Clinical trial NCT03909295
Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
Keywords: heart failure with preserved ejection fraction, Japanese patients, extension study, long-term safety and tolerability, open-label
Sponsor: Novartis Pharmaceuticals
Start date: 2019-05-07; Completion date: 2019-11-19
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluated the safety and tolerability of LCZ696 treatment in Japanese heart failure patients (NYHA Class II-IV) with preserved ejection fraction after CLCZ696D2301 (PARAGON-HF).

Detailed description:
This study was an open-label extension study following the PARAGON-HF. Patients who have completed the PARAGON-HF were eligible to participate. During the study, open-label LCZ696 was taken in addition to background treatments of comorbidities. All subjects were treated with LCZ696 (sacubitril/valsartan) at maximally tolerated dosed with a target dose of 200 mg b.i.d (twice a day).

The subject were to continue to receive LCZ696 until it became commercially available, or for a period up to 24 months from the first patient enrolled in this study whichever came first. However, this study was terminated early based on the pre-defined early termination criteria of "the primary endpoint of PARAGONHF was not met" in the protocol.

Arms: arm 1: Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient
Interventions: intervention 1: LCZ696
Intervention descriptions: intervention 1: Starting dose was either 50 mg b.i.d. or 100 mg b.i.d. largely depending on the last dose level taken by the patient at the time of completing PARAGON-HF and patient condition. The dose level was gradually up-titrated with the goal of reaching the target dose of 200 mg b.i.d. as soon as tolerated by the patient

Protocol documents:
Prot_001.pdf: 
Novartis Research and Development
LCZ696
Clinical Trial Protocol CLCZ696D1301E1 / NCT03909295
A multicenter, open-label study to evaluate the safety and 
tolerability of LCZ696 treatment in Japanese heart failure 
patients (NYHA Class II-IV) with preserved ejection fraction 
after CLCZ696D2301 (PARAGON-HF)
Document type:
Clinical Trial Protocol
EUDRACT number:
NA
Version number:
00 (Original Protocol)
Clinical Trial Phase:
III
Release date:
17-Dec-2018
Property of Novartis/sponsor
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018


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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
Protocol summary................................................................................................................9
1
Introduction .......................................................................................................................10
1.1
Background............................................................................................................10
1.2
Purpose ..................................................................................................................12
2
Objectives and endpoints...................................................................................................12
3
Study design ......................................................................................................................12
4
Rationale............................................................................................................................14
4.1
Rationale for study design .....................................................................................15
4.2
Rationale for dose/regimen and duration of treatment ..........................................15
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................15
4.4
Purpose and timing of interim analyses/design adaptations..................................15
4.5
Risks and benefits..................................................................................................15
5
Population..........................................................................................................................16
5.1
Inclusion criteria ....................................................................................................16
5.2
Exclusion criteria...................................................................................................16
6
Treatment...........................................................................................................................17
6.1
Study treatment......................................................................................................17
6.1.1
Investigational and control drugs..........................................................17
6.1.2
Additional study treatments ..................................................................17
6.1.3
Treatment arms/group ...........................................................................17
6.1.4
Treatment duration................................................................................18
6.2
Other treatment(s)..................................................................................................18
6.2.1
Concomitant therapy.............................................................................18
6.2.2
Prohibited medication ...........................................................................19
6.2.3
Rescue medication ................................................................................19
6.3
Subject numbering, treatment assignment, randomization....................................19
6.3.1
Subject numbering ................................................................................19
6.3.2
Treatment assignment, randomization ..................................................20
6.4
Treatment blinding.................................................................................................20
6.5
Dose escalation and dose modification..................................................................20


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6.5.1
Dose escalation guidelines....................................................................20
6.5.2
Dose modifications................................................................................20
6.5.3
Follow-up for toxicities.........................................................................21
6.6
Additional treatment guidance...............................................................................22
6.6.1
Treatment compliance...........................................................................22
6.6.2
Emergency breaking of assigned treatment code..................................22
6.7
Preparation and dispensation.................................................................................22
6.7.1
Handling of study treatment and additional treatment..........................22
6.7.2
Instruction for prescribing and taking study treatment .........................23
7
Informed consent procedures ............................................................................................24
8
Visit schedule and assessments .........................................................................................24
8.1
Screening ...............................................................................................................27
8.1.1
Information to be collected on screening failures.................................27
8.2
Subject demographics/other baseline characteristics.............................................27
8.3
Efficacy..................................................................................................................27
8.3.1
Appropriateness of efficacy assessments..............................................27
8.4
Safety.....................................................................................................................27
8.4.1
Laboratory evaluations..........................................................................27
8.4.2
Pregnancy and assessments of fertility .................................................28
8.4.3
Appropriateness of safety measurements..............................................28
8.4.4
Physical assessments.............................................................................28
8.4.5
Vital sign...............................................................................................28
8.4.6
Angioedema ..........................................................................................28
8.5
Additional assessments..........................................................................................29
9
Study discontinuation and completion ..............................................................................29
9.1
Discontinuation......................................................................................................29
9.1.1
Discontinuation of study treatment .......................................................29
9.1.2
Withdrawal of informed consent...........................................................30
9.1.3
Lost to follow-up...................................................................................30
9.1.4
Early study termination by the sponsor.................................................30
9.2
Study completion and post-study treatment ..........................................................31
10 Safety monitoring and reporting........................................................................................31
10.1
Definition of adverse events and reporting requirements......................................31
10.1.1
Adverse events ......................................................................................31
10.1.2
Serious adverse events ..........................................................................32
10.1.3
SAE reporting........................................................................................33
10.1.4
Pregnancy reporting ..............................................................................34


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10.1.5
Reporting of study treatment errors including misuse/abuse................35
10.2
Additional Safety Monitoring................................................................................35
10.2.1
Liver safety monitoring.........................................................................35
10.2.2
Angioedema Adjudication Committee..................................................36
11 Data Collection and Database management......................................................................37
11.1
Data collection.......................................................................................................37
11.2
Database management and quality control............................................................37
11.3
Site monitoring ......................................................................................................37
12 Data analysis and statistical methods ................................................................................38
12.1
Analysis sets ..........................................................................................................38
12.2
Subject demographics and other baseline characteristics......................................38
12.3
Treatments .............................................................................................................38
12.4
Analysis of the primary endpoint(s) ......................................................................39
12.4.1
Definition of primary endpoint(s).........................................................39
12.4.2
Statistical model, hypothesis, and method of analysis..........................39
12.4.3
Handling of missing values/censoring/discontinuations.......................39
12.4.4
Sensitivity and Supportive analyses......................................................39
12.5
Analysis of secondary endpoints ...........................................................................40
12.6
Interim analyses.....................................................................................................40
12.7
Sample size calculation..........................................................................................40
12.7.1
Primary endpoint(s)...............................................................................40
13 Ethical considerations and administrative procedures ......................................................40
13.1
Regulatory and ethical compliance........................................................................40
13.2
Responsibilities of the investigator and IRB/IEC..................................................40
13.3
Publication of study protocol and results...............................................................40
13.4
Quality Control and Quality Assurance.................................................................41
14 Protocol adherence ............................................................................................................41
14.1
Protocol amendments.............................................................................................41
15 References .........................................................................................................................42
16 Appendices ........................................................................................................................44
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................44
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................45
16.3
Appendix 3: Treatment guidelines for hyperkalemia (serum potassium greater 
than or equal to 5.3 mmol/L [mEq/L]....................................................................47
16.4
Appendix 4: Guidelines for the management of blood pressure ...........................48
16.5
Appendix 5: Guidelines for the management of renal dysfunction.......................49


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................12
Table 3-1
Study drug level at the start of the study...............................................14
Table 6-1
Prohibited medication ...........................................................................19
Table 6-2
Dose and treatment schedule.................................................................23
Table 8-1
Assessment Schedule ............................................................................26
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................35
Table 16-1
Liver event and laboratory trigger definitions ......................................45
Table 16-2
Follow-up requirements for liver events and laboratory triggers..........45
List of figures
Figure 3-1
Study design..........................................................................................13


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List of abbreviations
ACC
American College of Cardiology
ACEI
angiotensin converting enzyme inhibitor
AE
adverse event
AF
atrial fibrillation
AHA
American Heart Association
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ARB
angiotensin receptor blocker
ARNI
angiotensin receptor neprilysin inhibitor
AST
aspartate aminotransferase
AT1
angiotensin type 1
ATC
Anatomical Therapeutic Chemical
b.i.d.
twice a day
BP
blood pressure
BUN
blood urea nitrogen
CAD
coronary artery disease
CCB
calcium channel blocker
CFR
Code of Federal Regulation
CHF
chronic heart failure
CMO&PS
Chief Medical Office and Patient Safety
COX-2
cyclo-oxygenase-2
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CTC
Common Toxicity Criteria
CV
cardiovascular
DBP
diastolic blood pressure
DM
diabetes mellitus
DMC
Data Monitoring Committee
EC
Ethics committee
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EF
ejection fraction
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOS
end of study
ESC
European Society of Cardiology
EU
European Union
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
hCG
human chorionic gonadotropin
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HTN
hypertension


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IB
Investigator’s Brochure
ICF
Informed consent form
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
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
JCS
The Japanese Circulation Society
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MoA
mechanism of action
MRA
mineralocorticoid antagonist
NEP
neprilysin
NP
natriuretic peptide
NSAID
non-steroidal anti-inflammatory drug
NT-
proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
OATP
organic anion-transporting polypeptide
PDE-5
phosphodiesterase-5
PT/INR
prothrombin time/international normalized ratio
QMS
Quality Management System
RAAS
Renin angiotensin aldosterone system
RAS
renin angiotensin system
RBC
red blood cell(s)
SAE
serious adverse event
SAF
safety set
SBP
systolic blood pressure
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SMQ
Standardized MedDRA query
SOP
standard operational procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
US
United States
WBC
white blood cell(s)
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is used as 
a comparator to the investigational drug being tested in the trial
Control drug
A study drug used as a comparator to reduce assessment bias, preserve blinding 
of investigational drug, assess internal study validity, and/or evaluate comparative 
effects of the investigational drug.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once 
a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study 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”.
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.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Screen Failure
A subject who is screened but is not treated or randomized
Study 
completion
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later.
Study 
treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Subject
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient.
Subject 
number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be used 
to identify the subject throughout the study for all data collected, sample labels, 
etc.
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.


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Protocol summary
Protocol number
CLCZ696D1301E1
Full Title
A multicenter, open-label study to evaluate the safety and tolerability of LCZ696 
treatment in Japanese heart failure patients (NYHA Class II-IV) with preserved 
ejection fraction after CLCZ696D2301 (PARAGON-HF)
Brief title
An Open-label extension study evaluating safety and tolerability of LCZ696 in subjects 
who completed PARAGON-HF in Japan.
Sponsor and 
Clinical Phase
Novartis, Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this open-label study is to evaluate long-term safety and tolerability of 
LCZ696 in eligible heart failure with preserved ejection fraction (HFpEF) patients who 
completed PARAGON-HF in Japan.
Primary Objective(s) 
The primary objective of this study is to evaluate further the safety and tolerability of 
long-term treatment with LCZ696 in eligible HFpEF patients who completed 
PARAGON-HF in Japan.
Secondary 
Objectives
Not Applicable
Study design
This study is an open-label extension study to the PARAGON-HF to assess the long-
term safety and tolerability of LCZ696 treatment.
Population
Approximately 70 Japanese patients with HFpEF who completed PARAGON-HF.
Key Inclusion 
criteria
1.
Signed informed consent must be obtained before any assessment is performed.
2.
Patients who have completed PARAGON-HF and are able to be safely enrolled 
into this study as judged by the investigator.
Key Exclusion 
criteria
1.
Patients who discontinued study drug treatment during PARAGON-HF due to an 
event or intercurrent illness. Eligibility can be re-considered if the event has 
resolved and no longer represents a risk to the patient and the patient can safely 
tolerate the administration of LCZ696 per the investigator’s assessment.
2.
Any medical condition that in the opinion of the investigator is likely to prevent the 
patient from safely tolerating LCZ696 or complying with the requirements of the 
study.
3.
Patients who have experience of angioedema event(s) which occurred and 
reported by the investigator during PARAGON-HF.
4.
Pregnant or nursing (lactating) women
5.
Women of childbearing potential unless they are using highly effective methods of 
contraception.
Study treatment
LCZ696
50 mg b.i.d.(dose level 1), 100 mg b.i.d. (dose level 2), 200 mg b.i.d. (dose level 3)
Efficacy 
assessments
Efficacy is not measured in this study.
Key safety 
assessments

Adverse events (AEs) and Serious adverse events (SAEs)

Laboratory values (including monitoring for hyperkalemia and renal dysfunction)

Sitting systolic Blood pressure (BP), sitting diastolic BP and heart rate

Angioedema surveillance
Data analysis
The assessment of safety will be based primarily on the frequency of AEs and SAEs. 
Other safety data will be summarized as appropriate.
Key words
heart failure with preserved ejection fraction, Japanese patients, extension study, 
long-term safety and tolerability, open-label


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1
Introduction
1.1
Background
Heart failure (HF) is a terminal condition of all heart diseases, characterized by worsening of 
symptoms such as exertional dyspnea and/or breathlessness requiring repeated hospitalization 
that lead to premature death, as well as significantly greater risks of sudden death 
(Ponikowski et al 2016). The mortality within 5 years after diagnosis is approximately 50% in 
Europe and the United States (US) (Yancy et al 2013); this rate is similar to the 5-year mortality 
in all patients with cancer. In Japan, a cohort study of chronic heart failure (CHF) Analysis and 
Registry in the Tohoku District (CHART)-2 (Shiba et al 2011) showed that the total annual 
mortality was 4.2% and the rate of hospital readmission for HF was 14.3% among Japanese 
CHF patients classified into Stage C (symptomatic HF) or Stage D (refractory HF) according 
to the American College of Cardiology (ACC)/American Heart Association (AHA) criteria. 
These indicated that the prognosis of CHF patients in Japan was as poor as that of CHF patients 
in Europe and US (Shiba and Shimokawa 2011, Sakata and Shimokawa 2013).
In recent years, the number of patients with HF has rapidly increased due to increased 
prevalence of ischemic cardiac diseases, outcome improvement of those acute treatment, and 
population aging, etc., and estimated at approximately 26 million across the world 
(Ambrosy et al 2014). In Japan, the number of patients with HF is currently approximately 1 
million, estimated to reach 1.3 million in 2030 (Okura et al 2008). According to the Japanese 
Registry of All cardiac and vascular Diseases (JROAD) conducted by the Japanese Circulation 
Society (JCS), the number of hospitalized patients with HF for FY2017 was 260,157, which 
have increased yearly (The Japanese Registry Of All cardiac and vascular Diseases (JROAD)). 
Frequent hospitalization not only adds physical, mental, and economic pressures on the patients 
and their families, but also imposes an enormous burden on health care financing.
In a part of patients with HF, it has been shown to occur with normal systolic function. HF with 
normal or “near-normal” ejection fraction (EF) has been designated HF with preserved ejection 
fraction (HFpEF). HFpEF accounts for approximately half of HF cases, and is associated with 
substantial morbidity and mortality (Lam et al 2011). Moreover, the prevalence of HFpEF, as 
well as its relative prevalence compared with HF with reduced ejection fraction (HFrEF), has 
been increasing in recent years (Owan et al 2006, Shiba and Shimokawa 2011). Increasing 
prevalence of HFpEF may be a consequence of growing aging population, and increases in 
hypertension (HTN) and obesity (Blanche et al 2010).
HFpEF is a serious condition associated with substantial morbidity. Hospitalization for
worsening HF is common (Lewis et al 2007, Hoekstra et al 2011) and large prospective 
registries have shown re-hospitalization rates for HFpEF to be high and similar to those of 
HFrEF (Lenzen et al 2004, Fonarow et al 2007, Tsuchihashi-Makaya et al 2009). The high rate 
of hospitalization for heart failure associated with HFpEF is a marker of disease progression 
and poor outcomes (including death) in patients (Solomon et al 2007, Ahmed et al 2008) . 
Finally, survival rates have not improved over time for HFpEF, unlike for HFrEF 
(Owan et al 2006).
Unlike HFrEF, no treatment has shown to reduce morbidity or mortality in patients with HFpEF. 
There is currently no approved therapy for the treatment of HFpEF. Previous therapies tested 
in patients with HFpEF mainly focused on blocking/inhibiting the detrimental effects of 


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neurohormonal activation (i.e. angiotensin converting enzyme inhibitor (ACEIs), angiotensin 
receptor blocker (ARBs), mineralocorticoid antagonist (MRAs)), and largely ignored the 
physiological compensatory effect of the natriuretic peptide (NP) system. These agents failed 
to demonstrate outcome benefits in this patient population. The current focus of treatment is to 
alleviate symptoms and improve well-being. Consequently, the guidelines from the ACC/AHA 
(Yancy et al 2017) and European Society of Cardiology (ESC) (Ponikowski et al 2016) 
recommend treating volume overload/symptoms with diuretics and treating comorbid 
conditions that are common in HFpEF, such as diabetes mellitus (DM), HTN, renal impairment, 
atrial fibrillation (AF) and coronary artery disease (CAD) as well as Japan 
(Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure). Addressing this 
need is of utmost importance given the high morbidity and mortality of patients with HFpEF 
and the consequent stress on the global health care system (Sharma and Kass 2014).
LCZ696 (sacubitril/valsartan) is a first-in-class, angiotensin receptor neprilysin inhibitor 
(ARNI), approved in more than 100 countries worldwide for the treatment of adult patients with 
heart failure and reduced ejection fraction (HFrEF).
LCZ696, through its dual mode of action, potentiates NPs via neprilysin (NEP) inhibition while 
inhibiting the renin angiotensin system (RAS) via angiotensin type 1 (AT1) receptor blockade; 
mechanisms which are considered to act in a complementary and at least additive manner. The 
mechanism of action (MoA) of LCZ696 suggests that it may impact the suspected 
pathophysiology of HFpEF, in which it is believed that excessive fibrosis and myocyte 
hypertrophy lead to abnormal left ventricular diastolic filling, impaired diastolic distensibility 
and/or increased vascular stiffness, with consequent elevated cardiac filling pressures 
(Krum and Abraham 2009).
CLCZ696B2214 (PARAMOUNT) was a phase II randomized, double-blind, active-controlled 
therapeutic validation trial in HFpEF patients (Solomon et al 2012). The study evaluates 
LCZ696 against the active comparator valsartan. The primary endpoint was change in 
N- terminal pro-brain natriuretic peptide (NT- proBNP) at 12 weeks. It has been shown that a 
decrease in NT- proBNP is correlated with reductions in left ventricular wall stress and is 
correlated with changes in central hemodynamics (Kazanegra et al 2001, Forfia et al 2005, 
Chow et al 2011, , ).
LCZ696 is the first agent with positive Phase II data in HFpEF, demonstrating significantly 
reduced NT- proBNP, improvement with left atrial reverse remodeling and improvement in 
New York Heart Association (NYHA) class. The results of PARAMOUNT in HFpEF 
emphasize the therapeutic rationale of targeting both neurohormonal systems through 
simultaneous inhibition of neprilysin and blockade of angiotensin II receptor type 1. Therefore, 
the phase III outcomes trial PARAGON-HF has started to evaluate the effect of LCZ696 on 
morbidity and mortality in HFpEF patients.
CLCZ696D2301 (PARAGON-HF) is the largest HFpEF trial ever conducted with 4,822 
patients from 43 countries worldwide including 79 patients from Japan. The study is ongoing 
and evaluates LCZ696 against the active comparator valsartan. The primary endpoint is a 
composite of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations. 
Patients will be followed until 1,847 primary composite events have occurred or at least 26 
months, whichever occurs last. The study has so far undergone multiple safety reviews by an 


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independent Data Monitoring Committee (DMC) which has recommended continuing the study 
without protocol modifications.
LCZ696 is the only product known to be in late stage clinical development that leverages 
beneficial effects of the endogenous NP system, while simultaneously limiting the detrimental 
effects of prolonged RAS activation, to provide complimentary dual effects of NEP inhibition 
and RAS blockade to HFpEF patients.
1.2
Purpose
The purpose of this open-label study is to further evaluate the safety and tolerability of long-
term treatment with LCZ696 for the eligible Japanese patients who completed CLCZ696D2301 
(PARAGON-HF) until marketed product is available in Japan or 2 years from the date of the 
first patient enrolled in the open label extension study, whichever occurs first.
2
Objectives and endpoints
The primary objective of this study will be to evaluate further the safety and tolerability of long-
term treatment with LCZ696 in eligible HFpEF patients who completed PARAGON-HF in 
Japan.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To further evaluate the safety and tolerability of long-term 
treatment with LCZ696 in eligible HFpEF patients who 
completed PARAGON-HF in Japan.

All safety data, including vital signs, 
adverse events, are considered 
primary endpoints.
3
Study design
This study is an open-label extension study to the PARAGON-HF. Patients who completed the 
PARAGON-HF are eligible to participate. During the study, open-label LCZ696 will be taken 
in addition to background treatments of comorbidities in place of ACEIs, ARBs, and renin 
inhibitors.
At the first visit of the study (Visit 1), all patients willing to participate will provide informed 
consent and will provide blood samples for local lab assessment of their health status and their 
eligibility for the study will be evaluated by the investigator. The patients can be enrolled at the 
same day as the last visit of PARAGON-HF, or enrolled up to about 6 months after the result 
of PARAGON-HF is known at the latest. If the first visit of the study (Visit 1) is the same as 
the last visit of PARAGON-HF, the procedure of blood samples will not be required and the 
data of the last visit of PARAGON-HF can be used as the data at Visit 1. The study treatment 
will be dispensed upon confirmation of eligibility.
Patients will start on open-label LCZ696 at a dose that is equivalent to the last dose level (or 
dose of other renin angiotensin aldosterone syste (RAAS) inhibitors if patient switched) taken 
at the time of completing PARAGON-HF, but no higher than dose level 2 (Figure 3-1, 
Table 3-1). The dose and regimen of background treatment medications should be maintained.


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Every attempt should be made to up-titrate and maintain the patient at the maximum tolerated 
LCZ696 dose with a target dose of 200 mg b.i.d. as soon as possible per the investigator’s 
medical judgement taking into account AEs including potassium level, kidney function, blood 
pressure (referred to Section 16.3 Appendix 3, Section 16.4 Appendix 4, and Section 16.5
Appendix 5).
At Visit 102 (Week 2-4), patients who tolerate open-label LCZ696 should be up-titrated to the 
next higher dose level by investigator judgement. If in the investigator's judgement, the patient 
does not tolerate the treatment dose level, then investigator should try to modify background 
medication in line with Section 6.5.1 in order to re-challenge the patient with a higher dose level 
at the earliest possible opportunity. Treatment guidelines for hyperkalemia, management of BP 
and renal dysfunction are provided in Section 16.3 Appendix 3, Section 16.4 Appendix 4, and 
Section 16.5 Appendix 5.
The patient will continue to receive LCZ696 until it is commercially available, or for a period 
up to 24 months from the first patient enrolled in this study, whichever comes first. If the 
primary endpoint of PARAGON-HF is not met, the study will be terminated.
S
Figure 3-1
Study design
Dose level 3: LCZ696 200 mg b.i.d. or Valsartan 160 mg bid, Dose level 2: LCZ696 100 mg b.i.d. or Valsartan 80 
mg b.i.d., Dose level 1: LCZ696 50 mg b.i.d. or Valsartan 40 mg b.i.d..
* patients receiving PARAGON-HF study drug at dose level 3 should start with LCZ696 100 mg (dose level 2) or 
might start with LCZ696 50 mg bid (dose level 1) at the investigator’s discretion taking into account patient 
condition.
** patients receiving PARAGON-HF study drug at dose level 2 have options to start with either the open-label 
LCZ696 100 mg b.i.d. (dose level 2) or LCZ696 50 mg b.i.d. (dose level 1) at the investigator’s discretion.
*** incudes no treatment case.
**** If the primary endpoint of PARAGON-HF is not met, the study will be terminated.
1) Dosage should be up-titrated at Visit 102 (2-4w) if patient tolerates by investigator’s judgement taking into 
account safety monitoring guidance, and follow the general protocol guidance regarding maintenance dose.
2) Dose adjustment is permitted during the study if the patient does not tolerat the assigned dose following the 
general protocol guidance regarding maintenance dose.
3) Attempt should be made to up-titrate and maintain the patient at the target LCZ696 200 mg bid for as long as 
possible.


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Table 3-1
Study drug level at the start of the study
Final dose level of study medication of 
PARAGON-HF
LCZ696
3*
100 mg b.i.d.
2**
50 mg b.i.d. or 100 mg b.i.d.
1
50 mg b.i.d.
No Treatment***
50 mg b.i.d.
* The patient receiving PARAGON-HF study drug at dose level 3 should start with LCZ696 100mg or might 
start with LCZ696 50 mg b.i.d. at the investigator’s discretion taking into account patient condition.
** The patient receiving PARAGON-HF study drug at dose level 2 has options to start with either LCZ696 100 
mg b.i.d. or LCZ696 50 mg b.i.d. at the investigator’s discretion.
***Patients who finish the PARAGON-HF on no treatment and on an ACEI should observe a 36 hours ACEI-
free washout period as per Table 6-1. Patients might start from LCZ696 100mg b.i.d. at the investigator's 
discretion taking into account patient condition and current treatment (e.g. RAAS inhibitors)
4
Rationale
The purpose of this extension study is to assess the safety and tolerability of long-term treatment 
with LCZ696 in Japanese HFpEF patients who completed PARAGON-HF trial. This study 
allows the option of use of LCZ696 in patients benefiting from the study treatment in 
PARAGON-HF by the investigator judgement. 
The mechanism of action of LCZ696 suggests that it may impact the suspected pathophysiology 
of HFpEF, in which it is believed that excessive fibrosis and myocyte hypertrophy lead to 
abnormal left ventricular diastolic filling, impaired diastolic distensibility and/or increased 
vascular stiffness, with consequent elevated cardiac filling pressures. In phase II proof of 
concept trial in HFpEF (PARAMOUNT), LCZ696 demonstrated greater reductions in NT-
proBNP and all echocardiographic measures of left atrial size compared with valsartan. Albeit 
for HFrEF patients, LCZ696 showed a large benefit in morbidity and mortality compared to 
enalapril, standard therapy in the guideline in phase III outcome study (PARADIGM-HF). 
The rationale for allowing patients the option to receive open-label LCZ696 in this study 
pending release of the PARAGON-HF study results is twofold. First, if the treatment plan is 
implemented for a patient by the treating physician, it will minimize treatment disruption in 
post-PARAGON-HF treatment. PARAGON-HF patients were randomized to either valsartan 
or LCZ696 (sacubitril/valsartan), which are all components of LCZ696. As of the date of this 
study, the independent DMC has reviewed the cumulative safety data of the PARAGON-HF 
study twice annually since its initiation (total of eight safety reviews) and has determined that 
LCZ696 continues to demonstrate an acceptable safety profile relative to valsartan. Another 
rationale for allowing PARAGON-HF patients to be offered open-label LCZ696 before release 
of the PARAGON-HF study results is that there is currently no approved treatment for patients 
with HFpEF in Japan. Allowing investigators and patients the option to receive open-label 
LCZ696 in this study will afford them a treatment option that will minimize disruption in their 
medical regimen. If the results of PARAGON-HF does not show the efficacy, the study will be 
terminated.


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4.1
Rationale for study design
An open-label study design was adopted for this study because it satisfies the main objective of 
obtaining safety and tolerability data of long-term treatment with LCZ696 in the Japanese 
HFpEF patients who completed PARAGON-HF. As there is no comparator in this extension 
study, study blinding is not necessary.
4.2
Rationale for dose/regimen and duration of treatment
The starting dose in this study was set based on the dose level administered in PARAGON-HF. 
The patients receiving study drug at dose level 3 in PARAGON-HF should start taking a 
LCZ696 at the next lower dose level to ensure patient's safety. The patients receiving study drug 
at dose level 2 in PARAGON-HF can start taking a LCZ696 at either the same dose level or the 
next lower dose level to ensure the patient’s safety based on the investigator's clinical judgement.
In case of the patients starting at the next lower dose level from PARAGON-HF, the dosage 
will be up-titrated to the next higher dose level (original dose level) as soon as possible if 
tolerated. The patients receiving study drug at dose level 2 in PARAGON-HF can start with 
either the same dose level or the next lower dose level based on the investigator's clinical 
judgement. The patients who are not on study medication at screening visit and eligible should 
start at dose level 1.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
Patients will be instructed not to take any RAS blockade medications (ACEI or ARB) while 
they take study drug to avoid excess RAS blockade. All patients will be allowed to continue 
receiving the rest of their background CV medications. The risk to patients in this study will be 
minimized by compliance with the eligibility criteria and close clinical monitoring. In women 
of child-bearing potential, a possible risk of developmental toxicity cannot be excluded. Women 
of child-bearing potential should therefore use a highly effective method of contraception 
during dosing and for 7 days off study medication. If there is any question that the patient will 
not reliably comply, they should not be entered in the study. All patients in this study will be 
≥50 years of age because all patients participated in PARAGON-HF were ≥50 years of age, 
and therefore the risk of pregnancy during the trial is minimal.
Since this study is following PARAGON-HF, participating patients to this study will benefit 
from continuous effect of LCZ696 thorough the continuous access from PARAGON-HF to 
open-label LCZ696 that avoids the treatment interruption. If the primary endpoint of 
PARAGON-HF is not met, the study will be terminated as soon as possible.


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5
Population
The study population will consist of Japanese patients with HFpEF who completed 
PARAGON-HF. It is anticipated that approximately 70 Japanese patients will complete the 
PARAGON-HF, of which approximately 80% are anticipated to enrol into this study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained before any assessment is performed.
2. Patients who have completed PARAGON-HF and are able to be safely enrolled into this 
study as judged by the investigator.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Patients who discontinued study drug treatment during PARAGON-HF due to an event or 
intercurrent illness. Eligibility can be re-considered if the event has resolved and no longer 
represents a risk to the patient and the patient can safely tolerate the administration of 
LCZ696 per the investigator’s assessment.
2. Any medical condition that in the opinion of the investigator is likely to prevent the 
patient from safely tolerating LCZ696 or complying with the requirements of the study.
3. Patients who have experience of angioedema event(s) which occurred and reported by the 
investigator during PARAGON-HF.
4. 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 human 
chorionic gonadotropin (hCG) laboratory test.
5. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
while taking study treatment and for 7 days of after stopping medication. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception)

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to Visit 1). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject

Combination of any two of the following (a+b, a+c, or b+c), acording to country 
approvals and availability:
a. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository


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b. Use of oral, (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception
c. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of childbearing potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the Informed Consent Form 
(ICF).
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
All eligible patients will receive LCZ696 b.i.d. in addition to optimal therapy for HF and other 
comorbidities, as considered appropriate by the investigator and in accordance with standard 
therapy guidelines. The use of an ACEI or an ARB, or a renin inhibitor in addition to the study 
drug is strictly prohibited.
The sponsor will provide the following study medication in bottles;

LCZ696 50 mg film coated tablets (Dose level 1)

LCZ696 100 mg film coated tablets (Dose level 2)

LCZ696 200 mg film coated tablets (Dose level 3)
Study medication will be provided for the treatment according to 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 the country. They will include storage conditions for 
the drug, but no information about the patients.
6.1.2
Additional study treatments
Any background treatment except for ACEI, ARB, and renin inhibitor are allowed to continue 
in this study.
6.1.3
Treatment arms/group
All patients will be treated with LCZ696.


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6.1.4
Treatment duration
This study will continue until marketed product is available in Japan, or approximately for 2 
years from the date of the first patient enrolled, whichever comes first. Subjects may be 
discontinued from treatment earlier due to unacceptable toxicity, disease progression and/or 
treatment is discontinued at the discretion of the investigator or the subject.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
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 subject was enrolled into the study must be recorded on the appropriate Case Report 
Forms (CRF).
CV medications
The patient should be on an optimal medical regimen of diuretics and background medications 
to effectively treat comorbidities, such as HTN, DM, AF and coronary artery disease. 
Investigators should take into consideration the patient’s risk factors, such as age and 
comorbidities, and make every effort to control a patient’s BP in accordance with international 
and local treatment guidelines, as well as other evidence-based medicine. The concomitant use 
of ACEIs, ARBs or renin inhibitor is strictly prohibited while the patient is receiving study drug 
(Section 6.2.2).
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements, MRAs and any other medications known 
to raise potassium levels should be used with caution while the patient is receiving the study 
drug due to the increased possibility of occurrence of hyperkalemia. The investigator is 
encouraged to assess patients’ potassium levels regularly, especially in those who are receiving 
these medications.
Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of the occurrence of hypotension.
Neseritide and intravenous (IV) nitrates
The concomitant administration of LCZ696 with neseritide and IV nitrates has not been studied. 
In the event a study patient requires the concomitant administration of neseritide and/or IV 
nitrates with the study medications, the investigator should consider starting them at a lower 
dose or a slower infusion rate while monitoring the patient’s BP carefully.


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HMG-CoA reductase inhibitors
Caution is recommended when co-administering LCZ696 with atorvastatin or other statins (e.g. 
simvastatin, pravastatin) that are substrates of organic anion-transporting polypeptide (OATP) 
1B1 and OATP1B3 because of the potential to raise plasma statin levels.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed after the start of study 
treatment due to safety reasons, unless the actions specified are taken.
Table 6-1
Prohibited medication
Medication
Action taken
Any ACEI
Discontinue study drug. The ACEI must be stopped for ≥36 
hours prior to re-initiation of study drug
Any ARB
Discontinue study drug. The ARB must be stopped prior to re-
initiation of study drug
Any renin inhibitor
Discontinue study drug. The renin inhibitor must be stopped 
prior to re-initiation of study drug
The concomitant use of ACEIs, ARBs or renin inhibitor is strictly prohibited while the patient 
is receiving study drug. If the addition of an ACEI, ARB or renin inhibitor is necessary, then 
study drug must be temporarily discontinued. If the patient is to be started on ACEI, the study 
drug must be stopped ≥ 36 hours prior to initiating ACEI. If study drug is to start the ACEI must 
be stopped ≥ 36 hours prior to re-initiating study drug. ARBs or a renin inhibitor should be 
stopped prior to resuming study drug.
6.2.3
Rescue medication
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in Section 16.3 Appendix3, Appendix 4 and Appendix 5, respectively. Patients 
may receive ACEIs, ARBs or a renin inhibitor during the study ONLY if the study drug has 
been temporarily discontinued.
Use of rescue medication must be recorded on an appropriate CRF.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.; as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available.


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6.3.2
Treatment assignment, randomization
No randomization will be performed in this study. During this study, all patients will be treated 
with LCZ696 at maximally tolerated dosed with a target dose of 200 mg b.i.d.
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the sponsor.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are permitted.
6.5.1
Dose escalation guidelines
6.5.1.1
Starting dose
LCZ696 will be dispensed and the patient will be required to take one tablet of the assigned 
study medication twice a day for the duration of the study. The dose level dispensed at Visit 
101 will be either 50 mg b.i.d. (dose level 1) or 100 mg b.i.d. (dose level 2) largely depending 
on the last dose level taken by the patient at the time of completing PARAGON-HF and patient 
condition. The dose level should be gradually up-titrated at subsequent visit with the goal of 
reaching the target dose of 200 mg b.i.d. (dose level 3) as soon as tolerated by the patient (see 
Figure 3-1 and Table 3-1).
6.5.2
Dose modifications
For subjects who do not tolerate the protocol-specified dosing schedule, dose level adjustments 
and interruptions of study treatment are permitted in order to allow subjects to continue the 
study treatment. The following guidelines should be followed:
Every attempt should be made to maintain patients at the target study drug dose level throughout 
the study. If the patient does not tolerate the target study drug dose level, the investigator can 
adjust or stop concomitant background medications for co-morbid conditions to rectify the 
situation, before considering down-titration to the next lower study drug dose level. For 
hypotension or dizziness, consideration should be given to reduce the dose or to stop 
concomitant antihypertensive agents and non-antihypertensive agents that lower BP, or the dose 
of diuretic can be reduced.
These dose changes must be recorded on the appropriate CRF.
Adjustment of study drug dose level
If despite adjustment of concomitant medications per the guidance provided the situation is not 
rectified, the investigator may consider down titrating the study drug dose level according to 
the following instructions:
During the study, down titration of the study drug at any time based on the judgment of the 
investigator will be allowed taking into account the safety and tolerability criteria defined in 
Section 16.3 Appendix3, Appendix 4, and Appendix 5. If down titration is necessary, the patient 


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should be down titrated to the next lower study drug dose level (Table 6-2). The patient may 
continue receiving the lower dose level for a recommended period of 1 to 4 weeks before being 
re-challenged at the next higher dose level. For example, a patient who encounters tolerability 
problems at the target study drug dose level (dose level 3), should receive the study drug at dose 
level 2 for 1 to 4 weeks at the discretion of the investigator. Then, he/she should be re-
challenged with up-titration back to dose level 3.
If the tolerability issues are not alleviated despite down titration by one dose level, the
investigator may down titrate further to the next lower study drug dose level for 1 to 4 weeks, 
up to temporary discontinuation 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 6-2).
In some instances, the investigator’s judgment, dose level 1 or 2 could be maintained if he/she 
considers that the patient’s condition would not allow any further up titration to the target dose 
level of study drug (dose level 3). In this case, it would be acceptable to maintain the patient at 
dose level 1 or level 2, whichever is the higher and tolerated dose level by the patient.
Study drug restart after temporary treatment interruption
Study drug should be reintroduced in those patients who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator.
Once the investigator considers the patient’s condition appropriate for receiving the study drug, 
the investigator should re-start the patient on the study drug at the most appropriate and 
allowable dose level (Table 6-2) per his/her medical judgment. If tolerated, the patient should 
be up-titrated a dose level every 1 to 4 weeks to the target dose level 3, as per the investigator’s 
judgment. Should the patient not tolerate the re-start study drug dose level, he/she may be down 
titrated again (if appropriate) or temporarily discontinue the study medication again and a new 
attempt to up titrate or reintroduce the study drug could be considered by the investigator as 
soon as medically justified in his/her judgment.
The use of an ACEI, ARB or a renin inhibitor is strongly discouraged while patient is taking 
study drug. However, if for any reason a patient off study drug has started treatment with an 
ACEI, it must be discontinued ≥36 hours prior to restarting study drug. For patients off study 
drug treated with an ARB or a renin inhibitor it must be discontinued prior to re-initiation of 
study drug (Table 6-1).
These changes must be recorded on an appropriate CRF.
In case of pregnancy discovered during the study, the patient will be withdrawn from the study 
immediately. See Section 10.1.4 for further details on pregnancies and reporting guidelines.
6.5.3
Follow-up for toxicities
Not applicable.


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6.6
Additional treatment guidance
6.6.1
Treatment compliance
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the appropriate CRF.
The investigator should promote compliance by instructing the patient to take the 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 for 
any reason to take the study drug as prescribed.
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient and/or the caregiver. This information should
be captured in the source document at each visit. The investigator and/or study personnel should 
counsel the patient if compliance is below 80% at any time during the study. Study drug 
accountability will be determined by the site monitor while performing routine site visits and at 
the completion of the study.
The duration of treatment exposure will be calculated based upon the start and stop dates 
recorded in the CRF.
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described for clinical trial use 
only.
As per the treatment assigned to the subject, investigator staff will select the study treatment to 
dispense to the subject. The site personnel will record the batch number of study medication 
dispensed to the subject’s source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study 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 designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure (IB). Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis Country Pharma Organization 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 study treatment but no information about 
the subject.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 


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monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
Novartis will supply the investigators with all medications sufficient for the course of the study. 
Patients will be provided with study drug corresponding to their assigned dose level, sufficient 
to last until the next scheduled visit. Patients will be required to take one LCZ696 tablet twice 
a day for the duration of this study. Table 6-2 summarizes the study drug that will be taken 
during this study.
Table 6-2
Dose and treatment schedule
Study visit
Dose level
LCZ696
Visit 102 and all subsequent visit
3 a
200 mg b.i.d.
Available for any visit after Visit 101
2
100 mg b.i.d.
Available for any visit after Visit 101
1
50 mg b.i.d.
a This dose level should be attempted and maintained for as long as possible. If down-titration is necessary due 
to side effects, the patient should be re-challenged as soon as medically possible per the investigator’s 
judgement.
Patients will be instructed to take their morning study drug doses at approximately 08:00 
(8 AM) and their evening study drug dose at approximately 19:00 (7 PM). The study drugs 
should be taken with water, with or without food. If vomiting occurs during the course of 
treatment, subjects should not take LCZ696 again before the next scheduled dose. 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.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the appropriate CRF.
The investigator should promote compliance by instructing the patient to take the 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 for
any reason to take the study drug as prescribed.


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7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification (IN) 
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the subject.
Women of child bearing potential must 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 requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
Table 8-1 lists all of the assessments for this study. The table indicates which data are entered 
into CRF from the source data (X), remain in the source documents only (S). At the study end, 
all patients will return to the study sites as soon as possible to undergo the End of Study (EOS) 
visit assessments.
Assessment schedule lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 


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for the final visit will be performed. Permanent discontinuation of study drug constitutes 
withdrawal from the study. At this final visit, all dispensed investigational product should be 
reconciled, and the adverse event and concomitant medications recorded on the CRF.
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit or following the last administration of study drug (whichever is later), 
including a final contact at the 30-day point. This follow up may be a phone call. Documentation 
of attempts to contact the patient should be recorded in the source documentation.


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Treatment
Unplanned
Visit Name
11
101
102
103
104
105
106
107
108
199(EOS)2
UPV3
Days
1
1
14 to 28
56
122
244
365
487
609
730
-
Weeks
1
1
2 to 4
8
18
35
53
70
87
105
-
Informed consent
X
Inclusion/exclusion/demographics
X
X
Physical Examination
S
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
Laboratory assessments(locally)4
S
S
S
S
S
S
S
S
S
S
(S)
Pregnancy test(locally)5
S
S
S
S
S
S
S
S
S
S
(S)
Concomitant medication/Non drug therapies
X
X
X
X
X
X
X
X
X
X
X
AE/SAEs
X
X
X
X
X
X
X
X
X
X
X
Drug accountability
X
X
X
X
X
X
X
X
Screening phase disposition form
X
Study completion/ discontinuation form
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit 1 and Visit 101 can be on the same day 
2 End of Study (EOS) visit will be completed at 2 years from the date of the first patient enrolled in the study, or prematurely withdraws from the study, or this study will 
be terminated by  Novartis, or when LCZ696 becomes commercially available and reimbursed for the HFpEF indication in Japan, whichever occurs first. 
3 Unplanned visits (UPV) may occur if a safety issue develops.
4 serum potassium and creatinine will be performed every visit. Additional laboratory evaluation should be performed by Investigator's judgement.
5 All pre-menopausal women who are not surgically sterile will have serum pregnancy test locally at Visit 1. A urine dip-stick pregnancy test should be performed locally 
at other visits by Investigator's judgement.


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8.1
Screening
Re-screening will not be allowed in this study.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographics, inclusion/exclusion, and informed consent pages must 
also be completed for screening failure subjects. No other data will be entered into the clinical 
database for subjects who are screen failures, unless the subject experienced a SAE after signing 
informed consent. A SAE occurred after signing informed consent until confirming screening 
failure should be reported.
For all patients who have signed informed consent and receive study treatment all AEs 
occurring after informed consent is signed will be recorded on the Adverse Event CRF.
8.2
Subject demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: age, 
sex, race, ethnicity. 
8.3
Efficacy
8.3.1
Appropriateness of efficacy assessments
Efficacy is not measured in this study.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. If the abnormality for each assessment (e.g. laboratory test, vital 
sign) induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis 
or medical condition must be entered on the AE CRF. For details on AE collection and reporting, 
refer to AE section.
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety profile 
of the study drugs. Such information may include diagnostic procedure reports, discharge 
summaries, autopsy reports, and other relevant information that may help in assessing the 
reported AE. All additional information will be de-identified prior to collection by Novartis or 
its agents.
8.4.1
Laboratory evaluations
Laboratory assessments will be analyzed locally during the study. 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 


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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.
Serum potassium and creatinine will be evaluated locally at all visits in Table 8-1. Additional 
laboratory evaluation should be performed by Investigator's judgement at any visits.
8.4.2
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have serum pregnancy test locally 
at visit 1. A urine dip-stick pregnancy test should be performed locally at other visits defined in 
Table 8-1. If positive, the patient must discontinue study drug until after the pregnancy and 
lactation period.
8.4.3
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.4.4
Physical assessments
A physical exam will include the examination of general appearance and vital signs (BP 
[systolic blood pressure (SBP) and diastolic blood pressure (DBP)] and pulse). If indicated 
based on medical history and/or symptoms, other exams will be performed by Investigator's 
judgement. A physical exam will be conducted at all visits starting from Visit 1(see Table 8-1).
Information from all physical examinations must be included in the source documentation at 
the study site.Significant findings made after signing the informed consent which meet the 
definition of an AE must be recorded on the AE section of the CRF.
8.4.5
Vital sign
Vital signs include BP and pulse measurements. BP will be measured in the sitting position 
after 5 minutes of rest using an automated validated device (e.g. OMRON) or a standard 
sphygmomanometer with an appropriately sized cuff on the non-dominant arm. Guidelines for 
the management of BP are provided in Appendix 4.
8.4.6
Angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise.
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an Angioedema-
like Event form (provided by Novartis) to summarize the event, its treatment, and its ultimate 
outcome. This report along with the requisite medical documentation must be submitted to 
Novartis as soon as possible. Follow-up reports must be communicated to Novartis as soon as 
new information regarding the event becomes available. All hospital records related to the event 
must be communicated to Novartis.
The investigator may be also be contacted by Novartis regarding AEs that may resemble an 
angioedema-like event. A list of terms that are considered “angioedema-like” (e.g., periorbital 


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swelling) will be provided to sites in a manual. The investigator or his/her delegated staff must 
complete the required forms and provide the required medical records for all such events, 
regardless of whether the investigator views the event in question as angioedema or not.
All angioedema reports will be forwarded to an Angioedema Adjudication Committee by 
Novartis for assessment.
Information regarding this committee is outlined in Section 10.2.2. Details on the procedures 
for reporting angioedema events will be provided to investigators in a manual.
8.5
Additional assessments
No additional tests will be performed on subjects entered into this study.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time.
Permanent discontinuation of study drug for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration, and can be initiated by either the subject or the 
investigator.
The investigator must discontinue investigational treatment for a given subject if, he/she 
believes that continuation would negatively impact the subject's well-being.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. Always consider reasons which are related to safety and efficacy 
first.
Subjects who discontinue investigational treatment permanently or who decide they do not wish 
to participate in the study further should NOT be considered withdrawn from the study 
UNLESS they withdraw their consent (see Section 9.1.2, withdrawal of informed consent). 
They will be expected to perform the EOS Visit.
If they fail to return for the EOS visit assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, letter) should be made to contact the subject/pre-designated contact as 
specified in the lost to follow-up section. This contact should preferably be done according to 
the study visit schedule.
Subjects who discontinue treatment early will be expected to perform the final visit(EOS). All 
dispensed investigational product should be reconciled and the adverse event and concomitant 
medications reconciled on the appropriate CRF.
In case that a patient is to be switched from an LCZ696 to an ACEI, a 36-hour LCZ696-free 
washout should be implemented prior to the initiation of ACEI intake to minimize the risk of 
occurrence of angioedema. Similarly, a ACEI-free 36-hour washout should be implemented 
when switching a patient from an ACEI to an LCZ696. Patient management and safety 


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monitoring guidelines, including implementation of the appropriate washout periods, should 
refer to LCZ696D2301 (PARAGON-HF) or approved label whichever is most appropriate.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
Assessment.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until the end 
of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons.
If the primary endpoint of PARAGON-HF is not met, this study will be terminated and the 
patient must be safely switched from open-label LCZ696 to alternative treatment based on the 
investigator’s clinical judgement as soon as possible.
In taking the decision to terminate the study, Novartis will always consider the subject's welfare 
and safety. Should early termination be necessary, subjects must be seen as soon as possible and 
treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.


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9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion (EOS) 
visit and any repeat assessments associated with this visit have been documented and followed-
up appropriately by the Investigator or, in the event of an early study termination decision, the 
date of that decision.
All treated subjects should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The Common Toxicity Criteria (CTC) AE grade (version 5 or higher).
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported


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4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn

its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment or end of study visit, whichever is longer.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
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 must 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 subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.1 Appendix1.
For lab values provided without related clinical information, the CTCAE scale must be used to 
determine the seriousness. Any value of Grade 4 and above on this CTCAE scale must be 
considered serious.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal


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
life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject 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 it were more severe (please refer to the ICH-E2D Guidelines).

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

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

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

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 (please refer to the ICH-
E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site. Any SAEs experienced after the 30 day period after the last study visit should only 
be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment.


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Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The Investigator must assess the relationship of each SAE to each specific 
component of the study treatment (if the study treatment consists of several components) 
complete the SAE Report Form in English and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the investigator folder provided to each site.
Consider the following 2 categories (as applicable) to determine SAE reporting timeframes:
1. Screen Failures (e.g. a subject who is screened but is not treated): SAEs occurring after 
the subject has provided informed consent until the time the subject is deemed a Screen 
Failure must be reported to Novartis.
2. Treated Subjects: SAEs collected between time subject signs ICF until 30 days after the 
subject has discontinued or stopped study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
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 study treatment, a Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 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 (EC) in accordance with European 
Union (EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site.
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 


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the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis/CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. The follow-up 
should be for up to 12 months following the birth of the baby. Any SAE experienced during 
pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE CRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter


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
Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 16-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2 . Repeat liver chemistry tests (i.e. alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL), prothrombin 
time/international normalized ratio (PT/INR), alkaline phosphatase (ALP), gamma glutamyl 
transferase (GGT)) to confirm elevation.

These liver chemistry repeats should be performed using the local laboratory used by the 
site. Repeated laboratory test results must be reported as appropriate.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Angioedema Adjudication Committee
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire in eCRF. Details on the process of reporting angioedema and 
angioedema like events are outlined in a manual provided to investigators.
Submission of an angioedema-like event report is not a substitution for the submission of an 
SAE report if the event meets the definition of an SAE. If an angioedema-like event satisfies 
the definition of an SAE, the investigator must submit an SAE report in addition to the 
Adjudication Questionnaire for an Angioedema-like Event.
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites.


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11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 Code of Federal Regulation (CFR) Part 11 requirements, 
Investigator site staff will not be given access to the Electric Data Capture (EDC) system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated Clinical Research Organization) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments, prior medications and non-drug therapy entered into the database will 
be coded using the World Health Organization (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.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 


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visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis Clinical Research Associates (CRA) organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject 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 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The following population will be used for the statistical analyses:
The Safety Set (SAF): comprises all patients who received at least one dose of study treatment. 
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all subjects for the SAF.
Continuous variables will be summarized using n, mean, standard deviation, median, minimum, 
and maximum. Categorical variables will be summarized using frequency and percentage. For 
selected parameters, 25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by overall.
12.3
Treatments
The Safety set will be used for the analyses below. 
The overall duration on the study drug will be summarized using mean, standard deviation, 
median, minimum, and maximum. Mean doses and dose levels will be summarized by visit. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 


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study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all subjects. 
12.4
Analysis of the primary endpoint(s)
The primary objective of this study will be to evaluate further the safety and tolerability of long-
term treatment with LCZ696 in eligible HFpEF patients who completed PARAGON-HF in 
Japan.
12.4.1
Definition of primary endpoint(s)
All safety data, including vital signs, adverse
events, are considered primary endpoints.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary objective of this study is to evaluate safety and tolerability so in this study there is 
no statistical model/hypothesis defined however the assessment of safety will be based 
primarily on the frequency of AEs and SAEs.
12.4.2.1 Primary analysis
The assessment of safety will be based primarily on the frequency of AEs and SAEs. Other 
safety data will be summarized as appropriate.
The incidence of treatment-emergent AEs (new or worsened) will be summarized by primary 
system organ class, preferred term, severity, and relationship to study drug. In addition, the 
incidence of death, SAEs, and AEs leading to discontinuation will be summarized separately 
by primary system organ class and preferred term. 
The incidence of AEs related to the identified and potential risks will be summarized by SMQ 
preferred terms.
Safety analyses will be performed based on the safety set. There will be no formal statistical 
inference analysis.
12.4.3
Handling of missing values/censoring/discontinuations
There will be no imputation done on any parameter or variable in this study.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
Not applicable.
Supportive analyses
Not applicable.


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12.5
Analysis of secondary endpoints
Not applicable.
12.6
Interim analyses
Not applicable.
12.7
Sample size calculation
12.7.1
Primary endpoint(s)
The study population will consist of Japanese patients who completed PARAGON-HF. It is 
anticipated that approximately 70 patients will survive to the end of PARAGON-HF, of which 
approximately 80% are anticipated to enrol into this study.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must 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 subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.) .


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operational procedures (SOPs), and are performed according to 
written Novartis processes.
14
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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
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.
14.1
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 required for subject safety 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 subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Ahmed A, Allman RM, Fonarow GC, et al (2008) Incident heart failure hospitalization and 
subsequent mortality in chronic heart failure: a propensity-matched study. J Card Fail; 14: 
211-8.
Ambrosy AP, Fonarow GC, Butler J, et al (2014) The global health and economic burden of 
hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J 
Am Coll Cardiol; 63: 1123-1133.
Blanche C, Fumeaux T, Polikar R (2010) Heart failure with normal ejection fraction 
(HFNEF): is it worth considering? Swiss Med Wkly; 140: 66-72.
Chow SL, O'Barr SA, Peng J, et al (2011) Renal function and neurohormonal changes 
following intravenous infusions of nitroglycerin versus nesiritide in patients with acute 
decompensated heart failure. J Card Fail; 17: 181-7.
Fonarow GC, Stough WG, Abraham WT, et al (2007) Characteristics, treatments, and 
outcomes of patients with preserved systolic function hospitalized for heart failure: a report 
from the OPTIMIZE-HF Registry. J Am Coll Cardiol; 50: 768-77.
Forfia PR, Watkins SP, Rame JE, et al (2005) Relationship between B-type natriuretic 
peptides and pulmonary capillary wedge pressure in the intensive care unit. J Am Coll 
Cardiol; 45: 1667-71.
Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure. (JCS 2017/JHFS 
2017)
Hoekstra T, Lesman-Leegte I, van Veldhuisen DJ, et al (2011) Quality of life is impaired 
similarly in heart failure patients with preserved and reduced ejection fraction. Eur J Heart 
Fail; 13: 1013-8.
Kazanegra R, Cheng V, Garcia A, et al (2001) A rapid test for B-type natriuretic peptide
correlates with falling wedge pressures in patients treated for decompensated heart failure: a 
pilot study. J Card Fail; 7: 21-29.
Krum H, Abraham WT (2009) Heart failure. Lancet; 373: 941-55.
Lam CS, Donal E, Kraigher-Krainer E, et al (2011) Epidemiology and clinical course of heart 
failure with preserved ejection fraction. Eur J Heart Fail; 13: 18-28.
Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al (2004) Differences between patients 
with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure 
Survey. Eur Heart J; 25: 1214-20.
Lewis EF, Lamas GA, O'Meara E, et al (2007) Characterization of health-related quality of 
life in heart failure patients with preserved versus low ejection fraction in CHARM. Eur J 
Heart Fail; 9: 83-91.
Okura Y, Ramadan MM, Ohno Y, et al (2008) Impending epidemic: future projection of heart 
failure in Japan to the year 2055. Circ J; 72: 489-91.


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Owan TE, Hodge DO, Herges RM, et al (2006) Trends in prevalence and outcome of heart 
failure with preserved ejection fraction. N Engl J Med; 355 251-9.
Ponikowski P, Voors AA, Anker SD, et al (2016) 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of 
acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J 37: 
2129-2200.
Sakata Y, Shimokawa H (2013) Epidemiology of heart failure in Asia. Circ J; 77: 2209-17.
Sharma K, Kass DA (2014) Unmet Needs in Cardiovascular Science and Medicine. Heart 
failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ 
Res; 115: 79-96.
Shiba N, Nochioka K, Miura M, et al (2011) Trend of westernization of etiology and clinical 
characteristics of heart failure patients in Japan--first report from the CHART-2 study. Circ J; 
75: 823-33.
Shiba N, Shimokawa H (2011) Prospective care of heart failure in Japan: lessons from 
CHART studies. EPMA J; 2: 425-38.
Solomon SD, Dobson J, Pocock S, et al (2007) Influence of nonfatal hospitalization for heart 
failure on subsequent mortality in patients with chronic heart failure. Circulation; 116: 1482-
7.
Solomon SD, Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor 
LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised 
controlled trial. Lancet; 380: 1387-95.
The Japanese Registry Of All cardiac and vascular Diseases (JROAD) (JCS2017).
Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, et al (2009) Characteristics and 
outcomes of hospitalized patients with heart failure and reduced vs preserved ejection 
fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-
CARD). Circ J; 73: 1893-900.
Yancy CW, Jessup M, Bozkurt B, et al (2013) 2013 ACCF/AHA guideline for the
management of heart failure: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll 
Cardiol; 62: e147-239.
Yancy CW, Jessup M, Bozkurt B, et al (2017) 2017 ACC/AHA/HFSA Focused Update of the 
2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American 
College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines and the Heart Failure Society of America. J Am Coll Cardiol; 70: 776-803.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:
Hematology
Hematocrit >50% increase, >20% decrease
Hemoglobin >50% increase, >20% decrease
Platelet count >75% increase, >50% decrease
RBC count >50% increase, >20% decrease
WBC count >50% increase, >50% decrease
Blood Chemistry
Alkaline phosphatase >100% increase
ALT(SGPT) >150% increase
AST(SGOT) >150% increase 
BUN >50% increase
Calcium >10% increase, >10% decrease
Chloride >10% increase, >10% decrease
Creatinine >50% increase
Potassium >20% increase, >20% decrease
Total bilirubin >100% increase
Uric acid >50% increase


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16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS

3 x ULN < ALT / AST ≤ 5 x ULN

1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × 
ULN [mainly conjugated fraction] without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal 
pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: Hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total 
bilirubin; ULN: upper limit of normal
Table 16-2
Follow-up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
> 3 × ULN and INR > 
1.5

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR,
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study treatment immediately

Hospitalize the patient

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation

Hospitalization if clinically appropriate

Establish causality

Record the AE and contributing factors (e.g. 
conmeds, med hx, lab) in the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.
Alb: Albumin, LFT: Liver Function test
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


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16.3
Appendix 3: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.3 mmol/L [mEq/L]
General principles
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken.
Any patient with a serum potassium > 5.3 mmol/L (mEq/L) at any time in treatment period 
requires the Investigator to confirm the potassium concentration in a non-hemolyzed sample 
via an immediate repeat lab sample to both the clinic local lab and the study central lab.
Regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) 
should continue until it is clear that the potassium concentration is stable and not rising into the 
range of concern (≥ 5.5 and < 6.0 mmol/L [mEq/L]) or potential danger (≥ 6.0 mmol/L [mEq/L]).
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below. Hyperkalemia should be followed until resolution.
Corrective action for management of hyperkalemia
Serum potassium greater than 5.3 and less than or equal to 5.5 mmol/L (mEq/L)

Confirm potassium concentration in a non-hemolyzed sample

Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
tomatoes, coffee, etc.)

Correct metabolic acidosis if necessary.

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: 

MRAs (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


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
Assess patient for dehydration or any condition that could lead to dehydration (e.g., 
diarrhea, vomiting) and/or hypovolemia and initiate appropriate corrective measures of 
rehydration.

Repeat serum potassium measurement within 3 to 5 days

If serum potassium remains > 5.3 and ≤ 5.5 mmol/L (mEq/L), regularly monitor serum 
potassium levels to ensure stability (suggested once monthly)

Consider down-titration of study drug, according to investigator’s medical judgment.
Serum potassium greater than 5.5 and less than 6.0 mmol/L (mEq/L)

Confirm potassium concentration in a non-hemolyzed sample

Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment.

Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L

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 (mEq/L)

Immediately discontinue study drug

Confirm potassium concentration in a non-hemolyzed sample

Urgently evaluate patient and treat hyperkalemia as clinically indicated

Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L (mEq/L)
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee.
16.4
Appendix 4: Guidelines for the management of blood pressure
Guidelines
1. Investigator should monitor BP closely
2. If symptomatic hypotension occurs: 
a. Correct any treatable cause, e.g. hypovolemia
b. If hypotension persists, any antihypertensive drug such as diuretics, calcium channel 
blockers (CCBs), nitrates, beta blockers, aldosterone antagonists and α-blockers, 
should be down-titrated or stopped first before down-titration of the study drug is 
considered. Any non-antihypertensive drug (such as nitrates) should be considered for 
down-titration prior to study drug as determined by the best judgment of the 
investigator.
c. If hypotension persists, the study drug should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medications adjust guidelines described in 
Section 6.5.2 should be adhered to as much as possible.


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16.5
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 astimulation of angiotensin II and could be affected by either study drug. 
Moreover, renal dysfunction may develop or may deteriorate in some patients after study drug 
administration. These recommendations have been developed to guide the investigators in 
managing patients with renal dysfunction after randomization.
Two types of response to serum creatinine increase are described:
Surveillance situationIf, at any time in treatment period, eGFR decreases by ≥25% from 
baseline (Visit 101) (or if serum creatinine concentration increase to 2.5 mg/dL [221 μmol/L]), 
the investigator will check for potentially reversible causes of renal dysfunction such as:

Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect creatinine

Volume decrease, including that resulting from excessive dosing of diuretics

Urinary infection

Urinary tract obstruction

Study drug
Action situation
If a patient’s eGFR decreases by ≥40% from baseline (Visit 101) (or if serum creatinine 
concentration rises above 3 mg/dL (265μmol/L), the investigator will check for potentially 
reversible causes of renal dysfunction (see above).
The investigator may consider down-titration of study drug. If the investigator judges that study 
drug has to be stopped, he/she will have to contact the Novartis medical monitor or his/her 
designee. Thereafter, serum creatinine assessments will have to be repeated at least each week 
until levels return to acceptable values. If study drug was stopped, every effort will be done to 
restart it again, according to clinical conditions.

SAP_000.pdf: 
Clinical Development
LCZ696
CLCZ696D1301E1 / NCT03909295
A multicenter, open-label study to evaluate the safety and
tolerability of LCZ696 treatment in Japanese heart failure
patients (NYHA Class II-IV) with preserved ejection fraction
after CLCZ696D2301 (PARAGON-HF)
Statistical Analysis Plan (SAP)
Author:
Trial Statistician,
Document type:
SAP Documentation
Document status:
Amendment 1.0
Release date:
17-December-2019
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time point
Reason 
for update
Outcome for update
Section
impacted 
(Current)
22APR2019
Prior to FPFV
Initial Version 
12DEC2019
Before DBL
The CTT suggested 
few updates
Few of the summary 
tables will be performed 
for Overall and removed 
by treatment group.
For vital signs, added the 
change from baseline.
2.3.1, 2.3.2, 
2.4.2
2.7.3.2


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................8
2.2
Analysis sets ............................................................................................................9
2.3
Patient disposition, demographics and other baseline characteristics .....................9
2.3.1
Patient disposition...................................................................................9
2.3.2
Background and demographic characteristics.......................................10
2.3.3
Medical history......................................................................................10
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................10
2.4.1
Study treatment / compliance................................................................10
2.4.2
Prior and concomitant therapies............................................................14
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoints .................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis..........................15
2.5.3
Handling of missing values/censoring/discontinuations.......................15
2.5.4
Supportive and sensitivity analyses ......................................................15
2.6
Analysis of secondary efficacy objective(s)..........................................................15
2.7
Safety analyses.......................................................................................................15
2.7.1
Adverse events (AEs)............................................................................15
2.7.2
Death .....................................................................................................18
2.7.3
Laboratory data .....................................................................................18
2.8
Pharmacokinetic endpoints....................................................................................19
2.9
PD and PK/PD analyses.........................................................................................19
2.10
Patient-reported outcomes .....................................................................................19
2.11
Biomarkers.............................................................................................................19
2.12
Other Exploratory analyses....................................................................................19
2.13
Interim analysis......................................................................................................19
3
Sample size calculation .....................................................................................................19
4
Change to protocol specified analyses ..............................................................................19
5
Appendix ...........................................................................................................................19


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5.1
Imputation rules.....................................................................................................19
6
Reference...........................................................................................................................19


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List of abbreviations
ACEi
angiotensin converting enzyme inhibitor
AE
adverse event
ARB
angiotensin receptor blocker
ATC
anatomical therapeutic classification
Bid
BP
twice a day
blood pressure
CRF
case report form
CSR
clinical study report
DBP
diastolic blood pressure
DMC
data monitoring committee
eGFR
estimated glomerular filtration rate
HFpEF
heart failure with preserved ejection fraction
MedDRA
mg
NYHA
RAAS
Medical Dictionary for Drug Regulatory Affairs
milligram(s)
New York Heart Association
Renin angiotensin aldosterone system
SAE
SAF
serious adverse event
safety set
SAP
SBP
SMQ
statistical analysis plan
systolic blood pressure
Standardized MedDRA query
SOC
system organ class
TEAE
treatment emergent adverse event
TESAE
treatment emergent serious adverse event


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1
Introduction
The statistical analysis plan (SAP) describes the detailed methodology and implementation of 
the planned statistical analyses outlined in the study protocol v00 for CLCZ696D1301E1. The 
analysis results will be summarized in the clinical study report (CSR).
1.1
Study design
This study is an open-label extension study to the PARAGON-HF. Patients who completed the
PARAGON-HF are eligible to participate. During the study, open-label LCZ696 will be taken
in addition to background treatments of comorbidities in place of ACEi’s, ARBs, and renin  
inhibitors.
At the first visit of the study (Visit 1), all patients willing to participate will provide informed
consent and will provide blood samples for local lab assessment of their health status and their
eligibility for the study will be evaluated by the investigator. The patients can be enrolled at the
same day as the last visit of PARAGON-HF, or enrolled up to about 6 months after the result
of PARAGON-HF is known at the latest. If the first visit of the study (Visit 1) is the same as
the last visit of PARAGON-HF, the procedure of blood samples will not be required and the
data of the last visit of PARAGON-HF can be used as the data at Visit 1. The study treatment
will be dispensed upon confirmation of eligibility.
Patients will start on open-label LCZ696 at a dose that is equivalent to the last dose level (or
dose of other renin angiotensin aldosterone syste (RAAS) inhibitors if patient switched) taken
at the time of completing PARAGON-HF, but no higher than dose level 2 (Figure 1-1,
Table 1-1). The dose and regimen of background treatment medications should be maintained.
Every attempt should be made to up-titrate and maintain the patient at the maximum tolerated
LCZ696 dose with a target dose of 200 mg b.i.d. as soon as possible per the investigator’s
medical judgement taking into account AEs including potassium level, kidney function, blood
pressure (referred to Section 16.3 Appendix 3, Section 16.4 Appendix 4, and Section 16.5
Appendix 5 of protocol).
At Visit 102 (Week 2-4), patients who tolerate open-label LCZ696 should be up-titrated to the
next higher dose level by investigator judgement. If in the investigator's judgement, the patient
does not tolerate the treatment dose level, then investigator should try to modify background
medication in line with Section 6.5.1 of protocol in order to re-challenge the patient with a 
higher dose level


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at the earliest possible opportunity. Treatment guidelines for hyperkalemia, management of BP
and renal dysfunction are provided in Section 16.3 Appendix 3, Section 16.4 Appendix 4, and
Section 16.5 Appendix 5 of protocol.
The patient will continue to receive LCZ696 until it is commercially available, or for a period
up to 24 months from the first patient enrolled in this study, whichever comes first. If the
primary endpoint of PARAGON-HF is not met, the study will be terminated.
Figure 1-1
Study design
Dose level 3: LCZ696 200 mg b.i.d. or Valsartan 160 mg bid, Dose level 2: LCZ696 100 mg b.i.d. or Valsartan 80
mg b.i.d., Dose level 1: LCZ696 50 mg b.i.d. or Valsartan 40 mg b.i.d..
* patients receiving PARAGON-HF study drug at dose level 3 should start with LCZ696 100 mg (dose level 2) or
might start with LCZ696 50 mg bid (dose level 1) at the investigator’s discretion taking into account patient
condition.
** patients receiving PARAGON-HF study drug at dose level 2 have options to start with either the open-label
LCZ696 100 mg b.i.d. (dose level 2) or LCZ696 50 mg b.i.d. (dose level 1) at the investigator’s discretion.
*** incudes no treatment case.
**** If the primary endpoint of PARAGON-HF is not met, the study will be terminated.
1) Dosage should be up-titrated at Visit 102 (2-4w) if patient tolerates by investigator’s judgement taking into
account safety monitoring guidance, and follow the general protocol guidance regarding maintenance dose.
2) Dose adjustment is permitted during the study if the patient does not tolerat the assigned dose following the
general protocol guidance regarding maintenance dose.
3) Attempt should be made to up-titrate and maintain the patient at the target LCZ696 200 mg bid for as long as
possible.
Table 1-1
Study drug level at the start of the study
Final dose level of study medication of
PARAGON-HF
LCZ696
3* 
100 mg b.i.d.
2** 
50 mg b.i.d. or 100 mg b.i.d.
1
50 mg b.i.d.
No Treatment***
50 mg b.i.d.
* The patient receiving PARAGON-HF study drug at dose level 3 should start with LCZ696 100mg or might 
start with LCZ696 50 mg b.i.d. at the investigator’s discretion taking into account patient condition.
** The patient receiving PARAGON-HF study drug at dose level 2 has options to start with either LCZ696 100 
mg b.i.d. or LCZ696 50 mg b.i.d. at the investigator’s discretion.


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Final dose level of study medication of
PARAGON-HF
LCZ696
***Patients who finish the PARAGON-HF on no treatment and on an ACEI should observe a 36 hours ACEI-
free washout period as per Table 6-1 in the protocol. Patients might start from LCZ696 100mg b.i.d. at the 
investigator's discretion taking into account patient condition and current treatment (e.g. RAAS inhibitors)
1.2
Study objectives and endpoints
Table 1-2 presents the objectives and related endpoints
Table 1-2
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
To further evaluate the safety and tolerability 
of long-term treatment with LCZ696 in eligible 
HFpEF patients who completed PARAGON-
HF in Japan.
Endpoint(s) for primary objective(s)
All safety data, including vital signs, adverse 
events, are considered primary endpoints.
2
Statistical methods
The following section contain important information on detailed statistical methodology used 
for analysis and reporting purposes.
2.1
Data analysis general information
Unless otherwise specified, data will be analyzed by 
 according to the protocol for 
CLCZ696D1301E1, using SAS 9.4 or higher. Further details on planned statistical analyses will 
be presented in the following section and in CSR Appendix 16.1.9.
An established program level data monitoring committee (DMC) independent of Novartis that 
reviews safety data from LCZ696 studies will be used for this study. The DMC will review 
patient safety data in an unblinded manner approximately every six months and determine if it 
is safe to continue the study. Any major recommendation from the DMC will be communicated 
to the Executive Committee and must be reviewed and ratified by the Executive Committee in 
consultation with Novartis prior to its enactment.
In general, the continuous variables will be summarized using number of observations, mean, 
standard deviation, median, quartiles, minimum and maximum; the categorical variables will 
be summarized using frequencies and percentages.
The analysis will be conducted on all data at the end of trial.
2.1.1
General definitions
Baseline assessment and study day
Unless otherwise specified, the baseline assessment is defiend as below.

For safety variables, the baseline assessment is defined as the last non-missing assessment 
(scheduled or unscheduled) prior to or on the first dose date of the study drug.
In the listings, the study day will be displayed, as applicable.


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
In the listings of safety data, the study day is defined as the date of assessment 
(event/visit) minus the date of first dose plus one day, i.e., Day 1 is the first dose date.
Post-baseline assessment
Unless otherwise specified, for safety variables, the post-baseline assessments are defined as 
those assessments taken later than the first dose date of the study drug.
Unscheduled assessments
Unscheduled assessments will be included in over period minimum/maximum, and in over 
period shift table, but will not be included in by-visit summary and longitudinal modelling.
2.2
Analysis sets
The following analysis sets will be used for the statistical analyses.

Screened set (SCR) – All patients who signed the informed consent for
CLCZ696D1301E1

Safety set (SAF) – All patients who received at least one dose of study drug. Patients will 
be analyzed according to the treatment actually received. Patients without valid written 
informed consent will be excluded from safety set. 
Rules leading to exclusion from the analysis sets are given in section 5.2 of protocol
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Disposition for the screening epoch
The number and percentage of patients who completed the screening visit will be provided. 
Besides, the primary reason for not completing the screening visit will be summarized, using 
the number and percentage of patients not qualifying for such reasons. For any patient who was 
screened more than once, the data from the last screening will be used in the summary.
The SCR will be used for the above analyses.
Disposition for the study treatment
The numbers and percentages of patients who took at least one dose of the study drug, who 
completed the study treatment and who permanently discontinued from the study treatment will 
be provided for overall; the primary reason for permanent discontinuation from the study drug 
will be summarized for overall and, using the number and percentage of patients discontinued 
for such reasons.
The SAF will be used for the above analyses.


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Protocol deviations
The protocol deviations will be summarized for overall and protocol deviation category, using 
the numbers and percentages of patients with at least one protocol deviation within the protocol 
deviation category.
The SAF will be used for the above analyses.
Analysis set dispositions
The numbers and percentages of patients within each analysis set will be for overall.
In addition, the number and percentage of patients satisfying each criteria leading to exclusion 
from analysis sets will be provided for overall.
2.3.2
Background and demographic characteristics
For overall, summary statistics will be provided for demographics and baseline characteristics, 
including age, age group (< 65 years, ≥ 65 years), age group (< 75 years, ≥ 75 years), sex, region,
race, ethnicity, pulse rate, sitting pulse, sitting systolic blood pressure (SBP), and sitting 
diastolic blood pressure (DBP). If an above variable is scheduled at screening. Few parameters 
like height, weight and BMI for all the subjects will be taken from the screening visit of the 
CLCZ696D2301 study. Also parameters includes BMI group (<=30 (kg/m2), >30-<=35 
(kg/m2), >35 (kg/m2)), pulse pressure, eGFR, eGFR group (<60 mL/min/1.73m2, >=60 
mL/min/1.73m2) and MMSE total score will be taken from the CLCZ696D2301 study.
Continuous variables will be summarized using number of observations, mean, standard 
deviation, median, minimum, the first quartile (Q1), the third quartile (Q3), and maximum.
Categorical variables will be summarized using frequencies and percentages.
The SAF will be used for the above analyses.
2.3.3
Medical history
Any condition entered on the relevant medical history/current medical conditions CRF will be 
coded using the most updated version of MedDRA dictionary. Medical history will be collected 
only for patients with SAE. A listing of such patients will be provided.
The SAF will be used for the above analyses.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The study drug administration will be recorded on the CRF page: “Study Treatment” using start 
date, end date and dispensing level of the study drug. Each pair of start date and end date will 
be considered as a dosing interval.
For each patient, the dosing intervals will be sorted according to the start date and the end date 
from the earliest to the latest. It is expected that, for each patient, there should be no gaps and 
overlaps among dosing intervals, with the exception that, the end date of a dosing interval can 


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be the same as the start date of its next dosing interval, when the patient may take the previous 
dispensing level in the morning and start a different dispensing level in the evening.
For patients who permanently discontinue from the study treatment, the date of premature 
treatment discontinuation will be their study end date. 
For each dosing interval, the dispensing level of the study drug will be recorded together with 
the start date and end date. The dose level and the daily dose (mg/day) are defined based on the 
dispensing level according to Table 2-1.
Table 2-1
Dose levels and daily doses of the study drug
Dispensing
Level
Dose
Level
Dose                      Daily Dose
LCZ696
LCZ696
Dose level 1
1
50 mg bid.
100 mg/day
Dose level 2
2
100 mg bid.
200 mg/day
Dose level 3
3*
200 mg bid.
400 mg/day
*  This dose level should be attempted and maintained for as long as possible. If down-titration is necessary due 
to side effects, the patient should be re-challenged as soon as medically possible per the investigator’s judgement.
Dispensing level, dose level and daily dose at each visit
For a given visit, the visit associated dosing interval is defined as the dosing interval with its 
start date prior to or equal to the date of visit AND its end date later than or equal to the date of 
visit; the dispensing level, dose level and daily dose (mg/day) at the visit are defined as the 
dispensing level, dose level and daily dose (mg/day) for the visit associated dosing interval. In 
the case that, the visit date is equal to the end date of an earlier dosing interval as well as the 
start date of a later dosing interval, the later dosing interval will be taken as the visit associated 
dosing interval.
The dispensing level will be summarized by treatment and visit, for overall using the number 
and percentage of patients on each level; the dose level will be summarized by treatment and 
visit, using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum; the daily dose (mg/day) will be summarized by treatment and visit, using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum.
The SAF will be used for the above analyses.
Duration of treatment
This study will continue until marketed product is available in Japan, or approximately for 2
years from the date of the first patient enrolled, whichever comes first. Subjects may be
discontinued from treatment earlier due to unacceptable toxicity, disease progression and/or
treatment is discontinued at the discretion of the investigator or the subject.
The SAF will be used for the above analyses.


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Duration on each dose level
For a given dose level, the duration (day) on this dose level is defined as the number of days on 
this dose level during the period from the date of the first dose of the study drug to the date of 
the last dose of the study drug. In the case that, the end date of an earlier dosing interval is the 
same as the start date of a later dosing interval, the day will be counted as 0.5 day on both the 
earlier dose level and the later dose level. In the case that, the date of permanent discontinuation 
of the study drug is the same as the date of the last dose the study drug, the day will be counted 
as 0.5 day on the dose level of the last dose but not counted on dose level 0.
The duration (week) will be converted from the duration (day) using a factor of 7 day/week, 
and will be summarized by overall.
The SAF will be used for the above analyses.
Duration of study drug exposure
The duration (day) of study drug exposure is defined as the sum of the duration (day) on dose 
level 1 to 3, excluding interruptions.
The duration (week) of study drug exposure will be converted from the duration (day) of study 
drug exposure using a factor of 7 day/week, and will be summarized by treatment, overall using
number of observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum.
The duration (week) of study drug exposure will be categorized into the following categories.

< 4 weeks

4 weeks to < 8 weeks

8 weeks to < 16 weeks

16 weeks to < 32 weeks

32 weeks to < 52 weeks (12 months)

≥52 weeks (12 months)
The categorized duration of study drug exposure will be summarized by treatment, using the 
number and percentage of patients within each category.
The SAF will be used for the above analyses.
Percentage of study drug exposure
For each patient, the percentage of study drug exposure is defined as the percentage of the 
duration (day) of study drug exposure out of the duration (day) of treatment.
The percentage of study drug exposure will be summarized by treatment, using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum.
The SAF will be used for the above analyses.


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Study treatment permanent discontinuation at each visit
For a given visit, a patient is considerred as permanently discontinued from the study treatment 
at this visit, if the patient permanently discontinued from the study treatment prior to or on the 
date of this visit.
For overall, the number and percentage of patients who permanently discontinued from the 
study treatment will be provided for each scheduled visit in the treatment period.
Mean daily dose and mean dose level
Mean daily dose and mean daily dose level for each patient will be computed as follows.
Mean daily dose (mg) = 

(	
    
 

 )×(
 

  )


	
    
  


Mean daily dose level = 

(	
    
 

 )× 


	
    
  


Frequency and percentage of patients at each dose level will be summarized by visit.
The SAF will be used for the above analyses.
Duration of study exposure
The duration (day) of study exposure is defined as the date of last visit minus the date of 
randomization plus one day.
The duration (week) of study exposure will be derived from the duration (day) of study exposure 
using a factor of 7 day/week, and will be summarized by treatment, using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum.
The duration (week) of study exposure will be categorized into the following categories.

< 4 weeks

4 weeks to < 8 weeks

8 weeks to < 16 weeks

16 weeks to < 32 weeks

32 weeks to < 52 weeks (12 months)

≥52 weeks (12 months)
The categorized duration of study exposure will be summarized by treatment, using the number 
and percentage of patients within each category.
The SAF will be used for the above analyses.
Last recorded dose level
The last recorded dose level is defined as the dose level for the last dosing interval.
The last recorded dose level will be summarized by treatment, using the number and percentage
of patients on each dose level.


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The SAF will be used for the above analyses.
Dose down-titration
A down-titration dosing interval is defined as a dosing interval whose dose level is changed to 
a lower dose level from its previous dosing interval.
The dose down-titration will be summarized by treatment, using the number and percentage of 
patients with at least one down-titration dosing interval.
The SAF will be used for the above analyses.
Dose interruption
A dose-interruption dosing interval is defined as a dosing interval whose dose level is 0.
The number and percentage of patients with at least one dose-interruption dosing interval will 
be provided by treatment.
The duration of dose interruption is defined as the sum of (the end date minus the start date plus 
one day) among all dose-interruption dosing intervals.
The number and percent of patients will be summarize by treatment interruption episodes such 
as none, at least once interruption.
The SAF will be used for the above analyses.
2.4.2
Prior and concomitant therapies
Prior and concomitant medications will be recorded on the CRF page: “Prior and Concomitant 
Medications”. Procedures and significant non-drug therapies (prior and concomitant) will be 
recorded on the CRF page “Surgical and Medical Procedures”.
The missing or partially missing start/end date for prior/concomitant therapies will be imputed 
based on the Novartis ADaM Governance Board (AGB) global standards.
Prior and concomitant medications/non-drug therapies will be identified based on recorded or
imputed start dates and end dates.
Prior medications are defined as any recorded medication with its start date (recorded or 
imputed) prior to the date of the first dose of the study drug.
Concomitant medications are defined as any recorded medication with its end date (recorded or 
imputed) later than or equal to the date of the first dose of the study drug AND its start date 
(recorded or imputed) prior to or equal to the end date of the study.
Prior non-drug therapies are defined as any procedure/significant non-drug therapy with its start 
date (recorded or imputed) prior to the date of the first dose of the study drug.
Concomitant non-drug therapies are defined as any recorded procedure/significant non-drug 
therapy with its end date (recorded or imputed) later than or equal to the date of the first dose 
of the study drug AND its start date (recorded or imputed) prior to or equal to the end date of 
the study.


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For overall, prior and concomitant medications will be summarized separately by treatment, 
anatomical therapeutic classification (ATC) and PT; prior and concomitant non-drug therapies 
will be summarized separately for overall, SOC, PT.
The SAF will be used for the above analyses.
2.5
Analysis of the primary objective
2.5.1
Primary endpoints
The primary endpoints for this study includes all safety data (adverse events and vital signs).
No statistical analyses for primary endpoints will be done and summaries for adverse events 
and serious adverse events will be provided as appropriate.
The incidence of treatment-emergent AEs (new or worsened) will be summarized by primary 
system organ class, preferred term, severity, and relationship to study drug. In addition, the 
incidence of death, SAEs, and AEs leading to discontinuation will be summarized separately 
by primary system organ class and preferred term.
Additional details regarding safety analysis are included in Section 2.7.
For patients who permanently discontinue from study treatment, assessment values collected 
after permanent discontinuation will generally be included in the analysis.
SAF will be used for analysis of primary endpoints.
2.5.2
Statistical hypothesis, model, and method of analysis
There will be no formal statistical inferential analysis.
2.5.3
Handling of missing values/censoring/discontinuations
There will be no imputation done on any parameter/variable in this study.
2.5.4
Supportive and sensitivity analyses
No additional sensitivity/supportive analysis will be performed for this study.
2.6
Analysis of secondary efficacy objective(s)
Not applicable.
2.7
Safety analyses
The SAF will be used for all safety analyses.
2.7.1
Adverse events (AEs)
All AEs will be recorded on the CRF page “Adverse Events” and be identified using Medical 
Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for reporting the 
study will be described in a footnote.
An AE with its severity increased should be considered and recorded as a new AE.


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The missing or partially missing start/end date for AEs will be imputed based on the Novartis 
AGB global standards.
Treatment emergent adverse events (TEAEs) are defined as any recorded AE with its start date 
(recorded or imputed) later than or equal to the date of the first dose of the study drug.
Study drug related AEs are defined as any recorded AE with “Relationship to study treatment” 
answered as “RELATED”.
AEs leading to permanent discontinuation of study treatment are defined as any recorded AE 
with “Action taken with study treatment” answered as “DRUG WITHDRAWN”.
AEs leading to dose adjustment or temporarily interruption of study treatment are defined as 
any recorded AE with “Action taken with study treatment” answered as “DOSE REDUCED”, 
“DOSE INCREASED” or “DRUG INTERRUPTED”.
Most common TEAEs are defined as any recorded TEAE corresponding to a PT.
SAEs are defined as any recorded AE with “Was the adverse event serious” answered as “Yes”.
The following rules are applicable to the summaries.

If a patient reported more than one AE with the same PT, the patient will be counted only 
once with the greatest severity at the PT level

If a patient reported more than one AE within the same SOC, the patient will be counted 
only once with the greatest severity at the SOC level, where applicable.
The following summaries will be performed.

TEAEs will be summariesed for overall by primary SOC and PT. Additional summaries 
along with maximum severity will be produced.

Study drug related TEAEs will be summariesed for overall by primary SOC and PT. 

TEAEs leading to treatment discontinuation will be summariesed for overall by primary 
SOC and PT. 

TEAEs leading to dose adjustment or temporarily interruption of study treatment will be 
summariesed for overall by primary SOC and PT. 

Most common TEAEs will be summariesed for overall by primary SOC and PT. 

Treatment emergent SAEs (TESAEs) will be summariesed for overall by primary SOC 
and PT. 

Most common TESAEs will be summariesed for overall by primary SOC and PT.

Study drug related TESAEs will be summariesed for overall by primary SOC and PT. 
The SAF will be used for the above analyses.
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for the are store 
in the LCZ696 Case Retrieval Strategy.
The following standard analyses will be applied to all risks.


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
Numbers and percentages of patients with any TEAE within the risk name (or SOC/PT 
within risk name) will be provided for dose level and overall by risk name, SOC, PT and 
maximum severity.

Exposure adjusted incidence rates per 100 patient-years for TEAEs within the risk name 
will be provided for dose level and overall by risk name.

Listing of patients numbers per risk.
2.7.1.1
Adverse events of special interest / grouping of AEs
AEs of special interest will also be summarized. AEs of special interest and their further 
specified events include the followings.
Hypotension

SBP <90 mmHg

SBP decline by ≥30 mmHg

Simultaneous SBP <90 mmHg and SBP decline by ≥30 mmHg
Angioedema (adjudicated)

No treatment or antihistamines only

Treated with catecholamines or steroids

Hospitalized but no mechanical airway protection, without airway compromise

Hospitalized but no mechanical airway protection, with airway compromise

Mechanical airway protection or death from airway compromise
Drug-related hepatic disorders

all preferred terms listed in the Standardized Med-DRA Query(SMQ) module 
“drugrelated hepatic disorders – comprehensive search SMQ code 20000006 - broad 
search”
Cough
Summary tables that summarize the numbers and percentages of subjects experienced the
above events at least once during study will be presented by event or SMQ (when drug-related 
hepatic disorders). 
Summary tables that summarize the numbers and percentages of subjects experienced the
above events at least once throughout the study will be presented by event or SMQ (when 
drug-related hepatic disorders).
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for 
hypotension, hyperkalaemia, renal impairment and cough are stored in the latest LCZ696 
Case Retrieval Strategy (CREDI directory: /CREDI Projects/L/LCZ696A/Integrated Medical 
Safety)).


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Numbers and percentages of subjects with adjudicated angioedema events with the
adjudicated maximum severity and angioedema-like (i.e. investigator-reported) events will be 
presented.
2.7.2
Death
Death and primary cause of death (reported as SAE) will be reported by the investigator.
The investigator reported death and primary cause of death will be recorded on the CRF page: 
“SAE_Death Information”.
Any finding determined by AUTOPSY will also be reported and recorded in description of the 
event CRF page.
The investigator reported death and primary cause of death will be summarized for overall,
using the number and percentage of patients who died, as well as the numbers and percentages 
of patients whose primary cause of death is in each category.
The SAF will be used for the above analyses.
2.7.3
Laboratory data
2.7.3.1
General laboratory data
Laboratory evaluations serum potassium and creatinine will be performed locally every visit.  
Additional laboratory evaluation should be performed by Investigator's judgement. Laboratory 
assessments will be analyzed locally during the study. 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. The laboratory results are not 
collected in this study. If abnormal laboratory values fulfill the AE criteria (protocol section 
10.1.1), the investigator should report the labolatory values as AE.
2.7.3.2
Vital signs
Vital signs (BP [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] and pulse
will be summarized by parameter, for overall , using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum, including changes from baseline. By-
visit summary will only include scheduled assessments.
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
The SAF will be used for the above analyses.


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2.8
Pharmacokinetic endpoints
Not applicable.
2.9
PD and PK/PD analyses
Not applicable.
2.10
Patient-reported outcomes
Not applicable
2.11
Biomarkers
Not applicable
2.12
Other Exploratory analyses
Not applicable.
2.13
Interim analysis
No formal interim efficacy analysis is planned.
3
Sample size calculation
The study population will consist of Japanese patients who completed PARAGON-HF. It is 
anticipated that approximately 70 patients will survive to the end of PARAGON-HF, of which 
approximately 80% are anticipated to enrol into this study.
4
Change to protocol specified analyses
No change from protocol.
5
Appendix
5.1
Imputation rules
The missing or partially missing start/end date for AEs and prior/concomitant therapies will be 
imputed based on the Novartis AGB global standards. Details will be provided in the study PDS.
6
Reference