Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Keywords: LCZ696 chronic heart failure ARNI Congestive heart failure (CHF) heart failure (HF) acute heart failure syndrome congestive cardiac failure (CCF)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1980
Healthy volunteers: no

Brief summary:
The purpose of this study was to collect safety and tolerability data on LCZ696 in eligible PARADIGM-HF patients who received open-label investigational drug. The parent PARADIGM-HF (NCT01035255) trial was terminated early due to compelling efficacy of LCZ696 in patients with heart failure with reduced ejection fraction (HFrEF) after the final pre-specified interim analysis in March 2014.

Detailed description:

Arms:
arm 1: Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid

Interventions: intervention 1: LCZ696
Intervention descriptions: intervention 1: Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid

Protocol document:
Prot_001.pdf: 
Global Clinical Development - General Medicine
LCZ696
Clinical Trial Protocol CLCZ696B2317 / NCT02226120
A multicenter study to evaluate safety and tolerability in 
patients with chronic heart failure and reduced ejection 
fraction from PARADIGM-HF receiving open label LCZ696
Authors:
 
 
Document type:
Amended Clinical Trial Protocol 
EUDRACT number:
2014-001971-30
Version number:
v02 clean
Development phase:
IIIb
Release date:
28-Apr-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0, November, 2013


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 2 .............................................................................................................................9
Amendment 1 .............................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................13
1.1
Background............................................................................................................13
1.2
Purpose ..................................................................................................................14
2
Study objectives.................................................................................................................14
2.1
Primary objective...................................................................................................14
2.2
Secondary objectives .............................................................................................14
2.3
Exploratory objectives...........................................................................................15
3
Investigational plan ...........................................................................................................15
3.1
Study design...........................................................................................................15
3.2
Rationale of study design.......................................................................................16
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....16
3.4
Rationale for choice of comparator .......................................................................17
3.5
Purpose and timing of interim analyses/design adaptations..................................17
3.6
Risks and benefits..................................................................................................17
4
Population..........................................................................................................................18
4.1
Inclusion criteria ....................................................................................................18
4.2
Exclusion criteria...................................................................................................18
5
Treatment...........................................................................................................................20
5.1
Protocol requested treatment .................................................................................20
5.1.1
Investigational treatment.......................................................................20
5.1.2
Additional study treatment....................................................................21
5.2
Treatment arms......................................................................................................21
5.3
Treatment assignment............................................................................................22
5.4
Treatment blinding.................................................................................................22
5.5
Treating the patient................................................................................................22
5.5.1
Patient numbering .................................................................................22


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5.5.2
Dispensing the investigational treatment ..............................................22
5.5.3
Handling of study treatment..................................................................23
5.5.4
Instructions for prescribing and taking study treatment........................23
5.5.5
Permitted dose adjustments and interruptions of study treatment ........25
5.5.6
Rescue medication ................................................................................28
5.5.7
Concomitant treatment..........................................................................28
5.5.8
Prohibited treatment..............................................................................29
5.5.9
Discontinuation of study treatment .......................................................30
5.5.10
Withdrawal of consent ..........................................................................30
5.5.11
Loss to follow-up ..................................................................................31
5.5.12
Emergency breaking of assigned treatment code..................................31
5.5.13
Study completion and post-study treatment..........................................31
5.5.14
Early study termination.........................................................................31
6
Visit schedule and assessments .........................................................................................31
6.1
Information to be collected on screening visit (Visit 1) ........................................35
6.2
Patient demographics/other baseline characteristics .............................................35
6.3
Treatment exposure and compliance .....................................................................35
6.4
Efficacy..................................................................................................................35
6.5
Safety.....................................................................................................................35
6.5.1
Physical examination ............................................................................36
6.5.2
Vital signs..............................................................................................36
6.5.3
Height and weight .................................................................................36
6.5.4
Laboratory evaluations..........................................................................36
6.5.5
Electrocardiogram (ECG) .....................................................................38
6.5.6
Pregnancy and assessments of fertility .................................................38
6.5.7
Appropriateness of safety measurements..............................................38
6.6
Other assessments..................................................................................................38
7
Safety monitoring..............................................................................................................38
7.1
Adverse events.......................................................................................................38
7.2
Serious adverse events...........................................................................................40
7.2.1
Definition of SAE .................................................................................40
7.2.2
SAE reporting........................................................................................41
7.3
Liver safety monitoring .........................................................................................42
7.4
Serum potassium safety monitoring (hyperkalemia).............................................43
7.5
Renal safety monitoring.........................................................................................43


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7.6
Pregnancy reporting...............................................................................................43
7.7
Reporting angioedema events................................................................................43
8
Data review and database management.............................................................................44
8.1
Site monitoring ......................................................................................................44
8.2
Data collection.......................................................................................................44
8.3
Database management and quality control............................................................45
8.4
Data Monitoring Committee..................................................................................45
8.5
Adjudication Committee........................................................................................45
9
Data analysis......................................................................................................................46
9.1
Analysis sets ..........................................................................................................46
9.2
Patient demographics and other baseline characteristics.......................................46
9.3
Treatments .............................................................................................................46
9.4
Analysis of the primary variable(s) .......................................................................46
9.5
Analysis of secondary variables ............................................................................47
9.5.1
Efficacy variables..................................................................................47
9.5.2
Safety variables .....................................................................................47
9.5.3
Statistical model, hypothesis, and method of analysis..........................47
9.5.4
Supportive analyses...............................................................................47
9.6
Interim analyses.....................................................................................................47
9.7
Sample size calculation..........................................................................................47
10 Ethical considerations........................................................................................................48
10.1
Regulatory and ethical compliance........................................................................48
10.2
Informed consent procedures.................................................................................48
10.3
Responsibilities of the investigator and IRB/IEC..................................................48
10.4
Publication of study protocol and results...............................................................49
11 Protocol adherence ............................................................................................................49
11.1
Protocol amendments.............................................................................................49
12 References .........................................................................................................................49
13 Appendix 1: Clinically notable laboratory values.............................................................52
14 Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ......................................................................................................................53
15 Appendix 3: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.3 mmol/L).....................................................................................................56
16 Appendix 4: Guidelines for the management of blood pressure .......................................58
17 Appendix 5: Guidelines for the management of renal dysfunction...................................59


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List of tables
Table 5-1
Recommended starting dose .................................................................21
Table 5-2
LCZ696 dispensed during the open-label treatment period..................27
Table 6-1
Assessment schedule.............................................................................33
Table 6-2
Full laboratory evaluations....................................................................37
Table 14-1
Liver event definitions ..........................................................................53
Table 14-2
Liver event follow up requirements......................................................53
List of figures
Figure 3-1
Overall study design and time interval between study visits ................16


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List of abbreviations
ACEI
Angiotensin converting enzyme inhibitor
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANP
Atrial natriuretic peptide
ARB
Angiotensin receptor blocker (antagonist)
AST
Aspartate aminotransferase
AT1
Angiotensin type 1 receptor
AUC
Area under the curve
β-hCG
Beta-human chorionic gonadotropin
bid
Bis in die, twice daily
BP
Blood pressure
BUN
Blood urea nitrogen
CCB
Calcium channel blocker
CFR
Code of Federal Regulation
CHF 
Chronic heart failure
CPK
Creatine phosphokinase
CPO
Country Pharma Organization
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
Cardiovascular
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic data capture
EOS
End of study
FSH
Follicle-stimulating hormone
GFR
Glomerular filtration rate


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γGT
Gammaglutamyl-transpeptidase
HF
Heart failure
IB 
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator notification
IRB
Institutional Review Board
IRT
Interactive Randomization Technology
ITD
Investigational treatment discontinuation
i.v.
Intravenous
LFT
Liver function test
MDRD
Modification of Diet in Renal Disease
NEP(i)
Neutral endopeptidase (inhibitor)
NPs
Natriuretic peptides
p.o.
Per os, oral
PARADIGM-HF
Clinical study CLCZ696B2314
PPW
Premature patient withdrawal
RAS
Renin-angiotensin system
SAE
Serious Adverse Event
SBP
Systolic blood pressure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total bilirubin
ULN
Upper Limit of Normal
US
United States
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort 
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical 
Epochs are: screening/recruitment, wash-out, treatment, and 
follow-up
Investigational drug
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Protocol
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial.
Part 
A single component of a study which contains different objectives 
or populations within that single study. Common parts within a 
study are: a single dose part and a multiple dose part, or a part in 
patients with established disease and in those with newly-
diagnosed disease.
Period
A subdivision of a cross-over study
Premature subject/patient 
withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s), active drug run-ins or background therapy 


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Study/investigational 
treatment discontinuation
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study
Amendment 2
Amendment rationale
This is the second amendment to be released for protocol CLCZ6962317 and is of 
administrative type.  Below is a list of items that have been addressed.

Correction of Figure 3-1, indicating study duration and visit number consistent with the 
main text

Clarification of recommended starting doses with addition of table title (Table 5-1)

Additional editorial changes addressing typographical errors
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
Amendment 1
Amendment rationale 
The purpose of this amendment is to clarify the patient population from the CLCZ696B2314 
(PARADIGM-HF) study who is eligible for enrolment in this study, as well as facilitate 
tracking of those patients.  Below is a list of items that have been addressed.

This amendment will extend the collection of all AEs and subsequently Section 7, safety 
reporting, has been updated to enable collection of all AEs reported.

Section 9.4 is updated with respect to safety data collection and analysis plan

Clarification of patients who have been enrolled in the PARADIGM-HF study is 
provided in Section 4.  Only patients who have been treated with study medication are 
eligible.  Those patients who were discontinued during the PARADIGM study due to an 
event are eligible, assuming they are fully recovered, the event has resolved and no longer 
represents a risk for the patient and, in the investigator opinion, and the patient can safely 
tolerate the administration of LCZ696.

Unlike what was stated in the original protocol, patients will be assigned a new 
identification (ID) number that is going to be similar to that previously assigned during 
the PARADIGM-HF study (CLCZ696B2314) at the time of Visit 1 (the exact identical 


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number will not be used, due to a change in the database system). Section 5.5.1 has been 
updated.

A clarification about safety reporting, which will include Adverse Events arising from 
notable laboratory abnormalities:  The actual laboratory data will not be reported as the 
values are not in the database but as source data.

 
 

Section 4.2, exclusion criterion No. 12 has been updated in response to the Health 
Authorities from the UK.

In the Assessment Schedule, Table 6-1, the database visit number for the 6-months visit 
was updated; additional pregnancy tests were added for safety monitoring.

Additional editorial changes have also been included to clarify processes and procedures, 
and also to clarify minimal duration of initial treatment with 50 and 100 mg LCZ696 bid.


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Protocol summary
Protocol number
CLCZ696B2317
Title
A multicenter study to evaluate safety and tolerability in patients 
with chronic heart failure and reduced ejection fraction from 
PARADIGM-HF receiving open label LCZ696
Brief title
Safety and tolerability during open-label treatment with LCZ696 
in patients with chronic heart failure and reduced ejection fraction
Sponsor and Clinical 
Phase
Novartis, Phase IIIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to collect safety and tolerability data 
on LCZ696 in eligible PARADIGM-HF patients receiving open-
label investigational drug. 
Primary Objective(s) 
and Key Secondary 
Objective
The primary objective of this study is to continue to evaluate the 
safety and tolerability of LCZ696 in heart failure patients from 
PARADIGM-HF receiving open-label investigational drug.
Secondary Objectives
There are no secondary objectives for this study.
Study design
This trial is a multicenter, open-label follow-up to PARADIGM-
HF, which evaluated the morbidity, mortality and safety of 
LCZ696 compared to enalapril in patients with chronic heart 
failure and reduced ejection fraction. Prior to enrollment in this 
trial, all patients must have been randomized and received double-
blind study medication in the PARADIGM-HF study and most 
will have transitioned to an ACEI or ARB. Investigators will be 
offered the option to initiate open-label treatment with LCZ696 
for any PARADIGM-HF patient that meets the eligibility criteria. 
Consenting patients will undergo a washout period, if necessary 
(36 h for patients on ACEIs only), be up-titrated to the maximally 
tolerated dose of LCZ696 and scheduled for visits to dispense 
study drug and assess safety and tolerability at 6-month intervals 
until the conclusion of the trial.
Population
All surviving patients that were randomized in PARADIGM-HF
can be considered for eligibility in this open-label
study 
(CLCZ696B2317). It is estimated that 5,000 patients (about 59% 
of the core study population and approximately 72% of the 
surviving patients) who meet the eligibility criteria will be 


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enrolled into this open-label trial. 
Inclusion criteria
1. Written informed consent for the extension must be obtained 
before any assessment is performed.
2. Patients who have been enrolled and treated with double blind
study medication in PARADIGM-HF and are able to safely 
enroll into the open-label study as judged by the investigator.
Exclusion criteria
1. Any condition that in the opinion of the investigator is likely 
to prevent the patient from safely tolerating LCZ696 or 
complying with the requirements of the study.
Investigational and 
reference therapy
LCZ696 (open-label); most patients titrated to 200 mg bid or 
lower doses of 50 or 100 mg bid depending on tolerability
Efficacy assessments
There will be no efficacy assessments in this study.
Safety assessments
All Adverse events reported will be recorded in the e-CRFs 
(including angioedema-like events).
Other assessments
Not applicable
Data analysis
Number and frequency of all AEs will be summarized by primary 
system organ class and preferred term. Narratives will be prepared 
for all Serious Adverse Events and AESIs. Vital signs will be 
reported as summary statistics.
Key words
LCZ696, chronic heart failure, open-label study, ARNI


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1
Introduction
1.1
Background
Chronic heart failure (CHF) is a major public health problem characterized by significant 
mortality, frequent hospitalization, and poor quality of life, with an overall prevalence that is 
increasing throughout the world. In the United States (US) alone, approximately 5 million 
patients have heart failure (HF) and there are over half a million newly diagnosed cases 
annually (Hunt et al 2009, McMurray et al 2012). In Europe, the prevalence of HF is between 
2 and 3%, and in the elderly is estimated between 10 to 20% (McMurray et al 2012). Medical 
therapies targeted at improving outcomes in HF with a low EF have been well studied over 
the past two decades, leading to an improvement in survival as well as a decrease in morbidity, 
mostly in the form of decreased re-hospitalization for HF. These medical therapies include 
angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-
blockers and mineralocorticoid antagonists (CONSENSUS Trial Study Group 1987, Cohn and 
Tognoni 2001, SOLVD Investigators 1991, SOLVD Investigators 1992, RALES Investigators 
1996, Pitt et al 1999, MERIT-HF Study group 1999, CIBIS II Investigators 1999, Packer et al 
2002, Pfeffer et al 2003, Flather et al 2005; Zannad et al 2011). However, despite advances in 
pharmacological (and device therapies), the outlook remains poor. Overall, 50% of patients 
die within 4 years and 40% of patients admitted to the hospital with HF die or are readmitted 
within 1 year (McMurray et al 2012). Thus, HF still represents a major cause of cardiac 
mortality and morbidity with a clear need for better therapy.
LCZ696 is a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI) being developed 
for the treatment of heart failure. Following ingestion, LCZ696 provides systemic exposure to 
AHU377, a neprilysin (neutral endopeptidase 24.11, NEP) inhibitor (NEPi) and valsartan, an 
angiotensin receptor blocker (ARB). 
 
 Neprilysin degrades biologically active natriuretic peptides (NPs), 
including atrial natriuretic peptide (ANP), B-type natriuretic peptide and C-type natriuretic 
peptide. The effects of NEP inhibition are attributed to the enhanced effects of biologically 
active NPs. NPs, acting through the second messenger cyclic GMP, have potent natriuretic 
and vasodilator properties, inhibit the activity of the RAS, lower sympathetic drive and have 
antifibrotic and antihypertrophic effects (Levin et al 1998, Gardner et al 2007, Pandey 2008). 
NEP also inactivates other vasodilators including bradykinin, adrenomedullin, enkephalins, 
substance P, calcitonin gene-related peptide and vasoactive intestinal polypeptide; however, 
the role of these peptides in mediating the beneficial effects of NEP inhibition is not known. 
Angiotensin receptor blockade is specific and competitive at the angiotensin type 1 (AT1) 
receptor, which mediates the deleterious effects of angiotensin II on the CV system. LCZ696, 
through its dual mode of action, potentiates NPs via NEP inhibition while inhibiting the RAS 
via AT1 receptor blockade.  Both of these mechanisms are considered to act in a 
complementary and additive manner to improve the morbidity and mortality of HF patients. 
The PARADIGM-HF study (protocol CLCZ696B2314) was a randomized, double-blind, 
Phase III outcome trial that evaluated the efficacy and safety of LCZ696 versus enalapril (an 


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ACEI) in 8,436 heart failure patients with reduced ejection fraction (McMurray et al 2013). 
The primary endpoint was time to first occurrence of either cardiovascular (CV) death or heart 
failure hospitalization, and the trial was also designed to be able to detect a significant 
difference in CV death alone (McMurray et al 2013).
The protocol and statistical analysis plan for PARADIGM-HF included a third interim 
efficacy analysis when approximately 2/3 of the total number of primary patient events 
occurred. In addition, the CV death component was also analyzed at each interim efficacy 
analysis. As pre-specified in the protocol, the study could be concluded early with a 
compelling claim of efficacy superiority for LCZ696 versus enalapril, if statistically 
significant results exceed the planned boundary (p ≤ 0.001 one sided for the third interim 
analysis) for, (1) cardiovascular mortality by itself and also, (2) the primary composite 
endpoint (first occurrence of cardiovascular death or heart failure hospitalization).
On March 28, 2014 the Data Monitoring Committee (DMC) for PARADIGM-HF reviewed 
efficacy and safety data for the third interim analysis with approximately 1,027 CV death 
events and concluded that LCZ696 was superior to enalapril in delaying the time to first 
occurrence of the primary composite endpoint and most importantly, in delaying the time to 
the CV death component as well. Based on these results and an acceptable safety profile, the 
DMC unanimously recommended early closure of the study, which was agreed by the study 
Executive Committee and Sponsor of the trial. 
In order to provide patients the opportunity to receive life-saving treatment with LCZ696 and 
to collect safety data, this open-label, safety and tolerability study will offer enrollment to all 
surviving, eligible patients that had been randomized in PARADIGM-HF.
1.2
Purpose
The purpose of this study is to collect safety and tolerability data on LCZ696 in eligible 
PARADIGM-HF patients receiving open-label investigational drug.
For each country, the
study has a minimum duration of 12 months and is expected to continue until marketing 
authorizations have been received in the participating countries and the drug product becomes 
commercially available which is anticipated to be approximately 30 months.
For the specific study duration in Denmark, the UK and in Germany, please see Section 3.3 of 
this document.
2
Study objectives
2.1
Primary objective
The primary objective of this study is to continue to evaluate the safety and tolerability of
LCZ696 in heart failure patients from PARADIGM-HF receiving open-label investigational 
drug.
2.2
Secondary objectives
There are no secondary objectives for this study.


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2.3
Exploratory objectives
Not applicable
3
Investigational plan
3.1
Study design
This trial is a multicenter, open-label follow-up to PARADIGM-HF, which was a double-
blind parallel treatment study that evaluated the morbidity, mortality and safety of LCZ696 
compared to enalapril in patients with chronic heart failure and reduced ejection fraction.
Investigators for PARADIGM-HF have been informed of the study’s early closure and will be 
offered the option to initiate treatment with LCZ696 for eligible patients by enrolling them in 
this study (CLCZ696B2317).  Only patients who were randomized in PARADIGM-HF and 
received study medication (i.e., either enalapril or LCZ696) are eligible (i.e., screen- or run-
in-fail are not eligible). For all consenting patients, visits to dispense study drug and assess 
safety will be conducted at baseline and at 6-month intervals (except for Visits 2 and 3
required for the up-titration step and the 3-month visit [Visit 4]) until conclusion of the trial.
If the patient is taking an ACEI at the time of enrollment, a 36-hour washout period is 
required before starting treatment with LCZ696. Patients will be up-titrated to the target oral 
dose of LCZ696 200 mg bid, as tolerated.  At the discretion of the investigator, patients may 
be maintained on LCZ696 50 mg bid or 100 mg bid, if that was the highest dose-level (dose-
level 1 or 2) tolerated in the PARADIGM-HF study, or if they are unable to tolerate up-
titration to higher doses of LCZ696 in this open-label study.
Similarly, while the starting dose is recommended to be 100 mg LCZ696 bid, at the 
investigator’s discretion patients could start at 50 mg LCZ696 bid.  More details are provided 
in Section 5.5.5 of this document.
An outline of the study design with recommended dose levels is presented in Figure 3-1 with 
the overall duration.  However, duration will be different for Denmark, Germany, and the UK, 
as per Section 3.3 of this document.


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Figure 3-1
Overall study design and time interval between study visits
**  While the starting dose is recommended to be 100 mg LCZ696 bid, at the investigator’s discretion 
patients could start at 50 mg LCZ696 bid.
3.2
Rationale of study design
The DMC for PARADIGM-HF reviewed efficacy and safety data for the third interim 
analysis and concluded that LCZ696 was superior to enalapril for the primary composite 
endpoint of CV death or hospitalization for HF as well as CV death alone. Based on these 
results, the DMC recommended early closure of the study and Novartis has initiated processes 
to close-out the trial.
The open-label design of the current study is appropriate to provide patients the opportunity to 
receive treatment with LCZ696 until marketing authorizations are received and the drug 
product becomes commercially available, and to enable the collection of safety and 
tolerability data for the investigational drug.
[For the United Kingdom only the above paragraph will read as follows:
The purpose of this study is to collect safety and tolerability data on LCZ696 in eligible 
PARADIGM-HF patients receiving open-label investigational drug. Study duration in the UK 
is specified in Section 3.3]
Enrollment will be available to all surviving, eligible patients who were randomized in 
PARADIGM-HF.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
Based on safety data from the PARADIGM-HF single-blind, sequential design run-in period, 
LCZ696 was well-tolerated, with over 90% of patients achieving the target dose.


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A strong rationale exists for the target dose of LCZ696 in HF-rEF patients. A p.o. dose of 
LCZ696 200 mg bid delivers similar exposures of valsartan (assessed by AUC) as Diovan®
160 mg bid, the highest approved Diovan® dose for HF and the dose recommended in 
international guidelines for the treatment of HF. In addition, biomarker analysis (increase in 
ANP and cGMP) indicates that this dose delivers approximately 90% of its maximal NEP 
inhibition. 
Most importantly, this study will target the oral dosing regimen for LCZ696 identical to that 
which showed a mortality and HF hospitalization benefit superior to that of enalapril in 
PARADIGM-HF. 
[*] The study will continue in an individual country for a minimum of 12 months and until a 
marketing authorization has been received and the drug product becomes commercially 
available in that country (which is expected to be up to 30 months) from the date of the first 
eligible patient enrolled in that country, or until the study is terminated, whichever comes first.
Within the study period, the duration of treatment for an individual patient will be at the 
discretion of the investigator.
[* For Denmark only, the above paragraph will read as follows:
From the date of the first eligible patient enrolled in Denmark, the study will have a duration 
of 12 months.  The treatment duration may be re-evaluated and an amendment issued to adjust 
the treatment duration.]
[* For the United Kingdom only the above paragraph will read as follows:
From the date of the first eligible patient enrolled in the UK, the study has a minimum 
duration of 12 months and a maximum duration of 20 months. The treatment duration may be 
re-evaluated and an amendment issued to adjust the treatment duration.].
[* For Germany only, the above paragraph will read as follows:
From the date of the first eligible patient enrolled in Germany, the study will have a maximum
duration of 24 months.  The treatment duration may be re-evaluated and an amendment issued 
to adjust the treatment duration.]
3.4
Rationale for choice of comparator
Not applicable
3.5
Purpose and timing of interim analyses/design adaptations
No interim analysis is planned.
3.6
Risks and benefits
PARADIGM-HF (protocol CLCZ696B2314) was a randomized, double-blind, Phase III 
outcome study that evaluated the efficacy and safety of LCZ696 versus enalapril in patients 
with heart failure with reduced ejection fraction. The primary endpoint was a composite of 
time to first occurrence of either CV death or heart failure hospitalization, and the trial was 
also designed to be able to detect a significant difference in CV death alone.


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On March 28, 2014 the Data Monitoring Committee (DMC) for PARADIGM-HF reviewed 
efficacy and safety data for the third interim analysis and disclosed that LCZ696 was superior 
to enalapril in delaying the time to first occurrence of both the primary composite endpoint 
(CV death or hospitalization for HF) as well as CV death alone. Based on these results and an 
acceptable safety profile, the DMC unanimously recommended early closure of the study. 
As a consequence of the DMC’s recommendation, the Sponsor believes that the results of 
PARADIGM-HF demonstrate superior efficacy over enalapril as well as a positive 
benefit/risk ratio and has initiated closure of the study. In order to provide patients the 
opportunity to receive open-label treatment with LCZ696 and to collect safety data, this open-
label study (CLCZ696B2317) will offer enrollment to all surviving, eligible patients who 
were randomized in PARADIGM-HF. The risk to patients in the open-label trial will be 
minimized by rigorous compliance with the inclusion/exclusion criteria and study procedures, 
and careful clinical monitoring during this study. These risks (e.g., hyperkalemia, hypotension, 
renal impairment) are well known to investigators who have gained experience managing 
them in PARADIGM-HF.
4
Population
All surviving patients who safely tolerated study drug in PARADIGM-HF can be considered 
for eligibility in this open-label study (CLCZ6962317). Following discussions amongst the 
Sponsor’s Clinical and Regulatory Departments and consultation with the PARADIGM-HF 
Executive Committee, is estimated that up to 5,000 patients (about 59% of the core study 
population and approximately 72% of the surviving patients) who meet the eligibility criteria 
will be enrolled into the trial.
1. Patients who were randomized and received study medication (LCZ696 or enalapril) in 
PARADIGM-HF will be considered for enrollment if they fulfill all entry criteria (screen-
or run-in-failures in PARADIGM-HF will not be eligible for this study).
2. Patients who discontinued study drug treatment during PARADIGM-HF due to an event 
intercurrent illness/event are eligible, assuming they meet all entry criteria, the event has
resolved and no longer represents a risk for the patient and, in the investigator opinion,
and the patient can safely tolerate the administration of LCZ696.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent for the extension must be obtained before any assessment is 
performed.
2. Patients who have been enrolled and treated with double-blind study medication in the
PARADIGM-HF study (protocol CLCZ696B2314) and are able to be safely enrolled into 
the open-label trial as judged by the investigator.
4.2
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer


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2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical 
classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications 
to LCZ696
3. Known history of angioedema
4. Requirement of simultaneous treatment with both ACEIs and ARBs
5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms) that may require intravenous therapy
6. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening)
7. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at 
Visit 1 (screening)
8. Presence of bilateral renal artery stenosis
9. Serum potassium > 5.2 mmol/L at Visit 1 (screening) 
10. Evidence of hepatic disease as determined by any one of the following: AST or ALT 
values exceeding 3 x ULN at Visit 1, history of hepatic encephalopathy, history of 
esophageal varices, or history of porta-caval shunt 
11. 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
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 7 days after discontinuation of LCZ696 treatment. 
Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject).
o Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception;
Male sterilization (at least 6 months prior to Visit 1). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject;
[For the United Kingdom ONLY:  Male sterilization (at least 6 months prior to Visit 1):
Prior to starting dosing of the female subject, medical assessment of the surgical 
success of the partner’s vasectomy must be provided.]
Combination of any two of the following (a+b or a+c, or b+c): 
a.
use of oral, injected or implanted hormonal methods of contraception (combined 
estrogen and progestogen or progestogen only) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception. 
b.
placement of an intrauterine device (IUD) or intrauterine system (IUS)
c.
barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.


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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or six months of 
spontaneous amenorrhea with the appropriate hormonal profile, or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to study 
treatment administration. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment she is considered not of child bearing potential.
13. Any condition, not identified in the protocol that in the opinion of the investigator is likely 
to prevent the patient from safely tolerating LCZ696 or complying with the requirements 
of the study.
If a patient has experienced a significant cardiovascular (e.g., acute coronary syndromes, 
stroke, transient ischemic attack) or non-cardiovascular event in the interim between the 
end of PARADIGM-HF and the start of CLCZ696B2317, the investigator should ensure 
that the individual is appropriately stable before enrolling them in the open-label study. 
If there is uncertainty about a patient’s eligibility, the investigator should consult the 
study medical monitor to determine if the individual should be enrolled.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
All eligible patients will receive LCZ696 in addition to optimal CHF therapy, as considered 
appropriate by the investigator and in accordance with standard therapy guidelines, but with 
the exception of an ACEI or ARB as this will be replaced by LCZ696. The use of an ACEI or 
an ARB in addition to LCZ696 is strictly prohibited.
The Sponsor will provide the following open-label study medication in bottles: 

LCZ696 50 mg film-coated tablets (LCZ696 dose level 1)

LCZ696 100 mg film-coated tablets (LCZ696 dose level 2)

LCZ696 200 mg film-coated tablets (LCZ696 dose level 3)
Sufficient medication will be provided for treatment according to the study protocol, 
including additional medication to allow for delayed visits.
Medication labels will be in the local language and comply with the legal requirements of
each country. They will include storage conditions for the drug.
The target p.o. dose of LCZ696 is 200 mg bid. For patients not tolerating the target dose, 
LCZ696 will be titrated down to a lower dose level twice a day, at the investigator’s 
discretion, based on the defined safety and tolerability criteria (Appendix 3, Appendix 4 and
Appendix 5).


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For the initial treatment doses (50 or 100 mg bid) administered up to visit 2 and 3, the 
protocol indicates that the dose could be administered 1-to-2 weeks prior to the next visit.  
However, treatment should last for a minimum of 1 week before up-titrating to the next dose
strength.
Recommended starting LCZ696 dose
For patients who tolerated dose level 3 (either 200 mg LCZ696 bid or 10 mg enalapril bid) in 
the PARADIGM-HF study, the recommended starting dose is 100 mg LCZ696 bid. Similarly,
for patients who maximally tolerated dose level 2 (either 100 mg LCZ696 bid or 5 mg 
enalapril bid) in the PARADIGM-HF study, the recommended starting dose could be 100 mg 
LCZ696 bid.  These patients can be up-titrated to 200 mg LCZ696 bid at a later time at the 
discretion of the investigator.
If, in the investigator’s judgment, the patient may not tolerate the proposed starting dose of 
100 mg LCZ696 bid, the patient could start with 50 mg LCZ696 bid and be up-titrated at the 
time of subsequent visits.
The starting dose of 50 mg bid is also recommended for patients who previously only 
tolerated dose level 1(either LCZ696 50 mg bid or enalapril 2.5 mg bid) in the PARADIGM-
HF study.
Table 5-1
Recommended starting dose
Dose levels used in 
CLCZ696B2314
Study treatment in 
CLCZ696B2314
Corresponding starting dose 
in this study
LCZ696, mg bid
1
50 mg LCZ696bid 
or 2.5 mg enalapril bid
50
2
100 mg LCZ696bid 
or 5 mg enalapril bid
50 or 100
3
200 mg LCZ696bid 
or 10 mg enalapril bid
50 or 100
If the patient is taking an ACEI at the time of enrollment, a 36-hour washout period is 
required before starting treatment with LCZ696.
If LCZ696 is permanently discontinued, treatment with an appropriate dose of an ACEI 
and/or ARB should be initiated. A 36-hour washout period is also required before starting 
treatment with an ACEI after discontinuation of LCZ696.
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
There is one treatment arm in this open-label study.


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5.3
Treatment assignment
Patients will not be randomized to treatment in this study; all patients previously treated with 
LCZ696 or enalapril in PARADIGM-HF will be treated with LCZ696 at maximally tolerated 
doses with a target dose of 200 mg bid. 
An Interactive Response Technology (IRT) system will be used to enroll patients into the 
study and dispense study drug. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all of the inclusion/exclusion criteria.  The IRT system will 
prompt the investigator to enter the patient’s Subject Number into the system and then assign 
a uniquely numbered medication kit for the first investigational treatment to be dispensed to 
the patient (at the time of successfully completing Visit 1).
The IRT will be used to assign additional uniquely numbered medication kits at Visits 2 
through 8 of the trial.
5.4
Treatment blinding
Treatment is not blinded to either investigators or patients during the course of the study (i.e., 
it is “open-label”).  All patients will receive LCZ696 at maximally tolerated doses with a 
target dose of 200 mg bid.
5.5
Treating the patient
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Identification (ID) Number. Patient will be
assigned an ID number similar to that assigned in PARADIGM-HF at the time of Visit 1 (the 
exact identical number will not be used, due a change in the database system). More details 
for the patient ID number assignment are included in the eCRF completion guide (eCCG).
Upon signing the informed consent form, the investigator or his/her staff will contact the IRT 
and provide the requested identifying information (including the current subject ID and the 
original subject ID from PARADIGM-HF) to register the patient into the IRT system.  
If the patient fails the first attempt to qualify for the study at Visit 1, the patient will have two 
(2) more opportunities to undergo screening with a minimum of 2 weeks between visits, as 
indicated in Section 6.1 of this protocol.  IRT must be contacted at each screening attempt.
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Disposition CRF.
5.5.2
Dispensing the investigational treatment
Each study site will be supplied by the Sponsor with investigational treatment in packaging of 
identical appearance.
The investigational treatment packaging has a 2-part label that includes the medication kit 
number. The site staff will identify the investigational treatment package(s) to dispense to the 


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patient by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the package(s) to the patient, the site staff will detach the outer part of the label 
from the packaging and affix it to the source document (Drug Label Form) for that patient’s 
unique Subject Number.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. Technical complaints are to be reported to the respective 
Sponsor‘s Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number. This study will be conducted 
as an open-label study, with no treatment blinding.
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 completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging at the end of the 
study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused investigational treatment, packaging, drug labels, and a 
copy of the completed Drug Accountability Log to the Sponsor’s monitor or to the Sponsor’s
address provided in the investigator folder at each site.
5.5.3.2
Handling of other study treatment
Not applicable
5.5.4
Instructions for prescribing and taking study treatment
The Sponsor will supply the investigators with LCZ696 for the course of the study. Patients 
will be provided with bottles of medication sufficient to last until the next scheduled visit.
Open-label study medication will be dispensed at 
Visit 1 upon fulfilling entry criteria, 
Visit 2 (at 1 to-2 weeks after starting treatment with LCZ696), 
Visit 3 (at 2-to-4 weeks), 
Visit 4 (3 months), 
Visit 5 (at 6 months), 


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Visit 6 (at 12 months), 
Visit 9 (at 18 months),
Visit 8 (at 24 months) and longer if required. 
LCZ696 will be supplied as film-coated tablets provided in the 50 or 100 or 200 mg strength. 
All dosages prescribed and dispensed to the patient must be recorded in the IRT and on the 
Dosage Administration Record eCRF.
Visit 1
All patients must provide informed consent before any study-specific procedure is performed.
At Visit 1, patients’ eligibility for enrollment will be assessed by the investigator.  Laboratory 
values obtained within the last 5 days from visit 1 can be used to establish eligibility.  If 
results from a recently drawn sample are not available, samples will be obtained during visit 1 
to assess eligibility.
Patients not on current ACEI therapy:  Patients will complete the tests required for visit 1
and, if fulfilling the entry criteria, they can be enrolled. 
Patients on current ACEI therapy:  Patients will complete the tests required for visit 1, and 
if fulfilling the entry criteria must complete a 36 h ACEI-free period prior to beginning
LCZ696 treatment.
Following completion of the study procedures for the visit 1, IRT will be contacted to enter 
the patient as screened.  If the patient is eligible to enroll into the study, IRT will be contacted 
again to dispense LCZ696. The patient will start with 100 mg LCZ696 bid, unless the 
investigator decides that the patient should start with 50 mg bid.  The patient will be 
instructed to take the bid p.o. dose for 1 to 2 weeks before returning to the study center for 
Visit 2.
The patients will be instructed to take their morning study drug p.o. dose at approximately 
08:00 (8:00 AM) and their evening study drug p.o. dose at approximately 19:00 (7:00 PM). 
The study medication should be taken with a glass of water with or without food. If the patient 
misses taking any study drug dose, he/she should take it as soon as possible, unless it is 
almost time for the following scheduled dose. In this case, the patient should skip the missed 
dose and return back to his/her regular study drug administration schedule.
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable to take the study drug as prescribed for any reason.
Visit 2 (at 1-to-2 weeks after staring LCZ696 treatment)
Study procedures will be completed, including an assessment of the patient’s tolerability to 
LCZ696 50 mg bid (dose level 1) or LCZ696 100 mg bid (dose level 2). 


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IRT will be contacted and the patient dispensed bottles of LCZ696 for the target dose 
appropriate for each patient (depending on the dose-level tolerated in PARADIGM-HF and 
the judgment of the investigator). The recommended steps to up-titrate the dose are indicated 
below.

For those who maximally tolerated dose level 1 in PARADIGM-HF, additional tablets 
for a dose of LCZ696 50 mg bid will be dispensed at Visit 2 (if the investigator chooses 
not to administer a higher dose to the patient) and taken for 1-to-2 weeks before returning 
to the study center for Visit 3.

For patients that maximally tolerated dose level 2 in PARADIGM-HF, additional tablets 
for a dose of LCZ696 100 mg bid will be dispensed at Visit 2 (if the investigator chooses 
not to administer a higher dose to the patient) and taken for 1-to-2 weeks before returning 
to the study center for Visit 3.
o However, if a patient tolerated dose level 3 in PARADIGM-HF, they will receive 
additional tablets for a dose of LCZ696 200 mg bid, which will be taken for 1-to-2 
weeks before returning to the study center for Visit 3.

Any patient at dose level 1 or 2 can be up-titrated to a higher dose of LCZ696 at Visit 2 
or any time thereafter at the discretion of the investigator.
LCZ696 tablets should be taken p.o. in the morning at approximately 08:00 (8:00 AM) and 
again in the evening at approximately 19:00 (7:00 PM). The instructions provided at Visit 1 
for taking the tablets and compliance should again be reviewed with each patient. 
Visit 3 (at 2-to-4 weeks), Visit 4 (at 3 months), Visit 5 (at 6 months), Visit 6 (at 12 
months), Visit 7 (at 18 months) and Visit 8 (at 24 months)
Study procedures will be completed before contacting the IRT to dispensed bottles of LCZ696 
50 mg, 100 mg or 200 mg tablets to patients. The instructions provided at Visits 1 and 2 for 
taking the tablets and compliance should again be reviewed with each patient.
Visit 9 (at 30 months)
Study procedures will be completed before contacting the IRT to record the patient’s 
attendance for this visit but not to dispense study drug.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Every attempt should be made to maintain patients on the target LCZ696 dose level of 200 mg 
bid throughout the trial. 
If in the opinion of the investigator, the patient does not tolerate the target dose of 200 mg 
LCZ696 bid (dose level 3), the investigator should consider the following:
1.
whether non-disease-modifying medication (e.g., CCBs, diuretics, nitrates, α-blockers)
can be reduced to rectify the situation, before reducing the dose of the study drug to a 
lower dose level (100 mg bid or 50 mg bid LCZ696). 
2.
may adjust doses of disease-modifying medications (e.g., -blockers, aldosterone 
antagonists) if it is believed that they are the most likely cause of the adverse effect. 


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3.
If adjustment/elimination of concomitant medications is not possible or does not 
alleviate the side effects of concern, the investigator may down-titrate the dose of the 
LCZ696 to:
a.
the next lower level
The patient should be re-challenged with a higher dose when the investigator feels 
it is appropriate to do so per the directions provided below in this section.
b. complete withdrawal of the study drug
If the study drug is temporarily discontinued, it should be reintroduced as soon as 
medically justified in the opinion of the investigator.
If needed, LCZ696 may be discontinued in favor of starting the patient on an ACEI or ARB 
(minimum of 36 h between last dose LCZ696 and first dose of ACEI; 12 h between last dose 
LCZ696 and first dose of ARB). 
Study drug dose level adjustments should mainly be based on overall safety and tolerability 
with special focus on:
a) hyperkalemia (Appendix 3:  treatment guidelines for hyperkalemia);
b) symptomatic hypotension (Appendix 4:  guidelines for management of BP);
c) clinically significant decrease in eGFR/increase in serum creatinine (Appendix 5:  
guidelines for management of renal dysfunction).
Any changes in the LCZ696 dose level must be recorded on the Dosage Administration 
Record eCRF and registered in the IRT.
Adjustment of study drug dose level
If despite adjustment of concomitant medications per the guidance provided above does not 
rectify the situation, the investigator may consider adjusting the dose of LCZ696 according to 
the following instructions.
If down-titration is necessary, the patient should be down-titrated to the next lower dose level 
(Table 5-2 below). The patient may continue to receive the lower dose level for a 
recommended period of 1 to 4 weeks, or longer based on the investigator’s judgment, before 
re-challenging the patient with the next higher dose level. For example, a patient who 
encounters tolerability problems at the target dose of 200 mg LCZ696 bid (dose level 3), 
should receive the study drug at dose of 100 mg LCZ696 bid (dose level 2) for 1 to 4 weeks. 
Then, based on the investigator’s judgment, he/she should be re-challenged with up-titration 
back to dose level 3.


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Table 5-2
LCZ696 dispensed during the open-label treatment period
Study visit
Dose level
LCZ696
Dispensed at Visit 2 and all subsequent visits
3a
200 mg bid
Dispensed at Visit 1 and available for any visit after Visit 1
2b
100 mg bid
Dispensed at Visit 1 for patients that tolerated only dose level 
1 in PARADIGM and available for any visit after Visit 1
1c
50 mg bid
a. This dose level should be maintained for as long a duration as possible. If down-titration is necessary due to 
side effects, the patient should be re-challenged as soon as medically possible per the investigator’s judgment.
b. Only if dose level 3 is not tolerated despite modification of other non-disease-modifying HF medications.
c. Only if dose levels 2 and 3 are not tolerated despite modification of other non-disease-modifying HF 
medications.
If the tolerability issues are not alleviated despite down-titration by one dose level, the 
investigator may lower the study drug dose further to the next lower level for 1 to 4 weeks, up 
to temporary or permanent withdrawal of the study drug. Again, once stable, the patient 
should be re-challenged with up-titration to the next higher dose level every 1 to 4 weeks in 
an attempt to bring back the patient gradually to the target study drug dose level (dose level 3).
The investigator may choose the next dose level for down- or up-titration according to his or 
her judgment (Table 5-2). As discussed in Section 5.5.5, the IRT should be contacted to 
register any changes in the patient’s LCZ696 dose level, including cases of temporary and 
permanent withdrawal of the study drug, and to obtain the medication numbers of the LCZ696 
supplies required for the new dose level.
In some instances, according to the safety and tolerability criteria and the investigator’s 
judgment, LCZ696 dose level 1 or 2 can be maintained if he/she considers that the patient’s 
condition would not allow any further up-titration to the target dose of study medication (level 
3). In this case it would be acceptable to maintain the patient at dose level 1 or level 2, 
whichever is the higher and tolerated dose level for the patient.
Study drug restart after temporary treatment interruption
LCZ696 should be reintroduced in those who temporarily discontinue it as soon as medically 
justified in the opinion of the investigator.
Once the investigator considers the patient’s condition appropriate for receiving LCZ696, the 
investigator should re-start the patient on the study drug at the most appropriate and allowable 
dose level (Table 5-2) per his/her medical judgment. If tolerated, the patient should be up-
titrated up-to dose level 3 every 1 to 4 weeks, as per the investigator’s judgment. 
Should the patient not tolerate the re-started study drug at a particular dose level, he/she may 
be down-titrated again (if appropriate) or the study medication discontinued again and a new 
attempt to up-titrate or reintroduce the study drug could be considered by the investigator if 
justified in his/her medical judgment.
Study visits should occur as close as possible to the time points indicated in the Assessment 
Schedule (Table 6-1). The time interval between the regular visits should be maintained as 


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scheduled, irrespective of the number of unscheduled visits that may be performed in between, 
according to the visit and time schedule described in Table 6-1.
Any changes in the study drug dose level, including temporary/permanent withdrawal or re-
start of the study drug, must be recorded on the Dosage Administration Record eCRF and 
registered in the IRT.
In case of pregnancy discovered during the open-label treatment period, the patient 
should be instructed to stop taking the study drug immediately.
See Section 7.6 for further details on pregnancies and reporting guidelines.
5.5.6
Rescue medication
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in Appendix 3, Appendix 4 and Appendix 5, respectively. Patients may receive 
open-label ACEIs and/or ARBs during the study ONLY if LCZ696 has been discontinued.  
Resuming ACEI therapy requires a 36 h washout from the last LCZ696 dose.
5.5.7
Concomitant treatment
The investigator should instruct the patient to notify the study site staff of any changes in 
concomitant medications (new medications or changes in dose regimens of existing 
medications). All concomitant medications for heart failure must be listed on the Heart Failure
Medications eCRF.
5.5.7.1
Heart failure medications and other cardiovascular medications 
Patients should be on an optimal medical regimen of background HF medications. The use of 
an aldosterone antagonist and a β-blocker should be considered in patients eligible for this 
study. In self-identified black patients, the use of isosorbide dinitrate/hydralazine 
hydrochloride (e.g., BiDil®) should be considered. Every effort should be made to keep the 
dose level of these background HF medications stable throughout the entire study. However, 
if the patient’s condition warrants a change in any of these medications (for example, if the 
investigator believes a medication is causing an adverse event), it is allowed at the discretion 
of the study investigator. 
Diuretics may be used and may be adjusted throughout the length of the study at the discretion 
of the investigator.
5.5.7.2
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements, aldosterone antagonists, and any other 
medications known to raise potassium levels should be used with caution while the patient is 
receiving the study medication due to the increased possibility of occurrence of hyperkalemia. 
The investigator is encouraged to assess patients’ potassium levels regularly, especially in 
those who are receiving these medications.


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5.5.7.3
Phosphodiesterase-5 (PDE-5) inhibitors 
PDE-5 inhibitors (e.g., sildenafil, vardenafil and tadalafil) should be used with caution while 
the patient is receiving study medication due to the increased possibility of occurrence of 
hypotension.
5.5.7.4
Intravenous neseritide, nitroprusside and nitrates
The concomitant administration of LCZ696 with intravenous (i.v.) nitrates has been studied in 
healthy volunteers. There was no significant difference in the magnitude, dose or time-course 
of the decrease in systolic and diastolic blood pressure when nitroglycerin was given alone 
compared to the co-administration of nitroglycerin and LCZ696.
In these healthy volunteers, the administration of LCZ696 and nitroglycerin was safe and well 
tolerated when given alone or in combination.
The concomitant administration of LCZ696 with i.v. neseritide or nitroprusside has not been 
studied. In the event a study patient requires the concomitant administration of neseritide
and/or nitroprusside with LCZ696, the investigator should consider starting them at a lower 
dose or a slower infusion rate while monitoring the patient’s blood pressure carefully.
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 in the source 
documents.
5.5.7.5
Atorvastatin and other statins
The concomitant administration of LCZ696 and atorvastatin was evaluated in healthy Chinese 
subjects. At steady state, the levels of atorvastatin increased when co-administered with 
LCZ696. 
 
valsartan levels decreased slightly when administered with atorvastatin. 
The effect of LCZ696 on other statins has not been examined. Based on these results, caution 
is recommended when LCZ696 is co-administered with atorvastatin or other statins that are 
substrates of the organic anion transporters, OATP1B1 and OATP1B3.
5.5.8
Prohibited treatment
5.5.8.1
ACEIs, ARBs and renin inhibitors
In this clinical trial, patients’ pre-study ACEIs/ARBs will be replaced with LCZ696.
The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient is 
receiving LCZ696. If the investigator believes that addition of an ACEI or ARB is necessary, 
then LCZ696 must be discontinued. In order to safely transition from LCZ696 to an ACEI, a 
period of 36 hours must transpire between the start of the last dose of LCZ696 and the start of 
the first dose of the ACEI (this is also true if transitioning from an ACEI to LCZ696). 
However, if the investigator discontinues LCZ696 and replaces it with an ARB, only 12 hours 


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must transpire between the start of the last dose of LCZ696 and the start of the first dose of 
the ARB (i.e., the next regularly scheduled dose).
Concomitant administration of renin inhibitors, such as aliskiren, is also prohibited.
5.5.8.2
Other medications
Bile acid sequestering agents, such as cholestyramine and colestipol are prohibited to avoid 
interference with study drug absorption.
5.5.9
Discontinuation of study treatment
Permanent discontinuation of LCZ696 constitutes withdrawal from the study. Under these 
circumstances, the patient should be evaluated at a final study visit but will not undergo 
assessments thereafter unless additional follow-up is required due to prior occurrence of an 
adverse event.
The investigator must also notify the IRT of the patient’s discontinuation of LCZ696 and 
record it on the Drug Administration Record of the eCRFs. 
The emergence of the following circumstances will require study drug discontinuation:

Withdrawal of informed consent

Pregnancy (Section 6.5.6 and Section 7.6)

Investigator thinks that continuation would be detrimental to the patient’s well-being 
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 
LCZ696 dose or the dose of another concomitant medication reduced or discontinued, or, if 
appropriate, have potentially contributing agents adjusted. Please refer to Appendix 3,
Appendix 4 and Appendix 5 for treatment guidelines for hyperkalemia, hypotension, or renal 
dysfunction, respectively.
5.5.10
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biological material.
If a patient withdraws consent, the investigator should make every effort to determine the 
primary reason for this decision and record this information. Treatment with LCZ696 must be 


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discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the patient 
are not allowed unless safety findings require communication or follow-up.
5.5.11
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
5.5.12
Emergency breaking of assigned treatment code
This is an open-label study therefore emergency breaking of treatment assignment is not 
applicable.
5.5.13
Study completion and post-study treatment
Patients who do not fulfill the eligibility criteria should not be enrolled in the study and only 
baseline characteristics, demographic information and the Screening Log entry should be 
completed on the eCRF.
When a patient has completed all scheduled study assessments, the investigator must call the 
IRT within 3 days to record the patient’s completion in the IRT. At the EOS visit (Visit 9) 
patients will be asked to return all remaining LCZ696.
5.5.14
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Following start of LCZ696 treatment (at Visit 1, or at the time of successfully complete the 
rescreening visits), initial visits up to the visit at 3 months (Visit 4) are set a relatively short 
interval.  The subsequent visits will occur at intervals of 6 months beginning at Visit 6. 
Visits 2 should be conducted between 1-to-2 weeks after starting treatment with LCZ696.  
Visit 3 should be conducted between 2-to-4 weeks and at least 1 week after Visit 2.
Visits 4 through 9 within +/- 7 days of the designated calendar day according to Table 6-1 or 
as close to it as possible. Specific circumstances surrounding missed or rescheduled visits 


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must be discussed with the study monitor. Missed or rescheduled visits SHOULD NOT 
LEAD automatically to patient discontinuation.
Patients should take their scheduled dose of LCZ696 in the morning of their study visits. 
Patients are not required to fast overnight on the day prior to or the day of the study visit.
The Assessment Schedule (Table 6-1) lists the assessments to be conducted at each of the 
study visits (indicated with an “x”).
For patients, who discontinue LCZ696, the discontinuation visit will be Visit 9 (EOS). 
Enrolled patients who  withdraw from the study for any reason, should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for Visit 9 (EOS) will be 
performed.  At this final visit all dispensed medication supplies should be reconciled and the 
Adverse Events and Heart Failure Medications updated on their respective CRFs.
All data obtained from the assessments listed in Table 6-1 must be supported in the patient’s
source documentation. The table indicates which data are entered into the CRF from the
source data (D), remain in the source documents only (S)or are loaded into the database from
separate source documents, i.e. outside vendors (DS). Assessments that generate data for
database entry and which are recorded on CRFs are listed using the CRF name.


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Table 6-1
Assessment schedule
Epoch
Epoch I
Screening
Epoch II
Open-label Treatment
Database visit numbering
1
101
102
103
104
105
106
107
199
Visit1
1 *
2
3
4
5
6
7
8
9 2
EOS and ITD 
Time
Category
0
1-2 w after 
start dose
2-4 w
3 m
§
6 m
§
12 m
§
18 m
§
24 m
30 m
§
Informed consent
D/S
X
Previous subject identifiers used in 
PARADIGM-HF (CLZC696B2314) 
study
D/S
X
Inclusion/Exclusion criteria
D/S
X
Demography/Medical history 
(including alcohol and smoking 
history)
D/S
X
IRT3
DS
X
X
X
X
X
X
X
X
X
Physical examination
S
X
X
X
X
X
X
X
X
X
Vital signs
D/S
X
X
X
X
X
X
X
X
X
Height (1st visit only)/ Weight
D/S
X4
X
X
X
X
X
X
X
X
Blood sample for abbreviated 
laboratory assessments 5 (locally)
S
X
X
X
X
X
X
X
X
Blood sample for full laboratory 
assessments (locally) 7
S
X


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Epoch
Epoch I
Screening
Epoch II
Open-label Treatment
Database visit numbering
1
101
102
103
104
105
106
107
199
Visit1
1 *
2
3
4
5
6
7
8
9 2
EOS and ITD 
Time
Category
0
1-2 w after 
start dose
2-4 w
3 m
§
6 m
§
12 m
§
18 m
§
24 m
30 m
§
Pregnancy test (urine dipstick)6
S
X
X
X
X
X
Pregnancy test (serum) 6
S
X
X
Prior/Concomitant heart failure 
medications
D/S
X
X
X
X
X
X
X
X
X
Adverse events
D/S
X
X
X
X
X
X
X
X
Dispense study medications
D/S
X
X
X
X
X
X
X
X
Drug accountability
S
X
X
X
X
X
X
X
X
EOS = end of study; ITD = investigational treatment discontinuation; D = assessment to be recorded on clinical data base; S = assessment to be recorded in source documentation; 
DS = data transferred from vendor
§  Within +/- 7 days of the designated calendar day
1  Unscheduled visits may occur if a safety issue develops  
* if a patient fails screening to qualify for the study at Visit 1, s/he may repeat Visit 1 up to two times in order to participate in the study.
2  Visit 9 (End of Study visit) will be completed at approximately 30 months or if the patient permanently discontinues LCZ696 or withdraws early from the study between Visit 1 and 
Visit 8 or when marketing authorizations are obtained and the product becomes commercially available in the patient’s country.
3  IRT will be used to enroll patients into the study, dispense open-label medication, track visit dates and record completion or early withdrawal from the trial.
4  Height will be measured at Visit 1 only.
5  Abbreviated laboratory assessments (performed locally) include serum sodium, potassium and creatinine measured at Visits 2, 3, 4, 7 and 9.  At Visits 5, 6 and 8 local labs will 
include serum sodium, potassium, creatinine, ALT, AST, alkaline phosphatase and total bilirubin.
6 Pregnancy testing performed in women of child-bearing potential only, see Section 6.5.6.
7  Laboratory values obtained from a sample collected either on the day of Visit 1, or within the last 5 days from Visit 1


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6.1
Information to be collected on screening visit (Visit 1)
Please refer to Table 6-1 Assessment Table for the information to be collected during the 
Screening visit.  If a patient is not eligible for enrollment, the investigator may consider re-
screening the patient at a later time if he/she believes that the patient’s condition has changed 
and may potentially be eligible. In this case, a completely new patient number will be 
allocated to the subject and he/she will need to re-perform all Visit 1 assessments. A patient 
may be re-screened for enrollment in this protocol up to two additional times with a minimum 
of 2 weeks between re-screening visits.
The patient must provide new written informed 
consent before each time they are to be re-screened.
For these patients that are considered screening failures only baseline characteristics, 
demographic information, and the Screening Log entry with the reason for screen failure 
should be completed on the eCRF.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected including: year of birth, 
age, sex, race and ethnicity, as well as the Identification Number (ID No.) the subject was 
formerly assigned in the PARADIGM-HF study (CLCZ696B2314). Relevant medical 
history/current medical condition data includes data until the start of study drug. When 
possible, diagnoses and not symptoms will be recorded. HF medications will be recorded on 
the prior/concomitant Heart Failure Medications eCRF.
6.3
Treatment exposure and compliance
Dosing information for study medication will be collected on corresponding Dosage
Administration Record eCRFs. Compliance will be assessed by the investigator and/or study
personnel at each visit using pill counts and information provided by the patient. This
information should be captured in the source document at each visit. All investigational
treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.4
Efficacy
Efficacy variables will not be assessed in this study.
6.5
Safety
The Sponsor may request additional information on specific adverse events or laboratory 
events of interest and may make requests to perform additional diagnostic tests to further 
assess the safety profile of LCZ696. Such information may include diagnostic procedure 
reports, discharge summaries, autopsy reports, and other relevant information that may help in 
assessing the reported adverse event. All additional information will be de-identified prior to 
collection by Novartis or its agents.


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6.5.1
Physical examination 
A physical examination will be performed at every visit through the End of Study visit (Visit 
9). It will include the examination of general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed.
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 eCRF. Significant findings made after signing the 
informed consent which meet the definition of an Adverse Event must be recorded in the 
Adverse Event section of the eCRF.
6.5.2
Vital signs 
Vital signs will be assessed at every visit. This will include SBP/DBP and pulse 
measurements. SBP/DBP will be measured by using a standard sphygmomanometer with an 
appropriate size cuff and the non-dominant arm in the sitting position after 5 minutes of rest.
6.5.3
Height and weight
Height in centimeters (cm) will be measured at Visit 1.
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing without shoes) will be 
measured every visit through the End of Study visit (Visit 9).
6.5.4
Laboratory evaluations 
Laboratory samples will be analyzed locally. Values outside the normal ranges and notable 
values should be flagged on the report. It is the responsibility of the investigator to review all 
laboratory results and make an assessment of whether an abnormal or notable value is 
clinically significant, whether additional evaluations should be performed as judged 
appropriate, and whether the patient may continue in the trial. Sample collection should be 
conducted according to the standards and requirements of the local laboratory.
Laboratory values that exceed the boundaries of a notable laboratory abnormality (refer to 
Appendix 1) must be commented on by the investigator in the source documents and 
additional laboratory evaluations should be performed, as judged appropriate by the 
investigator. 
If the laboratory abnormality induces clinical signs or symptoms, or requires therapeutic 
intervention, and satisfies the criteria defined in Section 7.1, then the diagnosis or medical 
condition must be entered on the AEs page of the patient's eCRF and any treatment 
necessary should be documented. If the laboratory abnormality is the primary reason for 
an unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then 
the procedure for rapid notification of SAEs must be followed. 
Likewise, if the laboratory abnormality leads to discontinuation of the study drug, the 
patient must be followed until the abnormality resolves or until it is judged to be 
permanent. This investigation may include continued monitoring by repeat laboratory 


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testing or by performing additional laboratory tests as deemed necessary by the 
investigator or the Sponsor’s medical monitor.
Clinically notable laboratory findings are defined in Appendix 1.
Full laboratory clinical chemistry (Table 6-2) will be performed locally at Visit 1 and 
abbreviated laboratory evaluations (sodium, potassium, creatinine) will be performed locally 
at Visits 2, 3, 4, 7 and 9. At Visits 5, 6 and 8 local labs will include sodium, potassium, 
creatinine, ALT, AST, alkaline phosphatase and total bilirubin.
Full laboratory tests will include the following:
Table 6-2
Full laboratory evaluations
Biochemistry
Sodium
Potassium
BUN
Creatinine
Total bilirubin
AST
ALT
γGT
Alkaline phosphatase
Creatine phosphokinase (CPK)
Uric acid
Total protein
Albumin
6.5.4.1
Hematology
Hematology will not be performed in this study unless requested by the investigator as part of 
the patient’s Standard of Care (conducted locally).
6.5.4.2
Clinical chemistry
Sodium, potassium, BUN, creatinine, total bilirubin, AST, ALT, γGT, alkaline phosphatase, 
CPK, uric acid, total protein, and albumin and will be measured as full laboratory evaluations 
at Visit 1 (Table 6-1).
The eGFR to determine eligibility of the patient for screening into the trial will be calculated 
at Visit 1 from the serum creatinine concentration. Estimated GFR will only be calculated 
using the following formula:  
Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154 × (age in years)-0.203 × 
(0.742 if female) × (1.212 if black), where SCr is the standardized serum creatinine value
Abbreviated laboratory evaluations (sodium, potassium and creatinine) will be performed 
at Visits 2, 3, 4, 7 and 9. At Visits 5, 6 and 8 the abbreviated laboratory evaluations will 


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include sodium, potassium, creatinine, ALT, AST, alkaline phosphatase and total bilirubin.  
Fasting is not required prior to the blood sampling for assessment of these laboratory 
parameters. 
If a patient experiences liver function test (i.e. ALT, AST, ALP, TBL) values greater than
three times the upper limit of normal during the study, additional information may be
collected. See Appendix 2 for the follow-up requirements.
6.5.4.3
Urinalysis
Not applicable
6.5.5
Electrocardiogram (ECG)
ECG measurements are not required per protocol but are recommended as part of the patient’s 
Standard of Care.
6.5.6
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have urine pregnancy tests 
performed locally at Visits 1, 5, 6, 7 and 8 and serum pregnancy tests performed locally at 
Visit 1 and the End of Study visit (Visit 9). A positive urine pregnancy test at Visit 1 
constitutes a screen failure unless the serum β-hCG test is performed and found to be negative. 
In case of pregnancy discovered at any time during the open-label treatment period, the 
patient should be instructed to stop taking LCZ696 immediately. If the urine pregnancy test at 
Visit 6 or 8 is positive, LCZ696 must be stopped immediately. A follow-up serum pregnancy 
test can be perform at the discretion of the patient and investigator but restarting LCZ696 
treatment can be considered only if the test is negative.
6.5.7
Appropriateness of safety measurements
The safety and clinical laboratory assessments performed in this study are similar to those 
used in the core study PARADIGM-HF (CLCZ696B2314). These assessments are appropriate 
for an investigational drug with the mechanism(s) of action of LCZ696 (angiotensin receptor 
antagonist and neprilysin inhibitor), the safety profile described in the LCZ696 Investigator 
Brochure, and the indication/patient population under study.
6.6
Other assessments
No additional tests will be performed on patients enrolled into this study.
7
Safety monitoring
7.1
Adverse events
All Adverse events reported will be recorded in the e-CRFs regardless of seriousness, 
causality, or actions (including angioedema-like events).  An AE is any untoward medical 
occurrence (i.e., any unfavorable and unintended sign [including abnormal laboratory 


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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 tests, 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 patients with 
the underlying disease. Investigators have the responsibility of managing the safety of 
individual patients and identifying adverse events. Alert ranges for labs and other test 
abnormalities are included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information.

the severity grade 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the investigational treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

whether it constitutes an SAE 

action taken regarding investigational 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)
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); investigational treatment dosage 
adjusted/temporarily interrupted; study drug(s) permanently discontinued; concomitant 
medication given; non-drug therapy given. The action taken to treat the adverse event should 
be recorded on the Adverse Event CRF. 


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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 investigational study 
treatment, the interventions required to treat it, and the outcome.
The Sponsor may request additional information on specific adverse events of interest and 
may make requests to perform additional diagnostic tests to further assess the safety profile of 
the study medications. Such information may include diagnostic procedure reports, discharge 
summaries, autopsy reports, and other relevant information that may help in assessing the 
reported adverse event. All additional information will be de-identified prior to collection by 
Novartis or its agents.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to the Sponsor.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is any adverse event with the 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 


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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.
Life-threatening in the context of an SAE refers to a reaction in which the patient was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.2.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to the Sponsor within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 days period should only be reported to the Sponsor 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 EDC 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 Sponsor’s local Drug Safety and Epidemiology 
Department.  The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology, specific to the site, are listed in the investigator folder 
provided to each site.  The original copy of the SAE Report Form and the fax confirmation 
sheet must be kept with the case report form documentation at the study site. Follow-up 


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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 EDC 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 the Sponsor’s 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 (not applicable in this 
study) and whether the patient continued or withdrew from study participation. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. The Sponsor may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
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 7.2.2. 
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 LCZ696 if appropriate

Hospitalization of the patient if appropriate


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
A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on the investigator’s discretion. All follow-up information, 
and the procedures performed should be recorded on appropriate CRF pages, including the 
liver event overview CRF pages.
7.4
Serum potassium safety monitoring (hyperkalemia)
To ensure patient safety, a standardized process for identifying, monitoring, and managing
hyperkalemia is summarized in Appendix 3.
7.5
Renal safety monitoring
To ensure patient safety, a standardized process for identifying, monitoring, and managing
renal dysfunction is summarized in Appendix 5. 
7.6
Pregnancy reporting
In case a patient becomes pregnant, or plans to become pregnant, LCZ696 must be 
discontinued permanently. To ensure patient safety, each pregnancy occurring while the 
patient is on LCZ696 treatment must be reported to the Sponsor 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 Sponsor’s local Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to LCZ696 treatment.
Any SAE experienced during pregnancy must be reported on the SAE Report Form.
7.7
Reporting angioedema events
It is important that the investigator pays special attention to any swelling or edema that may
resemble angioedema that may be reported by patients. If such an event occurs, the
investigator will complete a Questionnaire for an Angioedema Event form (provided by the 
Sponsor in the eCRFs) to summarize the event, its treatment, and its ultimate outcome and
communicate this report to the Sponsor as soon as possible. Follow up reports must be
communicated to the Sponsor as soon as new information regarding the event becomes 
available. All hospital records related to the event must be communicated to the Sponsor.
Occasionally, the investigator may be contacted by the Sponsor regarding AEs that were
reported on behalf of patients that may resemble an angioedema event. The investigator or
his/her delegated staff must complete the required report forms and supply the required


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medical records for such events, regardless of whether the investigator views the event in
question as angioedema or not.
All angioedema reports will be forwarded to an angioedema adjudication committee by the 
Sponsor for assessment. 
Submission of an angioedema report is not a substitution for the submission of an SAE report.
If an angioedema event satisfies the definition of an SAE, the investigator must submit an 
SAE report (as described in Section 7.2.2) in addition to the Adjudication Questionnaire for 
an Angioedema Event.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s Meeting, the Sponsor’s
representative will review the protocol and eCRFs with the investigators and their staff. 
During the study, the field monitor will regularly check the completeness of patient records, 
the accuracy of entries on the eCRFs, the adherence to the protocol and to Good Clinical 
Practice, and ensure that investigational treatment is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the field 
monitor.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. The Sponsor’s monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the EDC system. 
Designated investigator site staff will not be given access to the system until they have been 
trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 


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database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
8.3
Database management and quality control
The Sponsor’s 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 the Sponsor’s
staff that will make the correction to the database. The signed copy of the Data Query Form is 
kept at the investigator site.
Concomitant heart failure medications entered into the database will be coded using the WHO 
Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Adverse events will be coded using the Medical dictionary for regulatory activities 
(MedDRA) terminology.
Laboratory samples will be analyzed locally. The data will be recorded in source documents 
but will not be entered into the clinical database.
Data about LCZ696 dispensed to the patient and all dosage changes will be tracked using an 
Interactive Response Technology (IRT). The system will be supplied by a vendor, who will 
also manage the database. The database will be sent electronically to Novartis (or a designated 
CRO).
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by the Sponsor’s Development management.
8.4
Data Monitoring Committee
A Data Monitoring Committee will not be used in this study.
8.5
Adjudication Committee
If swelling or edema that resembles angioedema occurs, the investigator will complete a 
Questionnaire for an Angioedema Event form (provided by the Sponsor in the eCRFs) to 
summarize the event, its treatment, and its ultimate outcome and communicate this report to 
the Sponsor as soon as possible. An angioedema AE will be recorded in the Adverse Event 
eCRFs if the criteria described in Section 7.1 are fulfilled. All angioedema reports will be 
forwarded to an angioedema adjudication committee for assessment.


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9
Data analysis
9.1
Analysis sets
The following analysis populations will be defined for statistical analysis:

Enrolled set (ENR) – All patients who signed the open-label study informed consent.

Safety set (SAF) - All patients who received at least one dose of open-label study
medication.
9.2
Patient demographics and other baseline characteristics
Demographics and baseline data will be collected in CLCZ696B2317. Summary statistics will 
be provided for demographics and other baseline characteristics including age, age group (<65, 
≥65, <75, and ≥75 years), sex, race, ethnicity, weight, height, Body Mass Index (BMI), and 
vital signs. BMI will be calculated as weight (kg) / height2 (m2) from the collected height and 
weight. Continuous variables will be summarized using n, mean, median, standard deviation, 
minimum, maximum, and categorical variables will be summarized using frequency and 
percentage.
The ENR set will be used for the above analyses.
9.3
Treatments
Summary statistics for duration (in days) of exposure to LCZ696 will be provided for the 
Safety set. 
Concomitant heart failure medications are defined as any HF medications administered after 
the enrollment date into the study. Concomitant HF medications will be summarized by 
therapeutic class and preferred term for the Safety Set.
Upon discontinuation of a patient from treatment, s/he is expected to resume ACEI or ARB 
therapy and those HF-related medications must be reported in the Concomitant Medication 
page of the eCRF.
9.4
Analysis of the primary variable(s)
The primary objective of this study is to evaluate the safety and tolerability of LCZ696 and to 
provide heart failure patients from PARADIGM-HF receiving open-label investigational drug. 
The primary assessment for safety will be based on the frequency of adverse events (AE) 
including:

Overall AEs

Serious adverse events (SAEs)

adverse events of special interest (AESI),i.e., hypotension, hyperkalemia, or renal 
dysfunction

Angioedema/angioedema-like events

Deaths


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
AEs leading to study drug dose adjustment/temporary interruption or permanent 
discontinuation

AEs leading to study drug permanent discontinuation, including deaths

AESIs leading to study drug permanent discontinuation with patients starting rescue 
medication(s) (ACEI/ARB)
AEs will be summarized as appropriate by resenting the number and percentage of patients 
reporting AEs by primary system organ class, by preferred term, by maximum severity, and 
by relationship to the investigational treatment.
In addition, the primary assessment for safety is the reporting of vital signs (i.e., sitting 
systolic blood pressure, sitting diastolic blood pressure, and heart rate) by visit with standard 
summary statistics (n, mean, standard deviation, minimum, Q1, median, Q3, maximum), 
including changes from baseline.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
There are no efficacy data being collected in this study.
9.5.2
Safety variables
Safety and tolerability are primary variables in this study; see Section 9.4.
9.5.3
Statistical model, hypothesis, and method of analysis
The number and frequency of adverse events will be summarized by primary system organ 
class, and preferred term. Serious adverse events and adverse events of special interest will be 
summarized in Clinical narratives.
9.5.4
Supportive analyses 
For supportive purposes, the above analysis of number and frequency of adverse events will 
be summarized by demographic subgroups of age (<65 years, ≥65 years and <75 years, ≥75 
years), sex, and race.
9.6
Interim analyses
No interim analysis will be performed.
9.7
Sample size calculation
All surviving patients randomized in PARADIGM-HF can be considered for eligibility in this 
open-label study (CLCZ6962317). It is estimated that 5,000 patients (about 59% of the core 
study population and approximately 72% of surviving patients) will meet the eligibility 
criteria and be enrolled into this open-label trial; however, since there is only one treatment 
arm in the study and treatment-related statistical comparisons are not planned, a specific 
sample size for the study is not required.


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10
Ethical considerations
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents. 
The Sponsor 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 the Sponsor before submission to the IRB/IEC, and a 
copy of the approved version must be provided to the Sponsor’s 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.
10.3
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to the Sponsor’s monitors, auditors, the Sponsor’s Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 


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inspection of the clinical site is requested by a regulatory authority, the investigator must 
inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR.
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in section 7 Safety Monitoring should be followed.
12
References
References are available upon request
CIBIS II Investigators (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a
randomized trial. Lancet; 353:9-13.
Cohn JN and Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker 
valsartan in chronic heart failure. N Engl J Med; 345:1667-1675.


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CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive 
heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study 
(CONSENSUS). N Engl J Med; 316:1429-1435.
Flather MD, Shibata MC, Coats AJ, et al (2005) Randomized trial to determine the effect of 
nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart 
failure (SENIORS). Eur Heart J; 26:215-225.
Gardner DG, Chen S, Glenn DJ, et al (2007) Molecular biology of natriuretic peptide system: 
implications for physiology and hypertension. Hypertension; 49:419-426.
Hunt SA, Abraham WT, Chin MH, et al (2009) Focused update incorporated into the 
ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a 
report of the American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. Circulation; 119:e391-e479.
ICH Harmonized Tripartite Guideline (2003) Post-approval safety data management: 
definitions and standards for expedited reporting, E2D. Published in the Federal Register; 15 
September 2003, Vol. 68, No. 178, p. 53983-53984.
Levin ER, Gardner DG, Samson WK (1998) Natriuretic peptides. N Engl J Med; 339:321-328.
McMurray JJ, Adamopoulos S, Anker SD, et al (2012) ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure (2012): The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. 
Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J; 
33(14):1787-1847.
McMurray JJ, Packer M, Desai AS, et al (2013) Dual angiotensin receptor and neprilysin 
inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with 
chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI 
with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial 
(PARADIGM-HF). Eur J Heart Fail; 15:1062-1073.
MERIT-HF Study group (1999) Effect of metoprolol CR/XL in chronic heart failure: 
Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). 
Lancet; 353:2001-2007.
Packer M, Fowler MB, Roecker EB, et al for the COPERNICUS Study Group (2002) Effect 
of carvedilol on the morbidity of patients with severe chronic heart failure: results of the 
carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation; 
106:2194-2199.
Pandey KN (2008) Emerging roles of natriuretic peptides and their receptors in 
pathophysiology of hypertension and cardiovascular regulation. J Am Soc Hypertens; 2:210-
226.
Pfeffer MA, Swedberg K, Granger CB, et al for the CHARM Investigators and Committees 
(2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: 
the CHARM-Overall programme. Lancet; 362:759-766.


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Pitt B, Zannad F, Remme WJ, et al (1999) The effect of spironolactone on morbidity and 
mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study 
Investigators. N Engl J Med; 341:709-717.
RALES Investigators (1996) Effectiveness of spironolactone added to an angiotensin-
converting enzyme inhibitor and loop diuretic for severe chronic congestive heart failure (the 
Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol; 78:902-907.
SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left 
ventricular ejection fractions and congestive heart failure. N Engl J Med; 325:293-302.
SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart 
failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med; 
327:685-691.
Zannad F, McMurray JJV, Krum H, et al (2011) Eplerenone in patients with systolic heart 
failure and mild symptoms. N Engl J Med; 364:11-21.


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


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14
Appendix 2: Liver event and laboratory trigger definitions 
and follow-up requirements
Table 14-1
Liver event definitions
Definition/ threshold
AE of special interest
Laboratory values
ALT or AST > 3 x ULN
ALP > 2 x ULN
TBL > 1.5 x ULN
Medically significant event 
(SAE)
Laboratory values
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction])
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction])
TBL > 3 x ULN
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and
TBL > 2 x ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 x ULN)
AEs
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
Table 14-2
Liver event follow up requirements
Criteria
Event type
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize, if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)


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Criteria
Event type
Actions required
Follow-up monitoring
> 5 to ≤ 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists for more 
than 2 weeks, discontinue the 
study drug
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 x ULN
accompanied by 
symptomsb
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 x ULN 
(patient is 
asymptomatic)
AESI
Laboratory to report to 
Investigator and Investigator to 
Novartis
Repeat LFT once or twice in the 
week
If elevation persists, establish 
causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 3 x ULN 
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
ALP (isolated)
> 5 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, report to 
Novartis as an SAE
Establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
> 2 to ≤5 x ULN 
(patient is 
asymptomatic)
AESI
Laboratory to report to 
Investigator and Investigator to 
Novartis
Repeat LFT once or twice in the 
week. If elevation persists, 
establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 2 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
TBL (isolated)
> 3 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 3 x ULN
AESI
Laboratory to report to 
investigator discretion


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


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15
Appendix 3: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.3 mmol/L) 
General principles
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken.
Any patient with a serum potassium > 5.3 mmol/L after enrollment into the study requires 
regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) 
until it is clear that the potassium concentration is stable and not rising into the range of 
concern (≥ 5.5 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L). 
Patients with an elevated potassium value will be managed according to the corrective actions 
outlined below. Hyperkalemia should be followed until resolution.
Corrective action for management of hyperkalemia
Serum potassium > 5.3 and less than or equal to 5.5 mmol/L

Confirm potassium concentration in a non-hemolyzed sample

Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.) 

Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents:

Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia)

Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 

Potassium supplements, e.g., potassium chloride

Salt substitutes 

Non-steroidal anti-inflammatory drugs (NSAIDs)

Cyclo-oxygenase-2 (COX-2) inhibitors

Trimethoprim and trimethoprim-containing combination products, such as Bactrim®
and Septra® (trimethoprim/sulfamethoxazole fixed combination)

Herbal Supplements:

For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily 
of the valley, Siberian ginseng, hawthorn berries

Repeat serum potassium measurement within 3 to 5 days

If serum potassium remains > 5.3 and ≤5.5 mmol/L, regularly monitor serum potassium
levels to ensure stability (suggested once monthly)


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
Consider down-titration of study medication, according to investigator’s medical 
judgment.
Serum potassium > 5.5 and < 6.0 mmol/L 

Confirm potassium concentration in a non-hemolyzed sample 

Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment. 

Apply all measures outlined for serum potassium > 5.3 and ≤5.5 mmol/L

Repeat serum potassium measurement after 2-3 days

If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days
Serum potassium greater than or equal to 6.0 mmol/L

Immediately discontinue study drug

Confirm potassium concentration in a non-hemolyzed sample

Urgently evaluate patient and treat hyperkalemia as clinically indicated 

Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L
Notification to the sponsor of a potassium level equal to- or above 6 mmol/L should be done 
within 48 h.  No resumption of study drug without individualized case discussion with and 
permission from the Sponsor’s Medical Monitor or his/her designee.


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16
Appendix 4: Guidelines for the management of blood 
pressure
Guidelines
1. Investigator should monitor blood pressure closely
2. If symptomatic hypotension occurs:
a.
Correct any treatable cause, e.g. hypovolemia
b. If hypotension persists, any antihypertensive drug and non-disease-modifying drugs, 
such as diuretics, CCBs, nitrates, and α-blockers, should be down-titrated or stopped 
first before down-titration of the study drug is considered
If hypotension persists, the study drug should be down-titrated or even temporarily withdrawn. 
The dose re-challenge and medication adjustment guidelines described in Section 5.5.5 should 
be adhered to as much as possible.


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17
Appendix 5: Guidelines for the management of renal 
dysfunction
General principles:
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by study medication. Moreover, renal 
dysfunction may develop or may deteriorate in some patients after study drug administration. 
The recommendations that follow have been developed to guide investigators in managing 
patients with renal dysfunction during the course of the study.
Two types of response to serum creatinine increase are described:
Surveillance situation 
If, at any time after enrollment, eGFR decreases by ≥ 25% from baseline (Visit 1) (or if serum 
creatinine concentration increases to 2.5 mg/dL [221 µmol/L]), the investigator will check for 
potentially reversible causes of renal dysfunction such as:

Non-steroidal anti-Inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia

Volume decrease, including that resulting from excessive dosing of diuretics

Urinary infection

Urinary tract obstruction

Study medication
Action situation 
If a patient eGFR decreases by ≥ 40% from baseline (Visit 1) (or if serum creatinine 
concentration rises above 3 mg/dL (265 µmol/L), the investigator will check for potentially 
reversible causes of renal dysfunction (see above).
If the investigator judges that study medication has to be stopped, he/she should do so and 
also  notify the Sponsor’s Medical Monitor or his/her designee. 
Thereafter, serum creatinine assessments will have to be repeated at least each week until 
levels return to acceptable values.  If able to resume study drug treatment, renal function must 
be periodically monitored to ensure stability of eGFR.

SAP_000.pdf: 
Clinical Development
LCZ696B
Clinical Trial Protocol CLCZ696B2317 / NCT02226120
A multicenter study to evaluate safety and tolerability in 
patients with chronic heart failure and reduced ejection 
fraction from PARADIGM-HF receiving open label LCZ696
RAP Module 3 – Detailed Statistical Methodology
Author:
 Trial Statistician
Document type:
RAP Documentation
Document status:
Final 1.0
Release date:
March 2, 2018
Number of pages:
10
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................2
9
Investigational plan .............................................................................................................3
9.7
Statistical methods planned in the protocol and determination of sample size.......3
9.7.1
Statistical and analytical plans ................................................................3
9.7.2
Interim analyses ....................................................................................10
9.7.3
Sample size calculation.........................................................................10
9.8
Changes in the conduct of the study or planned analyses .....................................10
List of tables
Document History – Changes compared to previous version of RAP module 3. ......................2
Table 9-1
Rules for subject classification in the analysis sets based on 
protocol deviations and non-protocol deviation classification 
criteria .....................................................................................................3
Table 9-2
Dose and dose level.................................................................................7
Document History – Changes compared to previous version of RAP module 3.
Version
Date
Changes
Amendment 1
Apr 13, 2016
Imputation algorithm for missing study drug stop date
Amendment 1
Dec 30, 2016
New AE outputs are added to address current HA data 
disclosure requirements (EudraCT and CT.gov)
Amendment 1
Jun 8, 2017
Updated PDs and exclusion criteria 
9


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9
Investigational plan
9.7
Statistical methods planned in the protocol and determination of 
sample size
This document contains details of the statistical methods which will be used in the phase IIIb 
clinical trial CLCZ696B2317. The purpose of this study is to collect safety and tolerability 
data on LCZ696 in former PARADIGM-HF patients receiving open-label investigational drug.  
For each country, the study has a minimum duration of 12 months.  
9.7.1
Statistical and analytical plans
The planned analysis is described in section 9 of the study protocol. All data analyses will be 
performed using SAS® statistical software (Version 9.3) unless otherwise noted. To ensure 
consistency across studies within the project, the RAP refers to the CSU harmonization MAP 
for heart failure (version number Final 1.0) and can be found in Novartis Clinical Research 
Documentation and Information system (CREDI) 
9.7.1.1
Analysis sets
The following analysis populations will be defined for statistical analysis:

Enrolled set (ENR) – All patients who signed the open-label study informed consent. 

Safety set (SAF) – All patients who enrolled in the study and received at least one 
dose of open-label study medication.
All cases of prospectively defined protocol deviations will be identified prior to clinical 
database lock and entered into a dedicated data panel as part of the locked database. 
All exceptional cases and problems and the final decisions on the allocation of patients to 
populations will be fully defined and documented before database lock and will be fully 
identified and summarized in the clinical study report according to ICH E9.
Criteria defining protocol deviations are referenced in the Data Review Plan (DRP).
Table 9-1
Rules for subject classification in the analysis sets based on protocol 
deviations and non-protocol deviation classification criteria
Analysis set
PD severity codes that cause a subject to be 
excluded
Non-PD criteria that cause 
a subject to be excluded
Enrolled set
INCL01 Written informed consent missing
NA
Safety set
WITH01 Subject withdrew consent but 
continued to receive study medication.  Data 
after withdrawal date will be excluded from 
SAF.
Subject did not receive 
study medication 


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9.7.1.2
Subject disposition, background and demographic characteristics
9.7.1.2.1 Subject disposition 
Patients who signed the CLCZ696B2317 study informed consent but do not meet all of the 
enrollment requirements at Visit 1 are considered screening failures.
The number and percent of patients in the enrolled set who discontinue the study will be 
summarized. Discontinuations will be further summarized by reasons.
The reason for screen failure will be tabulated and listed. For patients who have re-screening 
visits, the reason for screen failure in the last screening visit will be reported. 
The patients’ center and patient numbers in this study and their corresponding center and 
patient numbers in PARADIGM-HF study (i.e., LCZ696B2314) will be listed.
9.7.1.2.2 Patient demographics and other baseline characteristics 
Demographics and baseline data at baseline (defined below) will be summarized in the safety 
set (SAF). Continuous variables will be summarized by using n, mean, median, standard 
deviation, minimum, maximum, and categorical variables will be summarized by using 
frequency and percentage. 
Summary statistics will be provided for demographics and other baseline characteristics 
including:

(continuous)
Age (years) 

(categorical)
Age group: <65 years, >=65 years, <75 years, >=75 years at Visit 1

(categorical)
Sex

(categorical)
Race

(categorical)
Ethnicity

(continuous)
Height (cm)

(continuous)
Body weight (kg)

(continuous)
BMI (kg/m**2)

(continuous)    Systolic blood pressure (SBP) mm/Hg

(continuous)    Diastolic blood pressure (DBP) mm/Hg

(continuous)    Pulse (beats/min)
Body mass index (BMI) will be calculated from the measurements of height (m) and body 
weight (kg) measured at Visit 1: BMI = weight / height2.
Relevant medical history will be summarized by primary system organ class and preferred 
term using frequency tables for the safety set.
Demographic, background, and medical histories data will be listed for the safety set.
The above analyses will also be performed for the ENR.


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9.7.1.3
Definitions of baseline, post-baseline, and unscheduled visit 
Baseline 
In general, based on the principle described in the protocol, the baseline measurement is 
defined as the available measurement at Study start/Visit 1. 
Post-baseline 
Any measurements taken after baseline will be considered as post-baseline measurements.
Unscheduled visit 
Unscheduled visit measurements will be taken into account for the analysis of safety 
laboratory evaluation
9.7.1.4
Missing date handling
All patients with imputed date will be listed for date imputation validation.
9.7.1.4.1 Event date missing or partially missing
If the date of an event is not known or is incomplete, the imputation rules are:
a) If the day of the event is unknown, then the 15th day of this month will be imputed for a 
missing day;
b) If only the month is unknown, then July will be used for imputation of the missing;
c) If only the year of the event is known, then the 1st  of July will be imputed for a missing 
day and month;
d) The above rules are only for general case. If there is additional information available for 
the missing date, then the information should be used and the imputation of missing date
should be treated differently. For example, if an event occurs between two visits and its 
date is missing, then the date in the middle of these visits may be used.
9.7.1.4.2 Study drug stop date missing
If study drug stop date is unknown or is incomplete, the imputation rules are:
a) If only the day field of the drug stop is missing, then the missing date is imputed by using 
the 15th of the month;
b) If year and month are missing, then use the date of completion/discontinuation of the 
open-label treatment epoch if it is non-missing and no earlier than the start date of 
treatment;
c) If the drug stop date is completely missing, then:
a.
If patient had fatal AE (identified  as either start or end date is equal to the date of 
death and the AE is flagged as an SAE), handling rules are (in the specified order):
i. AE end date is not missing: use the AE end date to replace the missing 
drug stop date;


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ii. AE end date is completely missing but AE onset date not missing: use the 
AE onset date to replace the missing drug stop date;
iii. AE end date is partially missing (only day field is missing): use Novartis 
standard procedure to impute the AE end date, and then use the imputed 
AE end date to replace the missing drug stop date;
iv. AE end date is completely missing and AE onset date is partial missing 
(missing the date field only): impute the AE onset date using Novartis 
standard procedure, and then use the imputed AE onset date to replace the 
missing drug stop date;
v. If both the AE onset and end dates are completely missing then use the last 
previous non-missing visit date plus 35 days to replace the missing drug 
stop date.
b. If patients had no fatal AE, handling rules are the same with the case that year and 
month are missing.
9.7.1.5
Study medication
9.7.1.5.1 Duration of treatment exposure
Duration of the treatment exposure (in days) will be summarized by using n, mean, standard 
deviation, minimum, Q1, median, Q3, maximum for the safety set. 
The duration of the treatment exposure for a patient, regardless of temporary interruptions of 
usage of the study drug, is defined as 
date of last study drug intake – first study drug date + 1.
The durations on each dose level, time from Visit 1 to the first dose of each dose level, and 
time from the first dose intake to the final top dose will also be summarized. 
Duration of total exposure to study drug (excluding interruptions) will be computed as 
•
date of last study drug intake – first study drug date + 1 – number of days of treatment 
interruption.
The duration of total exposure to study drug will be summarized by using n, mean, standard 
deviation, minimum, Q1, median, Q3, maximum for the safety set.


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9.7.1.5.2 Doses and Dose levels
Table 9-2
Dose and dose level

Dose level 
Level  dose
0
0
    0 mg
1
1
  50 mg
2
2
100 mg
3
3
200 mg
Average dose and dose level will be summarized by visit and overall study (n, mean, standard 
deviation, minimum, Q1, median, Q3, maximum). 
Average dose at a given visit will be calculated as the sum of reported doses (including zero 
doses for interruption) / Total number of patients.
The formula for the average dose level will be calculated as the sum of reported dose levels 
(including dose level 0 for interruption) / Total number of patients.
The overall average (daily) dose will be calculated as:
1. Daily dose for each patient will be calculated as 
∑
(. 
       )×(  )


∑
(. 
       )


, 
The definitions of dose level i and level i dose are described in Table 9-1. If a patient takes 
two different dose levels in one day (e.g., drug titrations or discontinuations due to safety 
concern), then 0.5 day will be counted for the patient on both two dose levels in the day.
2. Average daily dose for each patient over patients.
For the average overall dose level, the formula is similar to that for overall average (daily) 
dose by using “dose level i”. to replace “level i dose”
Frequency and percentage of patients at each dose level will be summarized by visit.
The last recorded treatment on the drug administration form will be presented with the 
number and percentage of patients on each dose level, including dose level 0. 
The average dose related to the last recorded treatment will also be summarized, for both 
cases of including all patients in the SAF and excluding dose level 0 patients. 
9.7.1.5.3 Treatment exposure in subgroups
The above treatment exposure analyses will be repeated for the following subgroups:
•
Age group <65, ≥65 years
•
Age group <75, ≥75 years


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•
Gender (male, female)
•
Race (Caucasian, Black, Asian, Other)
9.7.1.5.4 Concomitant heart failure medications
Concomitant heart failure medications are defined as any HF medications administered after 
the enrollment date into the study. Concomitant HF medications will be summarized by ATC 
and preferred term using frequency tables for the safety set.
9.7.1.6
Analysis of the primary variable
The primary objective of this study is to evaluate the safety and tolerability of LCZ696 and to 
provide heart failure patients from PARADIGM-HF with open-label access to this 
investigational drug. The safety evaluation will include:
•
Adverse events
•
Vital signs
9.7.1.6.1 Adverse events
Any adverse events (AEs) occurred during the study period will be assessed, overall, by 
primary system organ class, by preferred term, by maximum severity, by relationship to the 
investigational drug according to the Medical Dictionary for Regulatory Activities (MedDRA).
The MedDRA version used for reporting the study will be described in a footnote.
Within each AE report, the following rules are applicable. If a subject reported more than one 
adverse events with the same preferred term, the adverse event with the greatest severity will 
be presented. If a subject reported more than one adverse event within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the 
system organ class level, where applicable. 
The number and percentage of subjects reporting the following AEs will be summarized by 
primary system organ class, preferred term. 

Overall AEs 

Serious adverse events (SAEs) 

AE of special interests (AESIs), i.e. AEs of hypotension, hyperkalemia or renal 
dysfunction

Angioedema/angioedema-like events

Deaths

AEs leading to study drug dose adjustment/temporary interruption or permanent 
discontinuation

AEs leading to study drug permanent discontinuation including deaths

AESIs leading to study drug permanent discontinuation with patients starting rescue 
medication(s) (ACEI/ARB)


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The most common adverse events reported (1% for each preferred term in the SOC-PT table) 
will be presented in descending frequency according to its incidence starting from the most 
common event. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and on treatment emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term on the 
safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective
9.7.1.6.2 Vital Sign 
Sitting systolic blood pressure, sitting diastolic blood pressure, and sitting pulse rate will be 
summarized by visit with standard summary statistics (n, mean, standard deviation, minimum, 
Q1, median, Q3, maximum), including changes from baseline. Baselines are defined in 
Section 9.7.1.3. Graphical mean plots for these vital signs will also be provided.
The descriptive summaries will be presented by vital sign and visit. Change from baseline will 
only be summarized for subjects with both baseline and post-baseline values and will be 
calculated as:
•
change from baseline = post-baseline value – baseline value
9.7.1.7
Analysis of the secondary variable
No secondary variable defined in this study.
9.7.1.8
Supportive analyses
For supportive purposes, the analysis of the primary variable described in Section 9.7.1.6 will 
be applied in the following subgroups:
•
Age group <65, ≥65 years
•
Age group <75, ≥75 years
•
Gender (male, female)
•
Race (Caucasian, Black, Asian, Other)


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9.7.2
Interim analyses
No interim analysis was planned.
9.7.3
Sample size calculation
All surviving patients randomized in PARADIGM-HF can be considered for eligibility in this 
open-label study (CLCZ696B2317). It is estimated that 5,000 patients (about 59% of the core 
study population and approximately 72% of surviving patients) will meet the eligibility 
criteria and be enrolled into this open-label trial; however, since there is only one treatment 
arm in the study and treatment-related statistical comparisons are not planned, a specific 
sample size for the study is not required.
9.8
Changes in the conduct of the study or planned analyses
The following changes from the planned analyses according to the study protocol were 
performed.