg valsartan, 97.2 mg 
sacubitril / 102.8 mg valsartan has been changed and replaced by the following rounded 
dosages strengths; 24 mg sacubitril / 26 mg valsartan, 49 mg sacubitril / 51 mg valsartan, 
97 mg sacubitril / 103 mg valsartan. 
• Appendix 3 (section 15) has been updated to allow the centers to perform the Six 


 
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Minutes Walk test either once or twice based on their routine practice. 
 
The opportunity was also taken to make the following changes: 
• The last paragraph of section 1.1 stating that “In addition it will provide guidance on 
the most effective up-titration approach for achieving and maintaining the optimal 
therapeutic dose of 300 mg bid.” has been revised to correct the optimal therapeutic 
dose which is 200 mg. 
 
 
  
 
 
 
  
• The list of the Adverse Events of special interest that are object of more targeted 
follow-up activities as per regulatory commitments has been updated in Section 7.1 
as follows:  
Previous list: 
 Angioedema 
 Cognitive Impairment/Dementia 
 Hepatotoxicity  
Updated list: 
 Angioedema-related events 
 Cognitive Impairment/Dementia-related events 
 Hepatotoxicity-related events 
 Statin-related events  
 
       
 
 


 
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Protocol synopsis 
  
Protocol number 
CLCZ696BCA02 
Title 
Prospective, multi-center, open lAbel, post-appRovAl Study 
AImed at characterizing the use of LCZ696 at  97 mg sacubitril 
/ 103 mg valsartan bid in patients with HFrEF  
Brief Title 
 
Prospective Canadian Study Describing the use of LCZ696 in the 
management of Patients with Heart Failure with Reduced 
Ejection Fraction (HFrEF).  
Sponsor and 
Clinical Phase 
Novartis, Canada 
Phase IV  
Investigation Type 
Drug 
Study type 
Interventional  
Purpose and 
Rationale 
Optimal dosage of LCZ696 has been established at 97 mg 
sacubitril / 103 mg valsartan bid based on results of controlled 
clinical trials. Up titration of lower doses, beginning at  
24 mg sacubitril / 26 mg valsartan bid, has been shown to be an 
effective approach to achieving optimal dose that is well 
tolerated by patients. However, generalization of results from 
controlled clinical trial to the general population is limited. 
There is therefore a need for the real life assessment of the 
effectiveness and safety of LCZ696 and the tolerability of the 
optimal 97 mg sacubitril / 103 mg valsartan bid dose. The current 
study will address this knowledge gap.   
 
The primary purpose of the study will be to describe the 
tolerability of treatment with the optimal dose of LCZ696 (97 
mg sacubitril / 103 mg valsartan bid), over six (6) months, in 
patients with HFrEF in Canada.  
 
The study will also describe the overall tolerability, effectiveness 
and safety of LCZ696 for the management of HFrEF over 12 
months of treatment, as well as describe the patterns of LCZ696 
up and down dose titrations occurring during the management 
of patients with HFrEF.  
 


 
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Primary 
Objective(s) and 
Key Secondary 
Objective 
To describe the tolerability of LCZ696 at  97 mg sacubitril / 103 
mg valsartan bid  after 6 months of treatment in patients with 
HFrEF   
Secondary 
Objectives 
 
In patients with HFrEF: 
• 
To describe the tolerability of LCZ696 at 97 mg sacubitril 
/ 103 mg valsartan bid after 12 months of treatment.  
• 
To evaluate the impact of the titration scheme on the 
tolerability of patients maintained on LCZ696 at 97 mg 
sacubitril / 103 mg valsartan bid at 6 and 12 months  
• 
To describe the impact of LCZ696 on functional exercise 
capacity, as measured by the Six Minute Walk Test, at 6 and 12 
months.   
• 
To describe the time of up-titration for each dose ( 24 
mg sacubitril / 26 mg valsartan and 49 mgsacubitril / 51 mg 
valsartan bid ) of LCZ696. 
• 
To describe the adherence to guideline recommended 
dosing of beta-blockers and MRAs at 6 and 12 months of 
treatment with LCZ696. 
• 
To evaluate the overall safety profile of LCZ696 during 12 
months of treatment 


 
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Study Design 
This will be a multi-center, open label, prospective post-
approval (phase IV) study. Patients with HFrEF that are eligible 
to be treated with LCZ696 as per the ENTRESTOTM product 
monograph will be enrolled in the study. The study patients will 
be enrolled at Canadian community cardiologists and IM 
specialists sites that treat patients with HFrEF. Follow up will be 
for 12 months, with the primary endpoint being assessed at 6 
months of treatment. 
 
The patients will continue on their background treatment with 
the exception of ACEIs and ARBs that will be replaced with 
LCZ696, as per recent guidelines, after a 36 hour wash-out 
period for ACEIs.  All patients will be initiated on the lower dose 
of LCZ696 as per the product monograph and the treating 
physician’s judgement. A starting dose of 24 mg sacubitril / 26 
mg valsartan twice daily may be considered in selected patients, 
for example, those on less than guideline-recommended doses 
of ACEI or ARB prior to initiation of LCZ696.  The dose of 
LCZ696 should be increased every 2-4 weeks, as tolerated by the 
patient and in accordance to the product monograph, to the 
target dose of 97 mg sacubitril / 103 mg valsartan twice daily. If 
patients experience tolerability issues, e.g. symptomatic 
hypotension or hyperkalemia, consideration should be given to 
temporary down–titration of LCZ696 (as per ENTRESTOTM 
Canadian product monograph). Dose reduction of other 
concomitant medications including nitrates, CCBs, alpha-
blockers and diuretics may be considered to optimize the 
tolerability of treatment with LCZ696. 
Population 
The target population of the study will be patients with HFrEF 
that are candidates for treatment with LCZ696 as per the 
Canadian product monograph. 
Inclusion Criteria 
• Age ≥ 18 years and ≤ 80 years.  
• Males or females. 
• Diagnosis of Heart Failure with reduced Ejection Fraction 
(LVEF  ≤ 40%) and NYHA class II or III.  


 
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• Stable on any dose of ACEI or ARB before enrolment in the 
study. 
• Stable dose of a beta-blocker before enrolment in the study. 
• Eligible for treatment with LCZ696 as per ENTRESTOTM 
Canadian product monograph). 
• Treated as an outpatient. 
• Signed an informed consent agreeing to participate in the 
study.  
Exclusion Criteria 
• Symptomatic hypotension and/or a SBP < 100 mmHg at 
baseline visit.  
• Estimated GFR < 30 mL/min/1.73m2 as measured by the 
simplified Modification of Diet in Renal Disease (MDRD) 
formula at baseline visit. 
• Known history of angioedema related to previous ACEI or 
ARBs therapy, or history of hereditary angioedema or 
idiopathic angioedema 
• Requirement of concomitant treatment with both ACEIs and 
ARBs. 
• Concurrent participation in other clinical trials or use of other 
investigational drugs at the time of enrollment, or within 30 
days. 
• Hypersensitivity to the active substances, sacubitril or 
valsartan, or to any of the excipients.  
• Concomitant use of aliskiren-containing drugs in patients 
with diabetes mellitus (type 1 or type 2) or moderate to 
severe renal impairment (GFR <60ml/min/1.73m2) 
• History of hypersensitivity to any of the study drugs or to 
drugs of similar chemical classes. 
• 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. 
• 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. 
• Women of childbearing potential, defined as all women 


 
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physiologically capable of becoming pregnant, unless they 
are using effective methods of contraception during dosing of 
study treatment. 
Investigational and 
Reference Therapy 
All patients will be treated with LCZ696 in combination with 
their background treatments. There is no reference treatment. 
Efficacy 
Assessments 
The primary endpoint of the study will be the proportion of 
patients at the 97 mg sacubitril / 103 mg valsartan bid dose of 
LCZ696 at 6 months.  
The following will be secondary endpoints: 
• 
The proportion of patients on  LCZ696 who  had required 
down-titration after reaching  the  97 mg sacubitril / 103 mg 
valsartan bid.  
• 
The number of down-titration changes from 97 mg 
sacubitril / 103 mg valsartan bid during 12 months of 
treatment. 
• 
The proportion of patients who tolerate 97 mg sacubitril / 
103 mg valsartan bid at 6 and 12 months of treatment. 
• 
Functional capacity as measured by the change from 
baseline to 6 months and 12 months in the Six Minute Walk 
Test distance. 
• 
Time to up-titration of LCZ696 doses. 
• 
Duration of treatment on each dose of LCZ696. 
• 
The proportion of patients on guideline recommended dose 
of beta-blockers and MRAs at baseline, 6 and 12 months. 
Safety Assessments 
All treatment emergent serious and non-serious adverse events. 
Data Analysis 
The data analysis for the current study will be primarily 
descriptive. The primary endpoint of the study will be the 
proportion of patients on LCZ696 97 mg sacubitril / 103 mg 
valsartan bid at 6 months of treatment. Ninety five percent 
(95%) confidence intervals will be calculated for the estimate of 
this proportion in order to assess precision and make inferences 
to the target population. 
Similarly for the proportion of patients on LCZ696 97 mg 
sacubitril / 103 mg valsartan bid at 12 months, requiring down 
titration and proportion of patient treated in accordance to 


 
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guideline recommended doses of beta blockers and MRAs will 
also be assessed for precision with the 95% Confidence Intervals. 
The number of down titrations during the 12-month treatment 
periods will be described with a Poisson distribution and the 
incidence density rate as the number of dose reductions per 100 
person – month of follow up. 
The change in the Six Minute Walk Test from baseline to 6 and 
12 months of treatment will be assessed with the 95% confidence 
intervals and with the Student’s t-test for paired observations. 
The time to LCZ696 up-titration to 97 mg sacubitril / 103 mg 
valsartan bid and the duration on treatment for each dose will 
be assessed with the Kaplan Meier estimator of the survival 
function. 
 
 
 
 
 
Safety will be assessed with the incidence of treatment emergent 
adverse events. 
Key words 
LCZ696, HFrEF, Tolerability, Effectiveness, Durability of 
Treatment, Safety. 
 
 
 
 
Introduction 
 
Background  
Heart failure (HF) is a common disease with high mortality rate and represents the second 
leading cause of hospitalizations in patients >65 years of age in Canada (1). Patients with HF 
usually have poor prognosis, frequent hospitalization and increased risk for mortality. The 
data from the Framingham cohort suggest a prevalence of 8/1000 in males between the ages 
of 50-59 that increases to 66/1000 for ages 80-89. The estimates are similar for women at 8.0 
and 79/000; respectively (2,3). HF can be classified in two categories, the first one with 
preserved EF (HFpEF) and the other one with reduced EF (HFrEF), the latter representing 
the majority at approximately 66% (3,4). 


 
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The aim of pharmacologic management of HF is to improve the symptoms and decrease 
morbidity and mortality. For HFrEF patients angiotensin-converting enzyme inhibitors 
(ACEIs) or angiotensin receptor blockers (ARBs) for ACEI intolerant patients combined 
with beta-adrenergic blockers are recommended. If symptoms persists mineralocorticoid 
receptors antagonists (MRAs) are also added and diuretics used to relieve congestive 
symptoms as per current Canadian Cardiology Society guidelines (5).  
More recently, the recognition of the role of natriuretic peptides (NP) as natriuretics and 
vasodilators along with the discovery that neprilysin (NEP) inhibition can increase the 
concentration of NPs, has identified these as potential therapeutic solutions that can 
produce cardiac, vascular and renal benefits to patients with HF (6)  
LCZ696 is the first NEP and angiotensin receptor inhibitor (ARNI).  The results of clinical 
trials have shown marked improvements in the reduction of mortality and cardiac events as 
well as symptom management in patients treated with LCZ696 when compared to current 
standard of care (6,7,8) .  
PARADIGM-HF was a phase III randomized controlled trial conducted in HFrEF patients 
that were well controlled on background therapy including ACEIs/ARBs, β-blockers and 
MRAs. The results of this study showed that, when compared to enalapril, LCZ696 
significantly reduced the risk of the composite endpoint of CV death or HF hospitalization 
by 20% after 27 months (8).  In the same study LCZ696 also reduced the risk of all-cause 
mortality by 16%, and the number of all-cause hospitalizations, CV and HF hospitalizations 
(including first and recurrent hospitalizations). LCZ696 was also found to be safe well 
tolerated. These results prompted recent changes to the Canadian Cardiovascular Society 
HF treatment guidelines, according to which LCZ696 has replaced ACEI inhibitors or ARBs 
in patients with HFrEF .  
The TITRATION randomized controlled study enrolled HFrEF patients who were either 
naïve or already treated with ACEIs or ARBs treated (with EF ≤ 35%) that were on any dose 
of ACEIs or ARBs managed as in-patients or outpatients before enrolment (9). The study 
compared a condensed regimen in which the dose of LCZ696 was up titrated from 24 mg 
sacubitril / 26 mg valsartan bid to 49 mg sacubitril / 51 mg valsartan bid in 3 weeks to a 
conservative regimen in which the up-titration was conducted over 6 weeks. The results 
showed that LCZ696 was well tolerated and the majority of patients were able to achieve 
the 97 mg sacubitril / 103 mg valsartan bid target dose without any dose adjustment or 
interruption over 12 weeks regardless of the ACEIs or ARBs used at baseline. Among the 466 
randomized patients, excluding those who discontinued due to non-AE related reasons, 
77.8% in the condensed regimen and 84.3% in the conservative regimen achieved the target 
LCZ696 97 mg sacubitril / 103 mg valsartan bid dose and had no down-titration or dose 
interruption (Senni et al, ESC-HF May 2015). The results of this study show that up-titration 
of LCZ696 from 24 mg sacubitril / 26 mg valsartan to the optimal 97 mg sacubitril / 103 mg 
valsartan bid is safe and well tolerated in a wide range of patients with HFrEF. 
Generalization of the results of controlled clinical trials to the real-life setting is problematic 


 
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due to the highly selective patients enrolled and the strict adherence to study protocols used 
in clinical trials. In addition, the fact that controlled clinical trials are conducted in academic 
or university research centers and to the community setting enhances the discrepancy 
between controlled trials and the real world setting. Post Approval Clinical Epidemiological 
Studies (PACES) can address this knowledge gap. Phase IV studies, are one type of PACES, 
in which patients are treated by community physicians according to a protocol driven pre-
specified regimen, in accordance to regional regulations, guidelines and product 
monographs. These studies can emulate the real – life setting and can provide valuable 
evidence regarding treatment effectiveness and safety in the real world. With respect to 
LCZ696 there is a need for the assessment of real – life effectiveness and safety. In addition, 
there is a need to describe and assess the effectiveness of up-titration regimens aimed at 
achieving the optimal dose of 97 mg sacubitril / 103 mg valsartan bid.  
The current study will address this knowledge gap by assessing the tolerability of LCZ696 
97 mg sacubitril / 103 mg valsartan bid in Canadian patients with HFrEF treated in 
community settings. The titration process by which the optimal dose is achieved and any 
dose reduction or treatment adjustment required will also be described. The study will also 
assess the therapeutic effectiveness LCZ696 and its overall safety in the real life setting in 
Canada. The results of this study will have important implications in providing much 
needed data for the valid evaluation of the benefits of LCZ696 in the management of HFrEF. 
In addition it will provide guidance on the most effective up-titration approach for achieving 
and maintaining the optimal therapeutic dose of 200 mg bid.     
 
Purpose  
The results of controlled clinical trials have shown that the optimal dosage of LCZ696 is 97 
mg sacubitril / 103 mg valsartan bid. In addition the TITRATION controlled clinical trial has 
shown that up titration of lower doses, beginning at 24 mg sacubitril / 26 mg valsartan bid, 
is an effective and well tolerated approach to achieving optimal dose of LCZ696. However, 
generalization of results from controlled clinical trial to the real – life setting is limited. 
There is therefore a need for the real life assessment of the effectiveness and safety of 
LCZ696 and the tolerability of the optimal is 97 mg sacubitril / 103 mg valsartan bid dose. 
The current study will address this knowledge gap.   
The primary purpose of the study will be to describe the tolerability of treatment with the 
optimal dose of LCZ696 (97 mg sacubitril / 103 mg valsartan bid), over six (6) months, in 
patients with HFrEF in Canada. 
The study will also describe the overall tolerability, effectiveness and safety of LCZ696 in 
the management of HFrEF over 12 months of treatment, as well as describe the patterns of 
LCZ696 up and down dose titrations occurring during the management of patients with 
HFrEF.  
 
 
 


 
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Study objectives 
 
Primary  
To describe the tolerability of LCZ696 at 97 mg sacubitril / 103 mg valsartan bid, after 6 
months of treatment in patients with HFrEF.   
 
Secondary objectives 
In patients with HFrEF: 
• To describe the tolerability of LCZ696 at 97 mg sacubitril / 103 mg valsartan bid, after 
12 months of treatment.  
• To evaluate the impact of the titration scheme on the tolerability of patients 
maintained on LCZ696 97 mg sacubitril / 103 mg valsartan bid at 6 and 12 months  
• To describe the impact of LCZ696 on functional exercise capacity, as measured by the 
Six Minute Walk Test, at 6 and 12 months.   
• To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan 
bid / 49 mg sacubitril / 51 mg51 mg valsartan bid) of LCZ696. 
• To describe the adherence to guideline recommended dosing of beta-blockers and 
MRAs at 6 and 12 months of treatment with LCZ696. 
• To evaluate the overall safety profile of LCZ696 during 12 months of treatment. 
 
Investigational plan 
 
Study design 
This will be a multi-center, open label, prospective post-approval (phase IV) study. Patients 
with HFrEF that are eligible to be treated with LCZ696 as per the product monograph will 
be enrolled in the study. The study patients will be enrolled at Canadian community 
cardiologists and IM specialists that treat patients with HFrEF. Follow up will be for 12 


 
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months with assessments at baseline, week 2, week 4, month 3, month 6 and month 12. The 
primary endpoint will be assessed after 6 months of follow-up. 
Potentially eligible patients with HFrEF will be invited to participate in the study and will 
be asked to sign an informed consent after the purpose, duration and requirements of the 
study have been explained to them. Treatment with ACEIs will be discontinued for 36 hours 
and then replaced with LCZ696 at 24 mg sacubitril / 26 mg valsartan bid. NO washout 
period is need for patients previously treated on ARBs. The dose of LCZ696 will be increased 
to 49 mg sacubitril / 51 mg valsartan bid within 2-4 weeks of enrolment and to 97 mg 
sacubitril / 103 mg valsartan bid within 2-4 weeks from the first up titration to 49 mg 
sacubitril / 51 mg valsartan bid as tolerated by the patient and in accordance to the product 
monograph (Figure 3-1). All other medications will be used as they were prior to the 
enrolment in the study; however, the treating physicians may modify the dose of nitrates, 
CCBs, α-blockers, and diuretics in order to facilitate tolerability of increased LCZ696 doses. 
Down titration of LCZ696 from the higher doses may be considered, as per the product 
monograph for patients that experience tolerability issues including, but not limited to, 
symptomatic hypotension or hyperkalemia. 
 
Figure 3-1 
Study design 
 
* LCZ696 50 mg bid is the equivalent of 24 mgsacubitril / 26 mg valsartan bid 
* LCZ696 100 mg bid is the equivalent of 49 mg sacubitril / 51 mg valsartan bid 
* LCZ696 200 mg bid is the equivalent of 97 mg sacubitril / 103 mg valsartan bid 
 
 
Rationale of study design 
This is a single cohort prospective study of HFrEF patients that will be initiated on treatment 
with LCZ696. Given that the primary purpose of the study is to describe the tolerability of 
LCZ696 97 mg sacubitril / 103 mg valsartan bid a comparison group is not relevant. Hence 


 
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there is no probability of bias in the results caused by the single cohort, no-comparator 
design.  
In addition the study will assess the overall safety and tolerability of LCZ696 over 12 months 
of treatment, and describe the process by which up-titration to the optimal dose of 97 mg 
sacubitril / 103 mg valsartan bid is achieved in the real world setting. The assessment of the 
incremental change in the Six Minute Walk Test since the substitution of ACEIs and ARBs 
will also be assessed in the study. The single cohort prospective design is appropriate to 
address these questions. 
 
Rationale of dose/regimen, route of administration and duration of 
treatment 
All patients will be treated with LCZ696 as a substitution of their current ACEIs or ARBs. 
The starting dose of LCZ696 will be 24 mg sacubitril / 26 mg valsartan bid that will be up-
titrated to 49 mg sacubitril / 51 mg valsartan and then to 97 mg sacubitril / 103 mg valsartan 
bid as the tolerability of the patient, the product monograph and judgement of the 
treatment physician. The LCZ696 dose regimen and up-titration algorithm utilized in the 
current study will be according to the approved Canadian product monograph and has been 
shown to be efficacious and tolerable in controlled clinical trials. 
 
Rationale for choice of comparator 
Not Applicable. 
 
Purpose and timing of interim analyses/design adaptations 
An interim analysis may be performed after 50 patients have reached 12 weeks of treatment, 
 and 
at any time during the study as long as it does not impact the study completion.  
 
Risks and benefits  
The study will be submitted for approval to local and central Independent Review Boards 
prior to any patient being enrolled. All participating patients will be asked to sign an 
informed consent prior to undergoing any study related procedures. Patient anonymity will 
be protected by the exclusive use of study specific identification numbers that will not be 
linked to personal identifying information. In addition, personal identifying information 
will never be entered in any study database or study data collection form. 
This is an open label study of LCZ696 in patients with HFrEF that will be conducted after 
approval of the product for marketing in Canada. All treatments will be provided as per the 
product monograph and the judgement of the physician. Only patients that are eligible for 
treatment with LCZ696, as per regional policies, treatment guidelines and the product 
monograph will be enrolled in the study. The risk to the patients is minimized by the close 
clinical monitoring and option to down-titrate the LCZ696 dose, change the doses of other 


 
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medications or terminate treatment. The benefits to the patients include the potentially 
higher efficacy of LCZ696 in controlling the symptoms of Heart Failure. 
 
Population 
The target population of the current study is that of patients with HFrEF that are on stable 
dose of ACEIs and ARBs and for whom treatment with LCZ696 is indicated as per the 
product monograph and recent guidelines.  
 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. 
Written informed consent must be obtained before any assessment is performed. 
2. 
Age ≥ 18 years and ≤ 80 years.  
3. 
Males or females. 
4. 
Diagnosis of Heart Failure NYHA class II-III.  
5. 
Diagnosis of Heart Failure with reduced Ejection Fraction (LVEF  ≤40%) and NYHA 
class II or III.  
6. 
Stable on any dose of ACEI or ARB prior to enrolment in the study  
7. 
Stable on any dose of a beta-blocker prior to enrolment in the study. 
8. 
Eligible for treatment with LCZ696 (ENTRESTOTM) as per Canadian product 
monograph. 
9. 
Treated as an outpatient. 
10. Signed an informed consent agreeing to participate in the study. 
 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Symptomatic hypotension and/or a SBP < 100 mmHg at baseline visit.  
2. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified Modification of 
Diet in Renal Disease (MDRD) formula at baseline visit. 
3. Known history of angioedema related to previous ACEI or ARBs therapy, or history 
of hereditary or idiopathic angioedema. 


 
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4. Requirement of concomitant treatment with both ACEIs and ARBs. 
5. Concurrent participation in other clinical trials or receiving other investigational 
drugs within 30 days of enrollment. 
6. Hypersensitivity to the active substances, sacubitril or valsartan, or to any of the 
excipients.  
7. Concomitant use of aliskiren-containing drugs in patients with diabetes mellitus 
(type 1 or type 2) or moderate to severe renal impairment (GFR <60ml/min/1.73m2). 
8. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes. 
9. 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. 
10. 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. 
11. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. 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 m prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository  
• 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 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 


 
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• In case of use of oral contraception women should have been stabile on the 
same pill for a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six 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 
childbearing potential.  
 
Treatment 
 
Protocol requested treatment 
 
Investigational treatment 
All patients will be treated with the following: 
• 
LCZ696 (sacubitril and valsartan) tablets 
• 
Starting dose of LCZ696 at 24 mg sacubitril / 26 mg valsartan, intermediate dose 
of 49 mg sacubitril / 51 mg valsartan and highest dose of 97 mg sacubitril / 103 mg 
valsartan  
• 
Packaging as per commercially available (under the commercial name 
ENTRESTOTM) or as per clinical supplies, (as applicable). 
 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
Due to the potential risk of angioedema when used concomitantly with an ACEI, 
LCZ696 must not be started until 36 hours has passed following discontinuation of 
ACEI therapy.  
Patients will terminate treatment with ARBs and may start on LCZ696 at the next schedule 
dose. All other background treatment for heart failure including diuretics, beta-blockers, and 
mineralocorticoid receptor antagonists (MRA) should be continued as prescribed. 
 
Treatment arms 
All patients will be treated with LCZ696. 
 
Treatment assignment, randomization  
Not Applicable. 


 
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Treatment blinding  
Not Applicable.  
 
Treating the patient 
 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number 
as given by the investigator using the next blank CRF book available from the EDC system.  
If a screened patient fails to be enrolled in the study or treated for any reason, the reason 
will be entered on the Screening Study Disposition CRF.  
 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with the open label study medication, (LCZ696), 
in sufficient quantity of the three dose levels that may be used during up-titration, (LCZ696 
at 24 mg sacubitril / 26 mg valsartan, 49 mg sacubitril / 51 mg valsartan), and 12 month-
treatment phase, LCZ696 (97 mg sacubitril/103 mg valsartan). 
 
Handling of study treatment 
 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed 
only in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the study specific Subject 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 each 
study visit and 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 


 
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copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site. 
 
Handling of other study treatment 
Not Applicable. 
 
Instructions for prescribing and taking study treatment 
During the baseline visit all patients will be instructed to stop taking their ACEIs for 36 
hours prior to taking the first dose of LCZ696.  Patient receiving an ARBs will only have to 
discontinue their medication and start LCZ696 at the next schedule time. All patients will 
be initiated on LCZ696 at 24 mg sacubitril / 26 mg valsartan that can be up-titrated to 
LCZ696 49 mg sacubitril / 51 mg valsartan bid after 2-4 weeks and then up-titrated again to 
97 mg sacubitril / 103 mg valsartan bid after another 2 – 4 weeks. Timing of LCZ696 up-
titration will be dependent on patient tolerability and the judgement of the physician.  
If patients experience any lack of tolerability including but not limited to hypotension and 
hyperkalemia, the dose of LCZ696 may be reduced or treatment suspended or terminated 
as per the judgement of the treating physician. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the LCZ696 as prescribed.  
 
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments and interruptions of LCZ696 are permitted in order to keep the patient on 
study drug. Attempt will be made to maintain patients on LCZ696 at 97 mg sacubitril / 103 
mg valsartan bid. If in the opinion of the investigator, the patient does not tolerate the 
highest dose of LCZ696, the investigator should consider whether non disease-modifying 
medication (such as nitrates, CCBs, α-blockers, and diuretics) can be reduced temporarily 
to permit up-titration and maintenance of a proven efficacious dose of LCZ696.  
 
Attempt should be made to maintain patients on the proposed study drug dose level for as 
long as 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 


 
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not alleviate the side effects of concern, the investigator may opt to down-titrate the dose 
of the study drug to the next lower level (either 24 mg sacubitril / 26 mg valsartan or 49 mg 
sacubitril / 51 mg valsartan depending which dose the patient is taking). If needed, the study 
drug may be stopped completely, but the patient should then discontinue the trial. 
 
These changes must be recorded on the Dosage Administration Record CRF. 
 
Rescue medication 
Not Applicable. 
 
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. 
 
Prohibited Treatment 
Any treatments prohibited as per the Canadian Product Monograph (ENTRESTOTM ). 
 
Discontinuation of study treatment and premature patient withdrawal 
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 on study completion/discontinuation CRF page. Study treatment 
must be discontinued. 
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. 
Study treatment must be discontinued and the patient withdrawn from the trial under the 
following circumstances:  
• Withdrawal of informed consent. 
• Pregnancy. 
• Investigator thinks that continuation would be detrimental to the patient’s well-being;  
• Suspected occurrence of angioedema during the run-in period. 
• Any other protocol deviation that results in a significant risk to the patient’s safety. 
 


 
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Study medication may be discontinued at the investigator’s discretion if any of the following 
occurs: 
• Any severe suspected drug related AE. 
• Suspected occurrence of angioedema. A patient with any signs or symptoms of 
clinically significant angioedema should be thoroughly evaluated by the investigator 
and constitute a reason for discontinuation of study medication. 
• Depending on the serum potassium, blood pressure, or eGFR, patients may need to 
have their study drug dose or the dose of another concomitant medication reduced or 
discontinued, or, if appropriate, have potentially contributing agents adjusted. 
If premature discontinuation of study occurs, after Visit 1, and after receiving at least one 
dose of study medication, the patient should return to the clinic as soon as possible for a 
last follow-up visit, as per routine clinical care. Attempt should be made to perform all 
assessments listed in Table 6-1 for the Visit 6. If the patient refuses, he/she should be 
contacted by telephone in place of protocol-specified visits unless the patient expressly 
refuses such contacts. 
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. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients. 
 
Emergency breaking of treatment assignment 
Not Applicable. 
 
Study completion and post-study treatment 
Patients will be treated and followed for 12 months in the current study. After the end of 
follow up or early termination the patients will be treated according to the judgement of 
their physicians and regional reimbursement policies. 
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. 
 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn 
patient, as outlined in section5.5.10, above. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial. 


 
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All patients must be informed of the study early termination and be instructed to return for 
final assessments, as outlined in section5.5.10, above. All study treatments must be 
terminated and the patient’s must be followed by the physician for appropriate management 
and reporting of adverse events. 
 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Patients should be seen for all visits on the designated day with an allowed “visit window” 
of 7 days, or as close to it as possible. 
Patients who discontinue study treatment should also return for a final Visit and perform 
all assessments indicated in Visit 6 of 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 to determine the patient’s  status as well as whether they have 
continued on treatment with LCZ696 and the daily dose. 
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.  
 


 
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Table 6-1 
Assessment schedule 
Visit number 
1 
2 
3 
4 
5 
6 
Time of Visit 
day 1 
week 2 
Week 4 
Month 3 
(Week 12) 
 
Month 6 
(Week 24) 
 
Month 12 
 
 
Inclusion/Exclusion criteria 
x 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
Physical examination1 
x 
x1 
x1 
x1 
x1 
x1 
Demographics 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Vital signs (BP, heart rate) 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
Weight 
x 
x 
x 
x 
x 
x 
Pharmacologic treatments2 
x 
x 
x 
 
x 
x 
Six Minute Walk Test3 
x 
 
 
 
x 
x 
Dosing information 
 
x 
x 
 
x 
x 
Dispense study medication 
x 
x 
x 
 
x 
 
Laboratory test4 
x 
 
x 
x 
 
x 
NYHA Class Assessment 
x 
 
 
x 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
Urine pregnancy test for 
women with childbearing 
potential 
x 
 
 
 
 
x 
1 Short physical exam, as described in Section 6.6.1 and to be captured only in the source documents 
2 All HF treatments and all concomitant medications used to treat adverse events. 
3 Details and instructions in Appendix 3. 
4 Routine lab test including potassium and serum creatinine for eGFR assessment, if done as part of routine 
care. 
 
 
 
Information to be collected on screening failures 
All patients who have signed informed consent but did not receive any dose of study 
medication will have CRF completed for the 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.   Patients who discontinue the study after Visit 1 and after 


 
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having received a first dose of study medication, should have the study 
completion/discontinuation page completed, in addition to the above listed CRF.  
For all patients who have signed informed consent and are entered into the next epoch of 
the study will have all adverse events occurring after informed consent is signed 
recorded on the Adverse Event CRF. 
Investigators will have the discretion to record abnormal test findings on the medical 
history CRF whenever in their judgement, the test abnormality occurred prior to the 
informed consent signature. 
 
Patient demographics/other baseline characteristics 
The following demographic and baseline parameters will be ascertained from the patient 
chart or interview during the baseline visit: 
• Demographics: 
o Age (date of birth) 
o Gender 
o Race (ethnic background) 
o Smoking history 
o Alcohol use history 
• Medical History 
o Chronic conditions 
 Listing of all cardiovascular chronic conditions 
o Concomitant medications 
 Listing and details of all HF treatments and all concomitant 
medications used to treat adverse events. 
o Heart Failure History 
 Date of diagnosis 
 Prior treatment for heart failure with duration  
 
Treatment exposure and compliance 
All patients will be treated with LCZ696 at 24 mg sacubitril / 26 mg valsartan, 49 mg sacubitril 
/ 51 mg valsartan and 97 mg sacubitril / 103 mg valsartan bid. The dose prescribed for each 
patient during the up-titration will be recorded in the CRF. All patients will be instructed 
to return all unused medication at each visit. The site staff will record the number of tablets 
returned versus those dispensed at the previous visit, and this information will be used to 
calculate the number of doses missed. In addition, at each follow up visit, the patients will 


 
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be asked how many times they did not take any of their prescriptions for heart disease as 
instructed by their physicians.  
 
Efficacy 
 
Primary Efficacy Outcome 
The primary outcome measure of the study will be the proportion of patients who have 
remained on treatment with LCZ696 (at the maximum dose of 200 mg bid; 97 mg sacubitril 
/ 103 mg valsartan) at month 6 of follow up. The proportion will be calculated as the number 
of patients at the maximum LCZ696 dose, over the total number of patients that received 
at least one dose of LCZ696. 
 
Secondary Efficacy Outcomes 
The following secondary outcome measures will be analyzed: 
• 
The proportion of patients who tolerate LCZ696 97 mg sacubitril / 103 mg 
valsartan bid at12 months of treatment. 
• 
The proportion of patients on  LCZ696 requiring down-titration after reaching  
the 97 mg sacubitril / 103 mg valsartan dose 
• 
The number of down-titration changes from 97 mg sacubitril / 103 mg valsartan 
during 12 months of treatment. 
• 
Functional capacity as measured by the change from baseline to 6 months and 12 
months in the Six Minute Walk Test*. 
• 
Time to up-titration of LCZ696 doses. 
• 
Duration of treatment on each dose of LCZ696. 
• 
The proportion of patients on guideline recommended dose of beta-blockers and 
MRAs at baseline, 6 and 12 months. 
* The Six Minute Walk Test (SMWT) measures the distance an individual is able to walk 
over a total of six minutes on a hard, flat surface (Appendix 3). The goal is for the individual 
to walk as far as possible in six minutes. The individual is allowed to self-pace and rest as 
needed as they traverse back and forth along a marked walkway (10).  
The purpose of the six minute walk is to test exercise tolerance in chronic respiratory disease 
and heart failure. 


 
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Appropriateness of efficacy assessments  
The outcome measures are in line with the overall study purpose and objectives. More 
specifically, the proportion of patients achieving and maintaining treatment with 97 mg 
sacubitril / 103 mg valsartan bid LCZ696 is the outcome for the primary objective.  The time 
to reaching the dose of 97 mg sacubitril / 103 mg valsartan bid for LCZ696 is relevant in 
understanding how the up-titration algorithm is applied in the real – life setting. The 
duration on treatment on 24 mg sacubitril /26 mg valsartan and 49 mg sacubitril / 51 mg 
valsartan bid LCZ696 is complementary information to the understanding of the real – life 
implementation of the up-titration scheme for LCZ696. The rate of down – titration of 
LCZ696 is an indication of tolerability. The change in functional capacity as measured by 
the six minute walk test, is an important outcome given that it will demonstrate that 
LCZ696 is not only tolerated at 97 mg sacubitril / 103 mg valsartan bid but also effective in 
reducing the impact of heart failure. 
 
Safety 
The safety assessments include adverse events. 


 
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Physical examination 
A complete physical examination that 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 may be performed at the 
baseline visit. 
A short physical exam will include the examination of general appearance and vital signs 
(blood pressure [SBP and DBP] and pulse) will be conducted for all follow up visits after 
baseline.  
Information for all physical examinations must be included in the source documentation at 
the study site. Significant findings that are present prior to signing informed consent must 
be included in the Medical History part of the CRF. Significant findings made after signing 
the informed consent which meet the definition of an Adverse Event must be recorded on 
the Adverse Event section of the CRF. 
 
Vital signs 
Vital signs include BP and pulse measurements. These will be measured as per the 
physician’s routine practice. However, physicians will be asked to use the same method and 
instruments, as much as possible, for all assessments of the same patient.  
 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured and recorded at the baseline visit. 
 
NYHA Class assessment  
NYHA class will be assessed at baseline (visit 1), at month 3 (visit 4), at month 6 (visit 5) and 
month 12 (visit 6). NYHA class will be recorded in the CRF and must be included in the 
source documentations at the study site. At baseline, only patients with heart failure NYHA 
class II or III can be enrolled in the study 
 
Laboratory evaluations 
Laboratory tests will be conducted as per routine care. When results are available these will 
be recorded in the CRF. Clinically notable laboratory findings are defined in Appendix 1.  
 
Hematology 
Hematology tests will be conducted as per routine care. When results are available these 
will be recorded in the CRF. 
 
Hematology tests performed may include the following: 
• Hemoglobin  
 


 
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Clinical chemistry 
Clinical chemistry tests will be conducted as per routine care. When results are available 
these will be recorded in the CRF.  
Blood Chemistry tests performed may include the following: 
• ALT (SGPT)  
 
• AST (SGOT)  
• BUN  
 
 
• Creatinine 
 
 
• CPK   
 
 
• Alkaline phosphatase 
 
• Potassium 
 
• Chloride 
 
 
• Uric acid 
 
 
Urinalysis 
Not Applicable. 
 
Electrocardiogram (ECG) 
Electrocardiograms will be conducted as per routine care and documented in the site’s 
source documents.  
 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile (women of child-bearing 
potential) will have a local urine pregnancy test conducted at screening and/or pre-dose 
and at the end of the trial, (Visit 6). If a local urine pregnancy test at screening shows a 
positive result, then a serum β-hCG test must be done.  If positive, the patient should not 
enter in the study or should be discontinued from the study. 
 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
 
Other assessments 
In additional renal (GFR) function tests may be performed, as per routine clinical care. 
 
Resource utilization 
Not Applicable. 


 
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Pharmacokinetics 
Not Applicable. 
 
Pharmacogenetics/pharmacogenomics 
Not Applicable. 
 
Other biomarkers 
Not Applicable. 
 
Safety monitoring 
 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
or clinical investigation subject after providing written informed consent for participation in 
the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at 
least one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through 
a review of values outside of normal ranges/clinically notable ranges, significant changes 
from baseline or the previous visit, or values which are considered to be non-typical in 
patient with underlying disease. Investigators have the responsibility for managing the 
safety of individual patient and identifying adverse events. Alert ranges for labs and other 
test abnormalities are included in Appendix 1. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms 
or diagnosis associated with them accompanied by the following information. 
• the severity grade:  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 


 
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• 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. 
For LCZ696, there are events which are the object of more targeted follow-up activities as 
per regulatory commitments.  The local Novartis DS&E Department will perform the follow-
up: on the following events regardless of seriousness: 
• Angioedema-related events 
• Cognitive Impairment/Dementia-related events 
• Hepatotoxicity-related events 
• Statin-related events 
 


 
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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); study treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
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 ENTRESTOTM Product Monograph. 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. 
 
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 visitation of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious 
Adverse Event Form within the OC/RDC system (where available). The Investigator must 
assess the relationship to each specific component of the study treatment (if the study 
treatment consists of several components).  
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis Drug Safety and Epidemiology 


 
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Department.  The telephone and fax number of the contact persons in the local department 
of Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 
provided to each site.  The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 
information should be provided using a new paper SAE Report Form stating that this is a 
follow-up to a previously reported SAE   
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should 
be entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an 
existing SAE. These data will automatically be submitted to Novartis Drug Safety & 
Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first.  
Follow- up information provided should describe whether the event has resolved or 
continues, if and how it was treated, whether the treatment code was broken or not and 
whether the patient continued or withdrew from study participation. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that 
event regardless of when it occurs. 
If the SAE is not previously documented in the Product Monograph (new occurrence) and 
is thought to be related to the study 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 use of LCZ696 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 in participating countries. 
 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and 
evaluation of liver events has to be followed.  
Liver events are divided into two categories: 
• Liver events of special interest (AESI) which consist of LFTs elevations 
• Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events. 
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver events.  
Any liver event which meets the criteria for “medically significant” event as outlined in 
Table 14-1 of Appendix 2 should follow the standard procedures for SAE reporting as 
described in Section 7.2.  


 
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Every liver event as defined in Table 14-1 of Appendix 2 should be followed up by the 
investigator or designated personal at the trial site as summarized below. Detailed 
information is outlined in Table 14-2 in Appendix 2. 
• 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. 
 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
 
 
Prospective suicidality assessment 
Not Applicable. 
 
 
Unusual Lack of Efficacy  
Unusual lack of efficacy is defined as a technical failure of a compound to meet its efficacy 
goals, to produce the expected intended effect, and is subject to quality assurance testing to 
confirm that the manufacturing of the compound is appropriate. Therefore, lack of efficacy 
should be sent within 24 hours of awareness to the local Novartis Drug Safety and 
Epidemiology Department at 
  The original copy of the e-mail 
correspondence should be kept at the study site. 


 
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Clinical judgement should be exercised by a qualified health care professional to determine 
if the problem reported is related to the product itself, rather than one of treatment 
selection or disease progression since health products cannot be expected to be effective in 
100% of the patients. One example of unusual failure in efficacy is a previously well-
stabilized condition that deteriorates when the patient changes to a different brand or 
receives a new prescription 
 
The following situations are examples when unusual lack of efficacy is considered:  
• The patient’s disease was stable and controlled. Suddenly, an unexplainable loss of efficacy 
is reported, with no change in the drug dosage or the severity of the medical condition.  
• The loss of efficacy happened despite proper dosage administration and adequate duration 
of therapy, as per labeling instructions.  
• The loss of efficacy happened after switching to a new batch of medication. 
• The loss of efficacy reported is in association with some specific units within the same 
package / box, only.  
 
Data review and database management 
 
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 the 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. If applicable, data not requiring a separate written record will be defined 
before study start and will be recorded directly on the CRFs. 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 


 
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according to the study-specific monitoring plan. No information in source documents about 
the identity of the patients will be disclosed. 
 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be 
confirmed or corrected online by the designated investigator site staff. The Investigator 
must certify that the data entered into the electronic Case Report Forms are complete and 
accurate. After database lock, the investigator will receive copies of the patient data for 
archiving at the investigational site.  
 
Database management and quality control 
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If 
the electronic query system is not used, a paper Data Query Form will be faxed to the site. 
Site personnel will complete and sign the faxed copy and fax it back to Novartis staff that 
will make the correction to the database. The signed copy of the Data Query Form is kept 
at the investigator site. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
 
Data Monitoring Committee 
Not Applicable. 
 
Adjudication Committee 
Not Applicable. 
 
Data analysis 
 
Analysis sets 
The Full Analysis Set (FAS) will be comprised of all patients that have received at least one 
dose of LCZ696. The Per-Protocol (PP) Analysis Set will be comprised of the patients that 


 
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complete the 6 month and 12 month follow up assessments depending on the time period 
analyzed. The primary analysis will be based on the FAS. The analyses will be repeated for 
the PP Analysis Set if there is a more than 10% difference between the FAS and PP samples. 
Patients in the FAS will also comprise the Safety Population. All analyses will be performed 
in both the FAS and PP Analysis Sets, unless otherwise specified. 
 
Patient demographics and other baseline characteristics 
Descriptive statistics will be reported for patient demographics and baseline characteristics. 
This will include the mean, median, standard deviation and 95% confidence interval of the 
mean for continuous scale variables. Frequency distributions with 95% confidence intervals 
around the estimate of proportions will be reported for categorical variables.  
 
Treatments 
All LCZ696 doses administered to the patients will be recorded in the CRF. The number of 
tablets dispensed at the previous visit minus the number of tablets returned by patients at 
each study visits, will be used as a measure of the number of tablets taken between study 
visits. 
 
Analysis of the primary and key secondary variable(s) 
 
Variable(s) 
 
Primary Outcome Analysis  
The primary outcome measure of the study will be the proportion of patients remaining on 
treatment with LCZ696 97 mg sacubitril / 103 mg valsartan at six months of follow up. The 
proportion will be calculated as the number of patients at 97 mg sacubitril / 103 mg valsartan 
over the total number of patients that received at least one dose of ENTRESTOTM. 
 
Secondary Outcome Analyses 
The following secondary outcome measures will be analyzed: 
1. 
The proportion of patients who tolerate the LCZ696 dose of 97 mg sacubitril / 103 
mg valsartan mg bid at 12 months of treatment. 
2. 
The proportion of patients on  LCZ696 who  had required down-titration after 
reaching  the 97 mg sacubitril / 103 mg valsartan 
3. 
The number of down-titration changes from 97 mg sacubitril / 103 mg valsartan 
during 12 months of treatment. 
4. 
Functional capacity as measured by the change from baseline to 6 months and 12 
months in the Six Minute Walk Test. 
5. 
Time to up-titration of LCZ696 doses. 
6. 
Duration of treatment on each dose of LCZ696. 


 
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7. 
The proportion of patients on guideline-recommended doses of beta-blockers 
and MRAs at baseline, 6 and 12 months. 
 
Statistical model, hypothesis, and method of analysis 
The data analysis for the current study will be primarily descriptive. Therefore there are no 
a-priori hypothesis being tested.  
 
Primary Efficacy Analysis 
The primary efficacy outcome will be assessed by the proportion of patients on LCZ696 97 
mg sacubitril / 103 mg valsartan bid at 6 months of treatment. Ninety five percent (95%) 
confidence intervals will be calculated for the estimate of this proportion in order to assess 
precision and make inferences to the target population. 
 
Secondary Efficacy Analyses 
Similarly, for the secondary efficacy outcomes, the proportion of patients on LCZ696 97 mg 
sacubitril / 103 mg valsartan bid at 12 months, the proportion of patients requiring down 
titration, and the proportion of patients treated in accordance to guideline recommended 
doses of beta blockers and MRAs, will also be assessed for precision with the 95% 
Confidence Intervals. 
The number of down titrations during the 12 month treatment periods will be described 
with a Poisson distribution and the incidence density rate (IDR) as the number of dose 
reductions per 100 person – month of follow up. 
The change in the Six Minute Walk Test from baseline to 6 and 12 months of treatment will 
be assessed with the 95% confidence intervals and with the Student’s t-test for paired 
observations. 
The time to LCZ696 up-titration to 97 mg sacubitril / 103 mg valsartan bid and the duration 
on treatment for each dose will be assessed with the Kaplan Meier estimator of the survival 
function. 
 
 
Handling of missing values/censoring/discontinuations 
There will be no replacement or imputation of missing values. All analysis will be conducted 
on observed cases only. For patients lost to follow up after achieving the LCZ696 dose of 97 
mg sacubitril / 103 mg valsartan bid, the conservative approach will be used according to 


 
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which they will be considered as not staying on treatment. A sensitivity analysis will be 
conducted to assess the impact of this assumption by using only the PP patients.  
 
Supportive analyses 
Not Applicable. 
 
Analysis of secondary variables 
 
Efficacy variables 
Not Applicable. 
 
Safety variables 
Adverse events (AEs) will be classified according to the MedDRA dictionary of terms 
(Version 18.1 or newer) and summarized using the total number of AEs, the total number 
and percentage of patients who experience an AE overall, and the number and percent of 
patients who experience an AE within each system organ class (SOC) and preferred terms 
(PTs) within individual SOCs. Analysis of the number of patients who experience each AE 
will be performed in the following manner: patients experiencing the same AE multiple 
times will only be counted once for the corresponding PT; similarly, if a patient experiences 
multiple AEs within the same SOC, that patient will be counted only once for that SOC. A 
similar table will be produced for serious adverse events (SAEs), AEs with reasonable 
probability to be related to the study treatment (definitely related, probably related, 
possibly related), and SAEs with reasonable probability to be related to the study treatment. 
Finally, a summary table reporting the breakdown of the total number of AEs by seriousness 
(serious, non-serious), severity (mild, moderate, severe), relationship to study medication 
(definitely related, probably related, possibly related, unlikely related, definitely not related), 
action taken, and outcome will be prepared. The Safety Analysis will be carried out on the 
Safety Population only.  
 
Resource utilization 
Not Applicable. 
 
Pharmacokinetics 
Not Applicable. 


 
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Pharmacogenetics/pharmacogenomics 
Not Applicable. 
 
Biomarkers 
Not Applicable. 
 
PK/PD 
Not Applicable. 
 
Sample size calculation 
The primary outcome measure for the current study will be the proportion of patients on 
97 mg sacubitril / 103 mg valsartan bid of LCZ696 at 6 months of treatment. The data from 
clinical trials have shown that at 12 weeks (3 months) approximately 80% of patients have 
achieved this dose. In this current real – life study of 6 months (primary endpoint) a 
reasonable estimate of patients achieving this dose would be 70%. 
Given that this is a single cohort, prospective study in which all patients are receiving the 
same treatment and the objective is to describe the proportion of patients reaching 97 mg 
sacubitril / 103 mg valsartan bid LCZ696, sample size requirements are based on the 
precision of the estimate. This is assessed with the 95% confidence interval. A reasonable 
level of precision is one with a 95% confidence interval width (ω) that is between 5 and 15% 
of the point estimate. With 300 patients enrolled in the study, the 95% Confidence Interval 
width will be ± 5.2% which is equivalent to 7.4% of the point estimate of 70%, with upper 
and lower limits of 64.8% – 75.2% respectively. This is within the limits of reasonable 
precision.  
 
Ethical considerations 
 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
 
Informed consent procedures 
Eligible patients may only be included in the study after providing written, 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. Informed consent must be obtained before 


 
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conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested 
by the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a 
copy of the approved version must be provided to the Novartis monitor after IRB/IEC 
approval. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must adhere to the contraception requirement 
for the duration of the study. If there is any question that the patient will not reliably comply, 
they should not be entered in the study. 
 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC must be given to Novartis before 
study initiation. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Novartis immediately that this request has been 
made. 
 
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. 
 
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. 


 
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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. 
 
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.  
 
References 
 
 (1)  Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, de SG, et al. Heart disease and 
stroke statistics--2010 update: a report from the American Heart Association. Circulation 
2010 Feb 23;121(7):e46-e215. 
 (2)  McMurray JJ, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: 
public and private health burden. Eur Heart J 1998 Dec;19 Suppl P:9-16. 
 (3)  Vasan R, Wilson PW. Epidemiology and causes of heart failure. UptoDate 2015 July 23 
 (4)  Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D'Agostino RB, Kannel WB, et al. 
Lifetime risk for developing congestive heart failure: the Framingham Heart Study. 
Circulation 2002 Dec 10;106(24):3068-72. 
 (5)  Moe GW, Ezekowitz JA, O'Meara E, Lepage S, Howlett JG, Fremes S, et al. The 2014 
Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: 
anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol 2015 
Jan;31(1):3-16. 
 (6)  Lefkowitz MP. LCZ696, an angiotensin receptor neprilysin inhibitor (ARNI): clinical 
development in heart failure and hypertension. BMC Pharmacology 201111 (Suppl 1)(O3) 


 
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  (7)   Kobalava Z, Pavlikova E, Averkov O, Moiseev V, Albrecht D, Feng A, Priyamvada C, 
Jordaan PJ: First experience with concomitant AT1 and neprilysin inhibition with LCZ696 
in patients with chronic heart failure. Circulation 2010, 122(21 Suppl):19378.     
 
 (8)    McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi 
VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. 
Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 
11;371(11):993-1004. [http://Clinicaltrials.gov], idenifier NCT01035255. 
 (9)   [http://Clinicaltrials.gov], idenifier NCT01922089 
10)   Balke B. A simple field test for the assessment of physical fitness. Rep Civ Aeromed ResInst 
US. 1963(53):  
(11)  Rector TS, Kubo SH, Cohn JN. Patinet`s self-assesment of their congestive heart failure. 
Part 2., Content, reliability and validation of a new measure, the Minnesota Living with 
Heart Failure Questionnaire. Heart Failure1987; Oct/Nov: 198-209 
 
  
 
(13) Packer M (2001) Proposal for a new clinical end point to evaluate the efficacy of drugs and 
devices in the treatment of chronic heart failure. J Cardiac Fail; 7: 176-182. 
 
 


 
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Appendix 1: Clinically notable laboratory values and vital signs 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
RBC count 
 
>50% increase, >20% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit 
 
>50% increase, >20% decrease 
WBC count 
 
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Blood Chemistry 
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: Liver event definitions and follow-up requirements 
Table 14.1 
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 14-2 
Liver Event Follow Up Requirements 
Criteria 
Event type 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
 
ALT or AST 
> 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 x ULN 
accompanied by 
symptomsb 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 x ULN  
(patient is 
asymptomatic) 
AESI 
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 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 


 
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Criteria 
Event type 
Actions required 
Follow-up monitoring 
Repeat LFT once or twice in the 
week If elevation persists, 
establish causality 
≤ 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, hemoglobin, 
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. 
 
 
 


 
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Appendix 3: Study Assessments and Questionnaires 
 
Six Minute Walk Test 
 
> Key Points 
• 
The 6MWT must be performed once or else twice to account for a learning curve. 
• 
*Note: consistency in administering the test is imperative.If the test was performed once at 
baseline it should be performed once at all subsequent visits, if performed twice at baseline it 
should be performed twice at all subsequent visits. 
• 
If the two tests are performed on the same day, at least 30 minutes rest should be 
allowed between tests. 
*Note: debilitated individuals may require tests to be performed on separate days, preferably less 
than one week apart. 
• 
Results of both tests are recorded with the best result used to determine 
functionality. 
• 
A health professional trained in CPR with the ability to run the test must be 
present. 
>Required Equipment 
• 
Walking Track or Area 
− The walking track or area must be the same for all tests for a patient 
− The track may be a continuous track (oval or rectangular) or a point-to-point area 
(stop- turn around-go back). 
− The track or area should be flat with no blind turns, traffic or obstacles. 
− The minimum walking length of 25m (82 feet) should be marked in meter (feet) 
increments. 
*Note: If you do not have access to a 25m track, make sure you use the same point-to- point area 
for all tests (be aware that the distance walked may be less due to the patient having to slow down 
and turn more often in the six minutes). 
• 
Stethoscope, vital sign equipment, pulse oximeter 
• 
Stop watch 
• 
Portable oxygen delivery system 
• 
Chairs in position for the patient to rest 
• 
Dyspnea scale 
 
>Before the 6MWT 
• 
Ensure that you have already obtained a medical history for the patient and have 


 
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taken into account any precautions or contraindications to exercise testing. 
• 
Instruct the patient to dress comfortably, wear appropriate footwear and to avoid 
eating for at least two hours before the test (where possible or appropriate). 
• 
Any prescribed inhaled bronchodilator medication should be taken within one 
hour of testing or when the patient arrives for testing. 
• 
The patient should rest for at least 15 minutes before beginning the test. 
• 
A comfortable ambient temperature and humidity should be maintained for all tests. 
• 
Record: 
- 
Blood pressure 
- 
Heart rate 
- 
Oxygen saturation 
- 
Dyspnea score 
* Note: Show the patient the dyspnea scale (e.g., Borg scale) and give 
consistent instructions on how to obtain a score. 
• 
Instructions to the Patient 
*Note: Instructions must be consistent. 
(Read out loud the instructions to the patient.) 
- 
Describe the walking track or area to the patient. 
- 
Explain the objective of the test. 
- 
Provide instructions on what to do and what not to do during the test. 
- 
Emphasize reporting any untoward effects. 
- 
Sample instructions: 
“You are now going to do a six-minute walking test. The object of this test is to walk 
as quickly as you can for six minutes around the track (or up and down the corridor 
etc... depending on your track set up) so that you cover as much ground as possible. 
You may slow down if necessary. If you stop, I want you to continue to walk again as 
soon as possible. You will be kept informed of the time and you will be encouraged to 
do your best. Your goal is to walk as far as possible in six minutes. Please do not talk 
during the test unless you have a problem or if I ask you a question. You must let me 
know if you have any chest pain or dizziness. When the six minutes is up I will ask 
you to stop where you are. Do you have any questions?” 
> Begin the Test by instructing the patient to start walking and start the stop watch. 
> During the Test 
• 
Monitor the patient for untoward signs and symptoms. 
• 
Use standard encouragements during the test. Example: 
- 
At minute one: “Five minutes remaining. Do your best!” 
- 
At minute two: “Four minutes remaining. You're doing well- keep it up! 
- 
At minute three: “Half way point. Three minutes remaining!” 
- 
At minute four: “Two minutes remaining. You're doing well- keep it up! 
- 
At minute five: “One minute remaining. Do your best!” 
> At the End of the 6MWT 
• 
Put a marker on the distance walked. 


 
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• 
Have the patient sit down or if the patient prefers, allow to the patient to stand. 
*Note: The measurements taken before and after the test should be taken with the 
patient in the same position. 
• 
Immediately record oxygen saturation (SpO2)%, heart rate, and dyspnea 
rating on the recording sheet. 
• 
Measure the excess distance with a tape measure and add up the total distance. 
• 
The patient should remain in a clinical area for at least 15 minutes following 
an uncomplicated test. 
>Clinical Notes 
Normally the clinician does not walk with the patient during the test to avoid the 
problem of setting the walking pace. The pulse oximeter should be applied immediately 
if the patient chooses to rest and at completion of the six-minute walking period. Any 
delay may result in readings being recorded that are not representative of maximum 
exercise response. 
In some instances, the clinician may choose to walk with the patient for the entire test 
(e.g., if continuous oximetry is desired). If this is the case the clinician should try to 
walk slightly behind the patient to avoid setting the walking pace. Alternatively, if the 
oximeter is small and lightweight, it may be attached to the patient and checked 
throughout the test without interfering with walking pace. 
> If the Patient Stops During the Six Minutes 
• 
Allow the patient to sit in a chair if they wish. 
• 
Measure the SpO2% and heart rate. 
• 
Ask the patient why they stopped. 
• 
Record the time the patient stopped (but keep the stop watch running). 
• 
Encourage the patient to begin walking as soon as he/she is feeling better and offer 
encouragement every 15 seconds if necessary. 
• 
Monitor the patient for untoward signs and symptoms. 
>Stop the Test in the Event of Any of the Following 
• 
Chest pain suspicious for angina. 
• 
Evolving mental confusion or lack of coordination. 
• 
Evolving light-headedness. 
• 
Intolerable dyspnea. 
• 
Leg cramps or extreme leg muscle fatigue. 
• 
Persistent SpO2 < 85%. 
• 
Any other clinically warranted reason. 
> Predicted Normal Values for the 6MWT 
The following predictive equation uses the reference values determined from a study 


 
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that performed two 6MWTs and recorded the best result: (For more details see 
Troosters T, Gosselink R, Decramer M. Six minute walk distance in healthy elderly 
subjects. Eur Respir J. 1999;14: 270-274). 
• 
Predicted six-minute walk distance in healthy elderly = 631 ± 93 meters 
• 
Predictive equation: 6MWDpred = 218 + (5.14 x heightcm - 5.32 x age) - 1.80 x 
weightkg + 51.31 x gender 
Note: Gender is factored into the equation by male = 1, female = 0. 
> 6MWT as an Outcome Measure 
The change in the distance walked in the 6MWT can be used to evaluate the efficacy of an 
exercise training program or to trace the natural history of change in exercise capacity 
over time. 
The minimum clinically important difference (i.e., improvement) in the distance walked in 
a 6MWT has been estimated as 54 meters (with 95% confidence limits of 37 to 71 meters) 
(For further details, see Redelmeier, 1997). 
However, this improvement in 6MWT distance may not occur in patients who walk a very 
short distance in their 6MWT before pulmonary rehabilitation. For these patients, it may 
be more reasonable to evaluate efficacy based on the percent change rather than a change 
in a set number of meters. However, the actual percent change that equates to a clinical 
improvement has not yet been established - further research is required. 
 
All Rights Reserved © Mark D. Pilley, MD  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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SAP_000.pdf: 
Clinical Development 
LCZ696 
 CLCZ696BCA02 / NCT02690974 
 PARASAIL - Prospective, multi-center, open lAbel, post-
appRovAl Study AImed at characterizing the use of LCZ696 at 
97 mg sacubitril / 103 mg valsartan bid in patients with HFrEF 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Amendment 1 
Release date: 
4-Jul-2017
Number of pages: 
28 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
1.2.1 
Primary objective .................................................................................... 7 
1.2.2 
Secondary objectives ............................................................................... 7 
 
 8 
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 ................... 10 
2.3.1 
Patient disposition ................................................................................. 10 
2.3.2 
Background and demographic characteristics ....................................... 10 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 11 
2.4.1 
Study treatment / compliance ................................................................ 11 
2.4.2 
Prior, concomitant and post therapies ................................................... 12 
2.5 
Analysis of the primary objective .......................................................................... 12 
2.5.1 
Primary endpoint ................................................................................... 12 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 13 
2.5.4 
Supportive analyses ............................................................................... 13 
2.6 
Analysis of the key secondary objective ............................................................... 13 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 13 
2.7.1 
Secondary endpoints ............................................................................. 13 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 13 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.8 
Safety analyses ....................................................................................................... 14 
2.8.1 
Adverse events (AEs) ............................................................................ 14 
2.8.2 
Deaths .................................................................................................... 15 
2.8.3 
Laboratory data ..................................................................................... 15 
2.8.4 
Other safety data ................................................................................... 17 
2.9 
Pharmacokinetic endpoints .................................................................................... 18 


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2.10 
PD and PK/PD analyses......................................................................................... 18 
2.11 
6 MWT analysis ..................................................................................................... 18 
 
 18 
 
 18 
 
 19 
 
 19 
 
 19 
2.15 
Interim analysis ...................................................................................................... 20 
3 
Sample size calculation ..................................................................................................... 20 
4 
Change to protocol specified analyses .............................................................................. 20 
5 
Appendix ........................................................................................................................... 21 
5.1 
Imputation rules ..................................................................................................... 21 
5.1.1 
Study drug ............................................................................................. 21 
If the date of an event is not known or is incomplete, the imputation rules are: ... 21 
5.1.2 
AE date imputation ............................................................................... 21 
5.1.3 
Concomitant medication date imputation ............................................. 22 
5.2 
AEs coding/grading ............................................................................................... 24 
5.3 
Laboratory parameters derivations ........................................................................ 25 
5.4 
Statistical models ................................................................................................... 25 
5.4.1 
Primary anlysis ...................................................................................... 25 
5.4.2 
Secondary anlysis .................................................................................. 26 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 26 
5.6 
Adverse event of special interest ........................................................................... 28 
5.7 
Target dose of cardiovascular medication ............................................................. 28 
6 
Reference ........................................................................................................................... 28 
 
 
 


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Document History – Changes compared to previous version of SAP module 3. 
Version 
Date 
Changes 
Final 1.0 
29-APR-2016 
Initial draft 
Amendment 1 
27-Jul-2017 
As per Protocol few amendment sections got updated 
Section 2.11 6MWT analysis updated; few sites won’t be 
performing 6MWT twice 
 
Section 2.2 Added definition of enrolled set 
Section 2.4.1 analysis regarding compliance 
 
Section 5.5 Rule of exclusion criteria of analysis sets  
Section 5.6 Adverse event of special interest 
Section 5.7 Target dose of cardiovascular medication 
Addendum 1 
24-Apr-2018 
Section 2.11 6 MWT analysis change, Observations with total 
distance walked >1000 m will be excluded from the analysis. 
Section 2.8.3 Laboratory data, handling unit coversion for 
creatinine and uric acid programmatically. 
 


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List of abbreviations 
ACE 
angiotensin converting enzyme  
ACEI(s) 
angiotensin converting enzyme inhibitor(s) 
AE 
Adverse event 
ALT 
alanine aminotransferase 
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 1bid twice a day 
bid 
bis in diem/twice a day 
BP 
blood pressure 
CHF 
chronic heart failure 
CSR 
Clinical Study report 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical Study Report 
CRO 
Contract Research Organization 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety & Epidemiology 
EC(s) 
Ethics Committee(s) 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
 
 
FAS 
Full Analysis Set 
HF 
Hearth Failure 
ICH 
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Randomization TechnologyLCZ696 Novartis compound code 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mg 
milligram 
NP(s) 
natriuretic peptide(s) 
NYHA 
New York Heart Association 
o.d. 
once a day 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
p.o. 
oral 


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PARASAIL / LCZ696BCA02 
 
QoL 
Quality of Life 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
1 
Introduction 
The main purpose of this Statistical Analysis Plan (SAP) is to provide summary of the statistical 
methodology that will be used for this 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 SAP module describes the statistical analysis according to Section 9 of the study protocol 
along with 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 (Efficacy evaluation), 2.8 (Safety evaluation), 2.14 (Interim analysis) and 3 (power 
and sample size considerations). 
1.1 
Study design 
This will be a multi-center, open label, prospective post-approval (phase IV) study. Patients 
with HFrEF that are eligible to be treated with LCZ696 as per the product monograph will be 
enrolled in the study. The study patients will be enrolled at Canadian community cardiologists 
and IM specialists that treat patients with HFrEF. Follow up will be for 12 months with 
assessments at baseline, week 2, week 4, month 3 (optional), month 6 and month 12. The 
primary endpoint will be assessed after 6 months of follow-up. 
Treatment with ACEIs will be discontinued for 36 hours and then replaced with LCZ696 at 24 
mg sacubitril / 26 mg valsartan bid. NO washout period is needed for patients previously treated 
on ARBs. The dose of LCZ696 will be increased to 49 mg sacubitril / 51 mg valsartan bid 
within 2-4 weeks of enrolment and to 97 mg sacubitril / 103 mg valsartan bid within 2-4 weeks 
from the first up titration to 49 mg sacubitril / 51 mg valsartan bid as tolerated by the patient 
and in accordance to the product monograph (Figure 1-1 ). Down titration of LCZ696 from the 
higher doses may be considered, as per the product monograph for patients that experience 
tolerability issues including, but not limited to, symptomatic hypotension or hyperkalemia. 
 
 


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Figure 1-1           Study design 
 
* LCZ696 50 mg bid is the equivalent of 24 mg sacubitril / 26 mg valsartan bid 
* LCZ696 100 mg bid is the equivalent of 49 mg sacubitril / 51 mg valsartan bid 
* LCZ696 200 mg bid is the equivalent of 97 mg sacubitril / 103 mg valsartan bid 
1.2 
Study objectives and endpoints 
1.2.1 
Primary objective 
The primary objective of this study is to describe the tolerability of LCZ696 at 97 mg sacubitril 
/ 103 mg valsartan bid, after 6 months of treatment in patients with HFrEF.   
1.2.2 
Secondary objectives 
In patients with HFrEF:  
• To describe the tolerability of LCZ696 at 97 mg sacubitril / 103 mg valsartan bid, after 
12 months of treatment.  
• To evaluate the impact of the titration scheme on the tolerability of patients maintained 
on LCZ696 97 mg sacubitril / 103 mg valsartan bid at 6 and 12 months  
• To describe the impact of LCZ696 on functional exercise capacity, as measured by the 
Six Minute Walk Test, at 6 and 12 months.  
• To describe the time of up-titration for each dose (24 mg sacubitril / 26 mg valsartan 
bid / 49 mg sacubitril / 51 mg valsartan bid) of LCZ696.  
• To describe the adherence to guideline recommended dosing of beta-blockers and 
MRAs at 6 and 12 months of treatment with LCZ696.  
• To evaluate the overall safety profile of LCZ696 during 12 months of treatment.  
 
 


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2 
Statistical methods 
The data analysis for the current study will be primarily descriptive. Descriptive statistics will 
be produced for all study variables. The descriptive statistics will include mean, median, SD 
and 95% confidence interval of the mean for continuous scale variables and frequency 
distributions with 95% confidence intervals around the estimate of proportions will be reported for 
categorical scale variables. 
For categorical data, percentages will be rounded up to 1 decimal place. For continuous data, 
mean, median and quartiles 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. 
The data analysis for the current study will be primarily descriptive. 95% confidence intervals 
will be calculated for the estimate of proportions in order to assess precision and make 
inferences to the target population. 
Safety will be assessed with the incidence of treatment emergent adverse events. 
2.1.1 
General definitions  
All patients who are eligible will be treated with the following:  
• Baseline: Refers to the last measurement made prior to administration of the first dose 
of study medication. 
• 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 


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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. 
• Incidence rate: The incidence rate is the number of new cases per population at risk in 
a given time period . When the denominator is the sum of the person-time of the at risk 
population, it is also known as the incidence density rate or person-time incidence rate.  
• IDR per 100 person-month: A rate of events per 100 patient months measures the 
intensity of the events over time for the underlying population events. Where event is 
defined as patient reaching 200 mg dose. 
2.2 
Analysis sets 
The following analysis sets will be used for statistical analysis: 
• Screened set (SCR) – Screened set will be comprised of all patients given informed 
consent. 
• Enrolled set (ENR) – Patients who have met the eligibility criteria or has taken at least 
one dose of study medication. 
• Full analysis set (FAS) – The Full Analysis Set (FAS) will be comprised of all patients 
that have received at least one dose of LCZ696. The primary analysis will be based on 
the FAS. 
• Per protocol set (PPS) – The Per-Protocol Set will be comprised of the patients that 
complete the 6 month and 12 month follow up assessments depending on the time period 
analyzed. The analyses will be repeated for the PPS if there is a more than 10% 
difference between the FAS and PPS samples. 
• Safety Set (SAF)- Safety set includes all the patients in FAS. 
All analyses will be performed in both the FAS and PPS, unless otherwise specified. All Safety 
analysis will be performed on Safety Set. 
2.2.1 
Subgroup of interest 
NYHA class will be used as subgroup of interest. Patient reported outcome will be provided by 
NYHA class II and NYHA class III. 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
Descriptive statistics will be reported for patient demographics and baseline characteristics. 
This will include the mean, median, standard deviation, minimum and maximum for continuous 
variables. Frequency distributions will be reported for categorical variables. 
2.3.1 
Patient disposition 
The number and percentage of enrolled, completed, and discontinued in the study and reason 
for the discontinuation and screen failure will be provided. For patient who was screened more 
than once, the information from the last screen will be used in the summary. Data will be 
summarized using 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 in separate table for the FAS. 
2.3.2 
Background and demographic characteristics 
Descriptive statistics will be provided for patient demographics and baseline characteristics.  
The following demographic and baseline parameters will be summarized at the visit 1 (day 1): 
• Demographics 
o Age (Years) 
o Gender 
o Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, 
Other) 
o Ethnicity (Hispanic or Latino, east Asian, Southeast Asian, South Asian, West 
Asian, Russian, Mixed Ethnicity, Not reported, Unknown, Other) 
o Height (Cm) 
o Weight (kg) 
o Body Mass Index (BMI)  (kg/m2) 
o Smoking history 
o Alcohol use history 
• Medical History 
Any condition entered on the relevant medical history / current medical conditions will be coded 
using the MedDRA dictionary. Medical history includes  cardiovascular disease history in this 
study, which are collected prior to informed consent signature. 
The number and percentage of subjects with each medical condition will be provided by system 
of organ class for the FAS. 
The above medical conditions will also be listed. 
• Heart Failure History 


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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) 
o Prior heart failure hospitalization(yes/no) 
o Number of hospitalization in the last 12 months 
o Ejection Fraction (%) in last 12 months 
o NYHA class at enrollement  
o Timing since last ejection fraction (months) 
The above demographic and heart failure history will also be listed based on FAS. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of the study treatment exposure will be summarized (n, mean, standard deviation, 
minimum, median, and maximum). Descriptive statistics will be based on SAF. 
The exposure duration categories are defined for each phase as: 
• Day 1  
• >= 2 Weeks  
• >= 4 Weeks  
• >= 12 Weeks 
• >= 24 Weeks 
• >= 52 Weeks (12 Months) 


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Treatment duration (days) = (date of last dose of LCZ696 – date of first dose of LCZ696) + 1 
Compliance with treatment will be defined as the percentage of doses taken by the patient and 
will be calculated using the following formula: 
Compliance (%) = 100 x (total number of capsules dispensed – total number of capsules 
returned) / total number of capsules dispensed.In addition listing for the total number of missed 
doses by each patient will be provided. 
This information will be used as a measure of the number of tablets taken between study visits 
for compliance. 
The durations on each dose level, time from the first dose intake to the final top dose will also 
be summarized. 
 
2.4.2 
Prior, concomitant and post therapies 
The concomitant medication information will be summarized based on the SAF. 
Concomitant medications and significant non-drug therapies, prior to and after the study 
treatment will be summarized by therapeutic class, preferred term according to the WHO-DRL 
dictionary. Also, cardiovascular concomitant medication will be summarized separately. 
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. 
The proportion of patients on guideline recommended dose of beta-blockers and MRAs at 
baseline ,6 and 12 months will also be summarized. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary outcome measure of the study will be the proportion of patients remaining on 
treatment with LCZ696 97 mg sacubitril / 103 mg valsartan at six months of follow up. The 
proportion will be calculated as the number of patients at 97 mg sacubitril / 103 mg valsartan 
over the total number of patients that received at least one dose of LCZ696.  
2.5.2 
Statistical hypothesis, model, and method of analysis 
The data analysis will be primarily descriptive. Therefore, there is no a-priori hypothesis being 
tested. 
The primary efficacy outcome will be assessed by the proportion of patients on LCZ696 97 mg 
sacubitril / 103 mg valsartan bid at 6 months of treatment. 95% confidence interval using 
binomial proportion will be calculated for the estimate of the proportion in order to assess 
precision and make inferences to the target population. 


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2.5.3 
Handling of missing values/censoring/discontinuations 
There will be no replacement or imputation of missing values. All analysis will be conducted 
on observed cases only. For patients lost to follow up after achieving the LCZ696 dose of 97 
mg sacubitril / 103 mg valsartan bid, the conservative approach will be used, according to which 
they will be considered as not staying on treatment.  
2.5.4 
Supportive analyses 
A sensitivity analysis will be conducted  for PPS if there is a more than 10% difference between 
the FAS and PPS samples.   
2.6 
Analysis of the key secondary objective 
There is no key secondary objective for this study.   
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The following secondary outcome measures will be analyzed:  
1. The proportion of patients who tolerate the LCZ696 dose of 97 mg sacubitril / 103 mg 
valsartan mg bid at 12 months of treatment.  
2. The proportion of patients on LCZ696 who had required down-titration after reaching 
the 97 mg sacubitril / 103 mg valsartan  
3. The number of down-titration changes from 97 mg sacubitril / 103 mg valsartan during 
12 months of treatment.  
4. Functional capacity as measured by the change from baseline to 6 months and 12 months 
in the Six Minute Walk Test.  
5. Time to each up-titration to 49 mg sacubitril / 51 mg valsartan and 97 mg sacubitril / 
103 mg valsartan.  
6. Duration of treatment on each dose of LCZ696.  
7. The proportion of patients on guideline-recommended doses and who are tolerant of 
beta-blockers and MRAs at baseline, 6 and 12 months.  
 
2.7.2 
 Statistical hypothesis, model, and method of analysis 
The data analysis will be primarily descriptive. For the secondary efficacy outcomes, the 
proportion of patients on LCZ696 97 mg sacubitril / 103 mg valsartan bid at 12 months, the 
proportion of patients requiring down titration, and the proportion of patients treated in 
accordance to guideline recommended doses of beta blockers and MRAs will be presented 
along with the 95% Confidence Intervals using binomial proportion to assess the precision. 


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The number of down titrations during the 12 month treatment periods will be described with a 
Poisson distribution and the incidence density rate (IDR) as the number of dose reductions per 
100 person – month of follow up.  
The change in the Six Minute Walk Test from baseline to 6 and 12 months of treatment will be 
assessed along with the 95% confidence intervals using Student’s t-test for paired observations.  
The time to LCZ696 up-titration to 97 mg sacubitril / 103 mg valsartan bid and the duration on 
treatment for each dose will be assessed with the Kaplan Meier estimator of the survival 
function. 
Duration of treatment on each dose of LCZ696 will be summarized descriptively. 
2.7.3 
Handling of missing values/censoring/discontinuations 
There will be no replacement or imputation of missing values. All analysis will be conducted 
on observed cases only. For patients lost to follow up after achieving the LCZ696 dose of 97 
mg sacubitril / 103 mg valsartan bid, the conservative approach will be used according to which 
they will be considered as not staying on treatment. 
A sensitivity analysis could be conducted for the PPS as required. 
2.8 
Safety analyses 
2.8.1 
Adverse events (AEs) 
Adverse events (AEs) will be classified according to the latest MedDRA dictionary of terms 
and summarized using :  
• The total number of AEs 
• The total number and percentage of patients who experience an AE overall, 
• The number and percent of patients who experience an AE within each system organ 
class (SOC) and preferred terms (PTs) within individual SOCs. 
Analysis of the number of patients who experience each AE will be performed in the following 
manner: patients experiencing the same AE multiple times will only be counted once for the 
corresponding PT; similarly, if a patient experiences multiple AEs within the same SOC, that 
patient will be counted only once for that SOC.  
Number and percent of patients who experience an SAE within each system organ class (SOC) 
and preferred terms (PTs) within individual SOCs will also be summarized. 
AEs and SAEs with related to the study treatment (definitely related, probably related, possibly 
related) will be summarized.  
Summary of the total number of AEs by seriousness (serious, non-serious), severity (mild, 
moderate, severe), relationship to study medication (definitely related, probably related, 
possibly related, unlikely related, definitely not related), action taken and outcome will also be 
provided.  


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Any AE/SAE occurred during the study will be included in AE/SAE summary tables, i.e. 
AEs/SAEs occurred on or after study day 1 and up to 30 days after the discontinuation of the 
study drug. 
The following summaries will be generated for AEs: 
• 
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 
Liver events of special interest (AESI) which consist of LFTs elevations will be presented. 
Adverse event (liver events) of special events defiend as: 
• 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 with a preferred term (PT) in the MedDRA dictionary falling under the SMQ 
sub-module “Drug-related” 
o hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions;  
o non-infectious hepatitis;  
o benign, malignant and unspecified liver neoplasms  
o Hy’s law case (PT)  
2.8.2 
Deaths 
Primary cause of death will be summarized by system organ class (SOC) and preferred term 
(PT) by providing number and percent. Death information will be summarized on SAF.   
2.8.3 
Laboratory data 
The Laboratory Analysis will be carried out on SAF. 
Clinically notable laboratory findings are defined as in section 5.3. 
The summary of laboratory evaluations will be presented for laboratory tests: hematology 
which include hemoglobin, hematocrit, RBC count, WBC count, platelet count, and blood 
chemistry which includes blood urea nitrogen (BUN), creatinine, AST (SGOT), ALT (SGPT), 
alkaline phosphatase, potassium, eGFR, chloride, and uric acid as conduct per routine care.  
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. Change from baseline will only be summarized for subjects with 


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both baseline and post baseline values and will be calculated as defined in section 2.1.1 i.e. 
General definations. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test. 
The number and percentage of subjects with clinically notable laboratory results after baseline 
will be presented. Clinically notable laboratory results, for those parameters where ranges are 
available, are given in Table 1 below. For the calculation the denominator are based on the 
evaluable post-baseline subjects who did not have the notable abnormality at baseline. 
For all laboratory evaluation scheduled and unscheduled laboratory measurements will be taken 
into account. 
As confirmed from the sites about erroneous lab unit entry of the parameters creatinine and uric 
acid, the appropriate conversion of these units will be handled programmatically. 
The parameters that will be considered for unit conversion are Creatinine and Uric acid. 
Parameter 
Original unit 
Standard unit 
Conversion factor 
Creatinine 
mmol/l 
umol/L 
1000 
Creatinine 
Mg/dL 
umol/L 
88.40 
Urate 
mmol/L 
umol/L 
1000 
Table 1 
Clinical notable criteria for selected laboratory tests 
Hematology 
 
RBC count 
>50% increase, >20% decrease 
Hemoglobin 
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
Blood Chemistry 
 
ALT (SGOT) 
>150% increase 
AST (SGPT) 
>150% increase 
BUN 
>50% increase 
 
>14.28 mmol/L 
Creatinine 
>50% increase 
 
>136.8 µmol/L 
CPK 
>300% increase 
Alkaline phosphatase 
>100% increase 
Potassium 
>20% increase, >20% decrease 
 
≥6.0 mmol/L 
 
>5.0 mmol/L 
 
<3.5 mmol/L 
Chloride 
>10% increase, >10% decrease 


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Uric acid 
>50% increase 
In the above table increase and decrease are defined as compared to the baseline value. 
2.8.3.1 
Urinalysis 
Not Applicable. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Electrocardiograms will be conducted as per routine care and documented in the site’s source 
documents. No analysis will be performed. 
2.8.4.2 
Vital signs 
Vital signs tests performed includes the following: 
• Sitting systolic blood pressure(SSBP) (mmHg) 
• Sitting diastolic blood pressure(SDBP) (mmHg) 
• Pulse rate (beats/min) 
• Body weight (kg) 
These parameters will be summarized by visit with standard summary statistics (mean, median, 
standard deviation, min, max), including changes from baseline. 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 i.e. General definations. 
The number and percentage of subjects with clinically notable vital signs changes from baseline 
will also be presented. Clinically notable vital sign results are provided in Table 2 below.  
Table 2 
Clinically notable changes in vital signs 
Vital Sign (unit) 
Clinically notable criteria 
Weight (kg) 
decrease > 7% from Baseline 
increase > 7% from Baseline 
Sitting systolic blood pressure (mmHg) 
<90 and decrease from baseline of >20 
>180 and increase from baseline of >20 
Sitting diastolic blood pressure (mmHg) 
<50 and decrease from baseline of >15 
>105 and increase from baseline of >15 
Pulse (bpm) 
<50 and decrease from baseline of > 15 
>120 and increase from baseline of >15 
 
2.8.4.3 
NYHA Class assessment 
Patients NYHA class will be assessed at Baseline, at month 3, at month 6 and at month 12. At 
baseline, only patients with heart failure NYHA class II or III can be enrolled in the study. The 
total number and percentage of patient with each NYHA class will be provided by visits based 


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FAS. The change in NYHA class at month 3, 6 and 12 each compared to baseline (Day 1) will 
be summarized by frequesncy distribution. 
2.9 
Pharmacokinetic endpoints  
Not applicable 
2.10 
PD and PK/PD analyses  
Not applicable 
2.11 
6 MWT analysis 
6 MWT data will be summarized for visit 1 (baseline), visit 5 (month 6) and visit 6 (month 12). 
Descriptive summary statistics (mean, median, standard deviation, min and max) for the 
baseline and change from baseline to visit 5 and visit 6 will be presented based on the total 
distance each patient walks in six minutes. The descriptive summaries will be presented by visit. 
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 6 MWT analysis will be summarized based on the FAS. For the patients with two six minute 
walk test, best of the results based on longest distance covered will be considered for analysis. 
The observations with total distance walked > 1000m will be excluded from the analysis as 
confirmed by the sites and CTT due to erroneous data entry. 


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2.13 
Biomarkers 
Not applicable 


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2.15 
Interim analysis 
An interim analysis may be performed after 50 patients have reached 12 weeks of treatment,  
 and at any 
time during the study as long as it does not impact the study completion. 
3 
Sample size calculation 
The primary outcome measure for the current study will be the proportion of patients on 97 mg 
sacubitril / 103 mg valsartan bid of LCZ696 at 6 months of treatment. The data from clinical 
trials have shown that at 12 weeks (3 months) approximately 80% of patients have achieved 
this dose. In this current real – life study of 6 months (primary endpoint) a reasonable estimate 
of patients achieving this dose would be 70%. 
Given that this is a single cohort, prospective study in which all patients are receiving the same 
treatment and the objective is to describe the proportion of patients reaching 97 mg sacubitril / 
103 mg valsartan bid LCZ696, sample size requirements are based on the precision of the 
estimate. This is assessed with the 95% confidence interval. A reasonable level of precision is 
one with a 95% confidence interval width (ω) that is between 5 and 15% of the point estimate. 
With 300 patients enrolled in the study, the 95% Confidence Interval width will be ± 5.2% 
which is equivalent to 7.4% of the point estimate of 70%, with upper and lower limits of 64.8% 
– 75.2% respectively. This is within the limits of reasonable precision. 
4 
Change to protocol specified analyses 
Not applicable. 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
If the date of an event is not known or is incomplete, the imputation rules are: 
a) If the day of the event is unknown, then the 15th day of this month will be imputed for 
a missing day; 
b) If only the month is unknown, then July will be used for imputation of the missing; 
c) If only the year of the event is known, then the 1st of July will be imputed for a missing 
day and month; 
d) The above rules are only for general case. If there is additional information available for 
the missing date, then the information should be used and the imputation of missing date 
should be treated differently. For example, if an event occurs between two visits and its 
date is missing, then the date in the middle of these visits may be used. 
5.1.2 
AE date imputation 
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the Table 1-2 below.   
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore: 
a. If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid year point (01JulYYYY). 
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid month point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore: 
a. If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY). 
b. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing or the AE month is equal to the treatment start month, 
the imputed AE start date is set to one day after treatment start. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid month point (15MONYYYY). 


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c. Else if the AE month is greater than the treatment start month, the imputed AE start 
date is set to the start month point (01MONYYYY). 
Table 1-2 AE date imputation 
 
MON 
MON < CFM 
MON = CFM 
MON > CFM 
 
MISSING 
YYYY 
MISSING NULL 
NULL 
NULL 
NULL 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY < 
CFY 
( D ) = 01JULYYYY 
( C )= 15MONYYYY ( C )= 15MONYYYY ( C )= 15MONYYYY 
 
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start 
YYYY = 
CFY 
(B)= TRTSTD+1 
( C )= 15MONYYYY (A)= TRTSTD+1 
(A)= 01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY > 
CFY 
(E)= 01JANYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
(A)= 01MONYYYY 
 
After Treatment Start  After Treatment Start  After Treatment Start  After Treatment Start  
 
 
 
 
 
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
LEGEND: 
(A) 
         MAX(01MONYYYY,TRTSTD+1) 
 
(B) 
         TRTSTD+1 
 
 
(C) 
15MONYYYY 
 
 
(D) 
01JULYYYY 
 
 
(E) 
01JANYYYY 
 
 
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 


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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 
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 


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(E) 
01JANYYYY 
Concomitant medication end date imputation 
If not ongoing then - 
If the CM end date year value is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end date is 
set to NULL. 
Else, if the CM end date month is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, 31DECYYYY, date of death). 
If the CM end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death). 
If the imputed CM end date is less than the existing CM start date, use the CM start date as the 
imputed CM end date 
Concomitant medication date flag 
If not a complete date then 
Y - If year of the imputed date is not equal to YYYY else 
M – If month of the imputed date is not equal to MON else 
D 
5.1.3.1 
Prior therapies date imputation 
As explained above in the section 5.1.3. 
5.1.3.2 
Post therapies date imputation 
As explained above in the section 5.1.3. 
5.2 
AEs coding/grading 
NA 
 
 


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5.3 
Laboratory parameters derivations 
                            
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 
 
5.4 
Statistical models 
5.4.1 
Primary anlysis  
For the proportion and percentage along with 95% confidence limits estimated using normal 
approximation (binomial proportion) , statistical programmer may use the following code: 
 
<Sample code> 
proc freq data= <xxx>; 
tables <xxx> / binomial; 
run; 
 


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5.4.2 
Secondary anlysis  
For Incidence density rate for the number of dose reduction, following code may be used: 
 
<Sample code> 
proc genmod data=mydata; 
model ndt =/dist=poisson link=log obstats; /* where ndt is the number of down    
                                       titrations for each of the patients.*/ 
run; 
For Kaplan-Meier estimates of the probability of reaching LCZ 200 mg, following code may 
be used: 
 
ods listing close; 
proc lifetest data = <xxx> outsurv = <xxx> ; 
      time TIME*censor(0); 
      ods output productlimitestimates = res; 
      ods output HomTests=pvalue; 
      ods output Quartiles=med; 
run; 
ods listing; 
 
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: 
 
Protocol 
Deviation ID 
(DVSPID) 
Decription used to Report PDs to 
HA/IRBs (DVTERM) 
Population 
Severity code 
INCL01  
Written informed consent is not 
obtained before assessment is 
performed 
Excluded from PPS 
4 
INCL02 
Age less than 18 years and greater 
than 80 years. 
-Excluded from 
PPS if Age < 18 
years  
-Included in both 
FAS & PPS if Age 
> 80 years 
4 
 
 
 
0 
INCL04 
Not diagnosed with Heart Failure 
NYHA class II or III 
Excluded from PPS 
4 
INCL05 
Not diagnosis of Heart Failure with 
reduced Ejection Fraction (LVEF 
lessthan 40%) and NYHA class II or 
III 
Excluded from PPS 
4 
INCL06 
Unstable to any dose of ACEI or ARB 
prior to enrolment in the study 
Excluded from PPS 
only if patient is 
NOT on any dose 
of ACEI or ARB 
4 
INCL07 
Unstable to any dose of a beta-blocker 
prior to enrolment in the study 
Excluded from PPS 
only if patient is 
4 


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NOT on any dose 
of Beta-Blocker 
INCL08 
Not Eligible for treatment with 
LCZ696 (ENTRESTOTM) as per 
Canadian product monograph 
Excluded from PPS 
4 
INCL09 
Not Treated as an outpatient 
Excluded from PPS 
4 
INCL10 
Informed consent is not signed on 
agreeing to participate in the study 
Excluded from, 
PPS, SAF and FAS 
 4, 3 
EXCL01A 
Symptomatic hypotension at Baseline 
Excluded from PPS 
4 
EXCL01B 
SBP less than 100 mmHg at baseline 
visit 
Excluded from PPS 
4 
EXCL02 
Estimated GFR lessthan 30 
mL/min/1.73m2 as measured by the 
simplified Modification of Diet in 
Renal Disease (MDRD) formula at 
baseline visit. 
Excluded from PPS 
4 
EXCL03 
Known history of angioedema related 
to previous ACEI or ARBs therapy, or 
history of hereditary or idiopathic 
angioedema. 
Excluded from PPS 
4 
EXCL04 
Requirement of concomitant 
treatment with both ACEIs and ARBs 
Excluded from PPS 
4 
EXCL05 
Concurrent participation in other 
clinical trials or receiving other 
investigational drugs within 30 days 
of enrollment. 
Excluded from PPS 
4 
EXCL06 
Hypersensitivity to the active 
substances, sacubitril or valsartan, or 
to any of the excipients. 
Excluded from PPS 
4 
EXCL07 
Concomitant use of aliskiren-
containing drugs in patients with 
diabetes mellitus (type 1 or type 2) or 
moderate to severe renal impairment 
(GFR lessthan 60ml/min/1.73m2). 
Excluded from PPS 
4 
EXCL08 
History of hypersensitivity to any of 
the study drugs or to drugs of similar 
chemical classes. 
Excluded from PPS 
4 
EXCL09 
History of malignancy of organ 
system (other than local basal cell 
carcinoma of skin), treated or 
untreated, within the past 5 years, 
regardless there is evidence 
Excluded from PPS 
4 
EXCL10 
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. 
Excluded from PPS 
4 


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5.6 
Adverse event of special interest 
For reporting of AESIs, document “AEs of special interest preferred terms” will be used. 
Document  received for  Medical Lead will be placed in CREDI as it is. 
 
5.7 
Target dose of cardiovascular medication 
For reporting of targed dose of beta blockers and MRAs, document “Canadian drugs for 
HFrEF” will be used. Document  received for  Medical Lead will be placed in CREDI as it is. 
6 
Reference 
Protocol has been used as a reference. 
EXCL11 
Women of childbearing potential, 
defined as all women physiologically 
capable of becoming pregnant, unless 
they are using effective methods of 
contraception during dosing of study 
treatment 
Excluded from PPS 
4 
WITH01 
Patient become pregnant, while taking 
study medication. 
Excluded from PPS 
0 
WITH02 
Due to the potential risk of 
angioedema when used concomitantly 
with an ACEI, LCZ696 is started 
within 36 hours without 
discontinuation of ACEI therapy. 
Excluded from PPS 
4 
OTH01 
Pregnancy test not performed as 
required per protocol 
Excluded from PPS 
0 
OTH02 
Pregnancy not reported within 24 hrs 
to Novartis while patient is on study 
treatment 
Excluded from PPS 
4  
OTH03 
Approved ICF update 
available but patient has 
not signed this version 
 
 
TRT01 
Treatment with ARBs is not 
discontinued prior to intiation of study 
treatment 
Excluded from PPS 
4