Conditions: Heart Failure
Keywords: heart failure pediatric LCZ696 sacubitril/valsartan open-label study angiotensin receptor neprilysin inhibitor PANORAMA-HF
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 216
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate long-term safety and tolerability and to provide post-trial access to sacubitril/valsartan to eligible participants who successfully completed CLCZ696B2319 (PANORAMA-HF) core study Part 2 as per protocol.

Detailed description:
This was a multicenter, open-label long-term extension study for participants who successfully completed PANORAMA-HF core study Part 2 of the trial or who discontinued study drug treatment early in Part 2 due to the implementation of Urgent safety measure (USM) of PANORAMA-HF core study. Provided that they fulfilled the protocol requirements, these patients were eligible to participate in the OLE. Depending on when and where the participant was enrolled, the duration of the study was of a minimum of 1 year, or until receipt of local marketing authorization and commercial availability, or reaching the maximum limit allowed by local regulations, or until Dec-2023, whichever occurred first.

Arms:
arm 1: single arm, open label sacubitril/valsartan

Interventions: intervention 1: sacubitril/valsartan
Intervention descriptions: intervention 1: Target dose 3.1 mg/kg bid

Formulations:

Tablets (50, 100, 200 mg) Granules \[12.5 mg (4 granules), 31.25 mg (10 granules), in capsules\] Liquid (1 mg/ml, 4 mg/ml, prepared from tablets)

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
Sacubitril/Valsartan
Clinical Trial Protocol CLCZ696B2319E1 / NCT03785405
A multicenter study to evaluate long-term safety and 
tolerability of open label sacubitril/valsartan in pediatric 
patients with heart failure due to systemic left ventricle 
systolic dysfunction who have completed study 
CLCZ696B2319
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2018-004154-25
Version number:
02 (clean)
Clinical trial phase:
3b
Release date:
30-Nov-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 (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
Amendment 2 ....................................................................................................................10
Amendment 1 ....................................................................................................................11
Protocol summary..............................................................................................................14
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................18
2
Objectives and endpoints...................................................................................................18
3
Study design ......................................................................................................................19
4
Rationale............................................................................................................................22
4.1
Rationale for study design .....................................................................................22
4.2
Rationale for dose/regimen and duration of treatment ..........................................22
4.3
Rationale for choice of control drugs ....................................................................23
4.4
Purpose and timing of interim analyses/design adaptations..................................23
4.5
Risks and benefits..................................................................................................23
4.6
Rationale for Public Health Emergency mitigation procedures ............................24
5
Population..........................................................................................................................24
5.1
Inclusion criteria ....................................................................................................24
5.2
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................26
6.1
Study treatment......................................................................................................26
6.1.1
Investigational and control drugs..........................................................26
6.1.2
Additional study treatments ..................................................................27
6.1.3
Treatment arms/group ...........................................................................27
6.1.4
Treatment duration................................................................................27
6.2
Other treatment(s)..................................................................................................27
6.2.1
Concomitant therapy.............................................................................27
6.2.2
Prohibited medication ...........................................................................29
6.2.3
Rescue medication ................................................................................29
6.3
Subject numbering and treatment assignment.......................................................29
6.3.1
Subject numbering ................................................................................29


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6.3.2
Treatment assignment ...........................................................................30
6.4
Treatment blinding.................................................................................................30
6.5
Dose escalation and dose modification..................................................................30
6.5.1
Dose modifications................................................................................30
6.6
Additional treatment guidance...............................................................................32
6.6.1
Treatment compliance...........................................................................32
6.6.2
Emergency breaking of assigned treatment code..................................32
6.7
Preparation and dispensation.................................................................................32
6.7.1
Handling of study treatment and additional treatment..........................33
6.7.2
Instruction for prescribing and taking study treatment .........................33
7
Informed consent procedures ............................................................................................34
8
Visit schedule and assessments .........................................................................................35
8.1
Screening ...............................................................................................................41
8.1.1
Information to be collected on screening failures.................................41
8.2
Subject demographics/other baseline characteristics.............................................42
8.3
Efficacy..................................................................................................................42
8.4
Safety/Tolerability.................................................................................................42
8.4.1
Laboratory evaluations..........................................................................43
8.4.2
Pregnancy and assessments of fertility .................................................45
8.4.3
Other safety evaluations........................................................................47
8.4.4
Appropriateness of safety measurements..............................................47
8.5
Additional assessments..........................................................................................47
9
Study discontinuation and completion ..............................................................................48
9.1
Discontinuation......................................................................................................48
9.1.1
Discontinuation of study treatment .......................................................48
9.1.2
Withdrawal of informed consent...........................................................48
9.1.3
Lost to follow-up...................................................................................49
9.1.4
Early study termination by the sponsor.................................................49
9.2
Study completion and post-study treatment ..........................................................50
10 Safety monitoring and reporting........................................................................................50
10.1
Definition of adverse events and reporting requirements......................................50
10.1.1
Adverse events ......................................................................................50
10.1.2
Serious adverse events ..........................................................................51
10.1.3
SAE reporting........................................................................................52
10.1.4
Pregnancy reporting ..............................................................................53
10.1.5
Reporting of study treatment errors including misuse/abuse................54


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10.2
Additional Safety Monitoring................................................................................54
10.2.1
Liver safety monitoring.........................................................................54
10.2.2
Renal safety monitoring........................................................................56
10.2.3
Angioedema Adjudication committee...................................................56
11 Data collection and database management........................................................................57
11.1
Data collection.......................................................................................................57
11.2
Database management and quality control............................................................57
11.3
Site monitoring ......................................................................................................57
12 Data analysis and statistical methods ................................................................................58
12.1
Analysis sets ..........................................................................................................58
12.2
Subject demographics and other baseline characteristics......................................58
12.3
Treatments .............................................................................................................59
12.4
Analysis of the primary endpoint(s) ......................................................................59
12.4.1
Definition of primary endpoint(s).........................................................60
12.5
Analysis of secondary endpoints ...........................................................................60
12.6
Analysis of exploratory endpoints.........................................................................60
12.7
Interim analyses.....................................................................................................60
12.8
Sample size calculation..........................................................................................60
12.8.1
Primary endpoint(s)...............................................................................60
12.8.2
Secondary endpoint(s)...........................................................................60
13 Ethical considerations and administrative procedures ......................................................60
13.1
Regulatory and ethical compliance........................................................................60
13.2
Responsibilities of the investigator and IRB/IEC..................................................60
13.3
Publication of study protocol and results...............................................................61
13.4
Quality Control and Quality Assurance.................................................................61
14 Protocol adherence ............................................................................................................61
14.1
Protocol amendments.............................................................................................62
15 References .........................................................................................................................63
16 Appendices ........................................................................................................................64
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................64
16.2
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ..........................................................................................................66
16.3
Appendix 3: Specific renal alert criteria and actions.............................................69
16.4
Appendix 4: Guidelines for the management of renal dysfunction.......................71
16.5
Appendix 5: American heart association (AHA) pediatric advanced life 
support (PALS) guidelines ....................................................................................72
16.6
Appendix 6: Guidelines for the management of blood pressure ...........................74


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16.7
Appendix 7: Treatment guidelines for elevated potassium and hyperkalemia 
(serum potassium ≥ 5.3 mmol/L)...........................................................................75
16.8
Appendix 8: Reference table – blood volume by weight ......................................77
List of tables
Table 2-1
Objectives and related endpoints ..........................................................18
Table 3-1
Safety monitoring criteria for initiation/up-titration of study drug.......20
Table 3-2
Study drug dose levels for sacubitril/valsartan .....................................20
Table 3-3
Total daily dose levels of commonly prescribed ACEI/ARBs for 
the purpose of comparing to dose levels of study drug.........................21
Table 6-1
Open-label sacubitril/valsartan formulations ........................................26
Table 6-2
Prohibited medications..........................................................................29
Table 8-1
Assessment Schedule ............................................................................37
Table 8-2
Physical Assessments............................................................................43
Table 8-3
Laboratory Assessments........................................................................45
Table 10-1
Events commonly seen in study population..........................................53
Table 10-2
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 16-1
Clinically notable laboratory values......................................................64
Table 16-2
Criteria for clinically notable vital signs...............................................65
Table 16-3
Liver event and laboratory trigger definitions ......................................66
Table 16-4
Follow-up requirements for liver events and laboratory triggers..........66
Table 16-5
Specific renal alert criteria and actions.................................................69
Table 16-6
GFR by age for initiation/up-titration and exclusion criteria................70
Table 16-7
5th percentile systolic blood pressure (SBP) table.................................72
Table 16-8
Reference table – blood collection volumes by body weight (kg)........77
List of figures
Figure 3-1
Study Design .........................................................................................22


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List of abbreviations
ACEI
Angiotensin Converting Enzyme (inhibitor)
AE
Adverse Event
Alb
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ARB
Angiotensin Receptor Blocker
ARNI
Angiotensin Receptor Neprilysin Inhibitor 
AST
Aspartate Aminotransferase
AT1
Angiotensin Type 1
bid
bis in die/twice a day
BUN
Blood Urea Nitrogen
CCB
Calcium Channel Blocker
CHBP
Child Bearing Potential Females
CHF
Chronic Heart Failure
CMO
Chief Medical Office
CMV
Cytomegalovirus
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTT
Clinical Trial Team
CV
Cardiovascular
DAR
Dosage Administration Record
DBP
Diastolic Blood Pressure
EBV
Epstein-Barr virus
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EMA
EoS
European Medicines Agency
End of Study
eSource
Electronic Source
EU
European Union
FDA
Food and Drug Administration
FPFV
First Patient First Visit
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HF
Heart Failure
HFrEF
HF with Reduced Ejection Fraction
HSV
Herpes Simplex Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio


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IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
LFT
Liver function test 
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Regulatory Activities 
MRP2
Multidrug resistance protein 2
NEP
Neprilysin
NSAID
Non-steroidal Anti-Inflammatory Drug
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PS
Patient Safety
PSD
Premature Subject Discontinuation
PT
Prothrombin Time
OLE
Open Label Extension
QMS
Quality Management System
RBC
Red Blood Cell(S)
RoW 
Rest of World
RRR
Relative Risk Reduction
R Value
ALT/ALP ×ULN
SAE
Serious Adverse Event
SAF
Safety Set
SBP
Systolic Blood Pressure
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOPs
Standard Operating Procedures
STD
Study Treatment Discontinuation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total Bilirubin
TEAE
Treatment- Emergent Adverse Event
ULN
Upper Limit of Normal
USM
UTI
Urgent safety measure 
Urinary Tract Infection 
WBC
White Blood Cell(S)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Biological Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject 
Cohort
A specific group of subjects fulfilling certain criteria and generally treated at the 
same time
Control drug
A study drug (active or placebo) 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)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the use of 
Electronic Case Report Forms (eCRFs) which are used to capture data transcribed 
from paper source forms used at the point of care
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last subject or at a later 
point in time as defined by the protocol
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained 
Investigational drug/
treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in subjects with established disease and in those with newly-
diagnosed disease
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in 
clinical trial database setup and eventually in analysis
Personal data
Subject information collected by the investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples. 
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion of 
all study drug administration and/or assessments; at this time all study drug 
administration is discontinued and no further assessments are planned
Randomization number
A unique identifier assigned to each randomized subject
Screen Failure
A subject who did not meet one or more criteria that were required for participation 
in the study
Source Data/Document
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or even 
hard-coded data, such as paper or an electronic source (eSource).
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed consent by 
the first subject


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Study treatment
Any single drug or combination of drugs or intervention administered to the subject 
as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also 
be the point/time of study discontinuation 
Subject
A trial participant (can be 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.
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of 
personal data 


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Amended Clinical Trial Protocol Version 02 (Clean) 
Protocol No. CLCZ696B2319E1
Amendment 2
Amendment rationale 
This is the second amendment to the protocol. 
On 26-Oct-2021, an urgent safety measure (USM) was implemented by Novartis in the 
PANORAMA-HF study (CLCZ696B2319). 
As a result, not all the patients were on study drug treatment at PANORAMA-HF Part 2 End of 
Study visit (Visit 416). The purpose of the second protocol amendment is to amend the inclusion 
and exclusion criteria to allow patients impacted by the USM to enroll into this open-label 
extension (OLE) study.
Changes to the protocol
The following changes have been implemented in the protocol and protocol summary: 
1. Section 5.1 Inclusion criteria#2: Patient was on study medication at the PANORAMA-HF 
Part 2 End of Study visit (Visit 416) or discontinued study drug treatment early due to the 
implementation of the USM and does not have any significant safety issue as determined 
by the investigator.  Based on the investigator judgement, the patient is able to safely enroll 
in the OLE study.
2. Section 5.2 Exclusion criteria#1: Patient who only participated in Part 1 of the 
PANORAMA-HF study or was a screen failure in PANORAMA-HF or permanently 
discontinued study drug in Part 2 of the PANORAMA-HF study for reasons other than the 
implementation of the USM.
3. Section 3, Section 5 and Table 8-1 were updated accordingly.
4. Section 8.1 clarified that the use complete lab results from Visit 416 of PANORAMA-HF 
for Visit 500 screening assessment would not be applicable to patients who discontinued 
study drug treatment early due to the implementation of the USM. 
5. Section 10.1.3 updated SAE reporting language per recent Health Authority Requirement 
in Germany. 
6. Updates have been made to the List of abbreviations. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, if applicable.


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Amended Clinical Trial Protocol Version 02 (Clean) 
Protocol No. CLCZ696B2319E1
Amendment 1
Amendment rationale 
This is the first amendment to the protocol. The primary purpose of the current protocol 
amendment is to extend the duration of the study. The current duration of the original protocol 
is expected to end as early as May-2022 and no later than Dec-2022. In this amendment the 
duration of the study is extended to ensure that study patients continue to receive age-
appropriate study drug treatment (especially those requiring the pediatric formulations not 
currently available outside investigational use) and safety follow-up until the expected time 
when pediatric use of sacubitril/valsartan receives local marketing authorization and becomes 
commercially available to patients. 
First patient first visit of this open-label extension (OLE) study occurred on 02-May-2019. As 
of 31-Jul-2021, 178 patients have been screened and 173 patients have been enrolled into this 
study.
Major changes to the protocol
The following changes have been implemented throughout the protocol: 

The duration of the study is extended to 2 years from last patient last visit (LPLV) of 
part 2 of the PANORAMA-HF core study (i.e., until approximately Dec-2023), receipt 
of local marketing authorization and commercial availability, or reaching the maximum 
limit allowed by local regulations, whichever occurs first (Section 4.2, Section 6.1.4, 
Table 8-1, and other places of the protocol).

In countries where the sacubitril/valsartan is already authorized for pediatric use (e.g., 
the United States), patients may participate in the study for up to 1 year before being 
transitioned to commercially available product. If the formulation the patient is taking 
is not yet commercially available at the end of 1 year, the patient may continue in the 
study until the formulation becomes commercially available or until the maximum limit 
allowed by local regulations or until Dec-2023, whichever occurs first (Section 4.2, 
Section 6.1.4, and other places of the protocol)

Clarification was added that the study may also be terminated prematurely if the results 
of the core study does not support local registration (Section 9.1.4).
Other changes to the protocol are:

The purpose of this study was updated by adding “to provide post-trial access to 
sacubitril/valsartan to eligible CLCZ696B2319 (PANORAMA-HF) patients” (Section 
1.2).

The phase of the study has been corrected from “2b” to “3” in protocol summary and 
Section 3.

A 30-day window from the PANORAMA-HF core study Visit 416 [End of study 
(EOS)]to the initiation of study treatment of this OLE study (Visit 501) was defined to 
ensure minimal change in health status of these patients roll-over to the OLE study 
(Section 3 and Section 8.1).


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
Study design Figure 3-1 was updated to clarify that there is no additional up-titration 
step after Dose level 4. Additional visit schedules were added to reflect change of the 
duration of the study.

Maximum study duration for patients in Germany was updated to 4 (Section 4.2).

Section 4.6 was added to include the disruption proofing aspects with respect to study 
procedures in case of a public health emergency per new Novartis guidelines. Section 7
and Section 8 included this change accordingly.

Clarification that the complete laboratory assessment at screening (Visit 500) should be 
conducted to assess eligibility. To reduce the burden to the patients, when Visit 500 is 
conducted within 14 days from the core study Visit 416 and when Visit 416 laboratory 
results are available at the time of Visit 500, Visit 416 laboratory assessments can be 
used to evaluate the OLE screening criteria instead of obtaining additional screening 
laboratory assessments at Visit 500 (Section 8.1 and Table 8-1).

Clarification that Visit 501 is the visit for first drug administration. Abbreviated local 
lab may be performed at Visit 501 per the investigator’s clinical judgement (e.g., if it is 
believed that the patient’s health status may have changed since the screening visit
laboratory tests were performed) (Section 8.1 and Table 8-1).

Clarification that the baseline laboratory assessments is the complete lab performed at 
screening (Visit 500), not the abbreviated lab performed at Visit 501 (Table 8-1 and 
other places of the protocol).

Considering the rapid growth in pediatric patients, additional height measurements at 6-
month intervals will be recorded in the source documents (Table 8-1). Statement was 
added for standing height measurement using a stadiometer in stocking feet (Table 8-2).

Clarification that if the study drug treatment is permanently discontinued, the patient 
should be discontinued from the entire study (Section 6.5.1 and Section 9.1.1). 

In Section 10.2.2 the guidance statements for renal safety monitoring were removed
since the renal safety monitoring guidance detailed in Appendix 3 are considered 
sufficient for the purposes of this study.

Clarification was added in Appendix 3 that the most recently available height should be 
used for eGFR calculation. The modified Schwartz formula was added for calculation 
of estimated glomerular filtration rate (eGFR) for patients < 18 years of age.

Table 16-2 criteria for clinically notable vital signs for age groups less than 1 year, which 
is not applicable to this study, was removed.

Miscellaneous changes were made to clarify some study procedures and details, to 
remove redundant text, and to correct typographical errors, and inconsistencies in the 
protocol.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs


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Amended Clinical Trial Protocol Version 02 (Clean) 
Protocol No. CLCZ696B2319E1
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, if applicable.
The changes herein are also reflected in the Informed Consent.


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Protocol summary
Protocol
CLCZ696B2319E1
Full Title
A multicenter study to evaluate long-term safety and tolerability of open-label 
sacubitril/valsartan in pediatric patients with heart failure due to systemic left 
ventricle systolic dysfunction who have completed study CLCZ696B2319
Brief Title
CLCZ696B2319E1 open-label extension (OLE) study to evaluate long-term 
safety and tolerability of sacubitril/valsartan in pediatric patients with heart 
failure
Sponsor and 
Clinical Phase
Novartis; Phase 3b
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate long-term safety and tolerability data
and to provide post-trial access to sacubitril/valsartan to eligible 
CLCZ696B2319 (PANORAMA-HF) patients receiving open-label 
sacubitril/valsartan. The rationale of providing post-trial access is to provide 
uninterrupted access to the study medication to patients until the medication 
can be obtained commercially.
Primary 
Objective(s)
The primary objective is to evaluate safety and tolerability of
sacubitril/valsartan in eligible PANORAMA-HF subjects receiving open-label 
sacubitril/valsartan.
Secondary 
Objectives
There are no secondary objectives for this study
Study design
This trial is a multicenter, open-label long-term study for subjects who have 
successfully completed Part 2 of the PANORAMA-HF trial. Subjects who 
successfully completed the 52-week randomized double-blind, treatment 
period of PANORAMA-HF (i.e. on dose level 1 or higher at the PANORAMA-
HF End of Study visit) and are eligible for the Open-Label Extension (OLE) or 
who discontinued study drug treatment early in Part 2 due to the 
implementation of USM of PANORAMA-HF, according to the protocol and in 
the opinion of the investigator, will be offered the option to initiate treatment 
with sacubitril/valsartan by enrolling into this study (CLCZ696B2319E1). For 
all consenting subjects eligibility for the OLE will be assessed at the 
Screening visit (Visit 500). During the study, visits to assess safety will be 
conducted at Visit 501 and at 3-month intervals until the conclusion of the 
study (except for Visits 502, 503, 504 and 505 for the up-titration steps, which 
are at 2-week intervals). 
Population
Study population consists of pediatric Heart Failure (HF) patients ≥ 13 
months, in-patients or outpatients. Subjects will be divided into two age 
groups (Age Group 1: 6 years and older; Age Group 2: 1 to < 6 years old). All 
patients who safely tolerated study drug in PANORAMA-HF, as defined by 
the Inclusion/Exclusion criteria for the OLE, can be considered for eligibility in 
this open-label study.
Key Inclusion 
criteria

Signed informed consent as well as assent at an appropriate age 
based on country regulations must be obtained prior to participation 
in the study.


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
Patient was on study medication at the PANORAMA-HF Part 2 End 
of Study visit (Visit 416) or discontinued study drug treatment early 
due to the implementation of the urgent safety measure (USM) and 
does not have any significant safety issue as determined by the 
investigator. Based on the investigator judgement, the patient is able 
to safely enroll in the OLE study.
Key Exclusion 
criteria

Patient who only participated in Part 1 of the PANORAMA-HF study 
or was a screen failure in PANORAMA-HF or permanently 
discontinued study drug in Part 2 of the PANORMA-HF study for 
reasons other than the implementation of the USM.

Use of investigational drugs within 5 half-lives of enrollment or within 
30 days whichever is longer; or longer if required by local regulations 
– with the exception of PANORAMA –HF study drug. For 
PANORAMA-HF study drug (sacubitril/valsartan/placebo; 
enalapril/placebo), a minimum of 36-hour washout period is required 
before the initiation of study medication visit (Visit 501).

History of hypersensitivity or allergy to any of the study treatments or 
its excipients or to drugs of similar chemical classes, Angiotensin 
Converting Enzyme (inhibitor) (ACEIs), Angiotensin Receptor 
Blockers (ARBs), or Neprilysin (NEP) inhibitors as well as known or 
suspected contraindications to sacubitril/valsartan.

Renal vascular hypertension (including renal artery stenosis).

Patients with significant renal estimated glomerular filtration rate 
(eGFR calculated using the modified Schwartz formula < 30% mean 
GFR for age, Appendix 3, Table 16-6); hepatic (serum aspartate 
aminotransferase or alanine aminotransferase > 3 times upper limit 
of normal); gastrointestinal or biliary disorders (that could impair 
absorption, metabolism, or excretion of orally administered 
medications).

Patients with a history of angioedema.

Patients who have parents or legal guardians who do not give 
consent or allow the child to give assent, or inability of the patient or 
the parents/legal guardians to follow instructions or comply with 
follow-up procedures.

Any medical condition(s) that may put the patient at risk in the 
investigator’s opinion, or that the investigator deems unsuitable for 
the study.
Study treatment
Sacubitril/valsartan
Efficacy 
assessments
There will be no efficacy assessments in this study.
Key safety 
assessments
Adverse Events (AEs), Serious Adverse Events (SAEs), laboratory values, 
vital signs, and duration of exposure
Data analysis
The primary safety assessment will be based on adverse events, which will 
be analyzed using frequencies and percentages. Summary statistics will be 
provided for each age group and overall for demographics and baseline 
characteristics, including age, age group (only for overall), sex, race, 
ethnicity, weight, height, vital signs. Continuous variables will be summarized 
using n, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized using frequencies and percentages. 
Relevant medical histories will be summarized, by system organ class and 


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preferred term, for overall and for each age group. The Safety Set (SAF) will 
be used for the above analyses.
Key words
Pediatric, LCZ696, sacubitril/valsartan, heart failure, open-label study,
angiotensin receptor neprilysin inhibitor (ARNI)


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1
Introduction
1.1
Background
Pediatric heart failure (HF) is characterized by significant morbidity and mortality, frequent 
hospitalization and medical care, and poor quality of life. It is estimated that between 12,000 to 
35,000 children below age 19 are diagnosed with HF in the United States (US) each year (Hsu 
and Pearson 2009). Congenital heart disease and cardiomyopathy are the two most common 
causes of pediatric HF (Sharma et al 2003, Andrews et al 2008). HF can develop or exacerbate 
in childhood, during adolescence and later in adulthood as made evident by the growing number 
of adults with congenital heart disease.
The clinical course and outcome for pediatric HF depends on the etiology. For congenital heart 
disease, corrective surgery will have a major impact on the clinical course. Following congenital 
heart surgery, HF can still develop for a number of reasons including myocardial systolic 
dysfunction.
Many pediatric patients with severe HF are usually listed for heart transplant if available; 
however, cardiac transplantation is usually a last resort given the limited availability of donor 
organs, complicated clinical course management and associated morbidity and mortality. In the 
US, one in four infants listed for heart transplant dies before a donor heart is available (Mah et 
al 2009).
In contrast to HF in adults, there is very limited research in pediatric HF. Consequently, the 
treatment of HF in children is based on information and results provided by adult studies 
(Kantor and Mertens 2010). The Diovan Pediatric Heart Failure Survey study confirmed that 
two factors; ‘efficacy shown in an adult trial’ and ‘Consensus Statements and Guidelines’ were 
the most important factors considered when making treatment decisions for pediatric patients 
with HF (CVAL489K2304 HF Survey 2011). According to this survey of pediatric cardiologists, 
current clinical management of pediatric HF includes angiotensin converting enzyme inhibitors 
(ACEI), angiotensin receptor blockers (ARBs), β-blockers, diuretics, aldosterone-blocking 
agents, digoxin and anticoagulants. At present, no trial has demonstrated an outcome benefit of 
any pharmacotherapy in children with HF.
Entresto (sacubitril/valsartan), also known as LCZ696, is a first-in-class, angiotensin receptor 
neprilysin inhibitor treatment for chronic HF (CHF) and reduced ejection fraction. Neprilysin 
(NEP) inhibition with chronic oral administration of sacubitril/valsartan can promote the 
endogenous capacity of the body to compensate for HF exacerbations by potentiating the 
activity of natriuretic peptides secreted by the heart in response to cardiac stress and increased 
intravascular volume. Sacubitril/valsartan, unlike any other therapy for HF, provides 
concomitant inhibition of NEP and the angiotensin type 1 (AT1) receptor. The resulting increase 
in natriuretic peptide activity due to NEP inhibition and AT1 receptor blockade through renin-
angiotensin-aldosterone system (RAAS) inhibition have complementary effects on the 
cardiovascular (CV) system that benefit HF patients.
In PARADIGM-HF (CLCZ696B2314; N = 8442), the pivotal Phase 3 study in adult patients 
with HF with reduced ejection fraction (HFrEF), sacubitril/valsartan was superior to enalapril 
(the standard of care) in delaying time to first occurrence of composite endpoint of CV death or 
HF hospitalization, with a 20% relative risk reduction (RRR) (p = 0.0000002). In addition, 


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sacubitril/valsartan was superior to enalapril in delaying time to CV death with a 20% RRR 
(p=0.00004) and in delaying time to first HF hospitalization with a 21% RRR (p=0.00004). 
PARADIGM-HF also showed that sacubitril/valsartan is generally safe and well tolerated in 
adult patients with HF (McMurray et al 2014).
Study CLCZ696B2319 (PANORAMA-HF) is a large, multicenter, double-blind, active 
controlled pediatric HF trial and includes patients with systemic left ventricular systolic 
dysfunction <18 years of age. PANORAMA-HF is designed to demonstrate whether 
sacubitril/valsartan provides greater clinical treatment benefit than enalapril as well as to assess 
its safety profile compared to enalapril over a 52-week treatment duration.
The collection of long-term safety and tolerability data in a pediatric population is equally 
important, as patients may be dependent on HF medication for a long period of time. For this 
purpose, upon successful completion of the 52-week double-blind treatment period in 
PANORAMA-HF, patients will be offered the opportunity to enroll in this open-label, long-
term extension study and receive open-label sacubitril/valsartan treatment. For subjects who 
may have successfully completed the double-blind study before the PANORAMA-HF Open 
Label Extension (OLE) CLCZ696B2319E1 study starts at their study center, participation in 
the OLE will be offered to them once the study is available.
1.2
Purpose
The purpose of this study is to evaluate long-term safety and tolerability and to provide post-
trial access to sacubitril/valsartan to eligible CLCZ696B2319 (PANORAMA-HF) patients. 
2
Objectives and endpoints
The primary objective is to further evaluate long- term safety and tolerability of
sacubitril/valsartan
in 
eligible 
PANORAMA-HF 
subjects 
receiving 
open-label 
sacubitril/valsartan. 
There are no secondary or exploratory objectives for this study.
Table 2-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 

To further evaluate long-term safety and 
tolerability of sacubitril/valsartan in eligible 
PANORAMA-HF subjects receiving open-
label sacubitril/valsartan

AEs, SAEs, laboratory values, vital signs, and duration 
of drug exposure
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

Not applicable

Not applicable
Exploratory Objective(s) 
Endpoint(s) for exploratory objective(s)

Not applicable

Not applicable


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3
Study design
This trial is a multicenter, open-label long-term extension study for subjects who have 
successfully completed Part 2 of the PANORAMA-HF trial. PANORAMA-HF is a Phase 3b
study in pediatric subjects with systemic left ventricular systolic dysfunction. 
Only subjects who successfully completed the 52-week randomized double-blind treatment 
period of PANORAMA-HF (Part 2, efficacy, safety) on study medication (i.e. on dose level 1 
or higher at the PANORAMA-HF End of Study visit) or who discontinued study drug treatment 
early in Part 2 due to the implementation of USM of PANORAMA-HF and fulfill protocol 
requirements (see Section 5) are eligible to participate in the OLE, and will be offered the option 
to initiate treatment with sacubitril/valsartan by enrolling into this study (CLCZ696B2319E1) 
at the discretion of the investigator. Subjects who only participated in Part 1 of PANORAMA-
HF, who were screen failures in PANORAMA-HF or who permanently discontinued study drug 
treatment during Part 2 of PANORAMA-HF for reasons other than the implementation of the 
USM are not eligible for this study (see Section 5 for details).
For all consenting subjects eligibility for the OLE will be assessed at the screening visit (Visit 
500) and the study medication will be initiated no later than 30 days after completion of Part 2 
of PANORAMA-HF Visit 416 (see Section 8.1 for details). 
Required 36-hour washout:

A 36-hour washout after the last dose of study medication taken in the PANORAMA-HF 
study (Visit 416) is required for all subjects before starting OLE study medication.  

A 36-hour washout before starting OLE study medication is also required for all subjects 
that have transitioned to an ACEI after completion of PANORAMA-HF.
An ARB or a renin inhibitor must be discontinued the morning of Visit 501  for subjects taking 
either of these drugs.
Subjects will be enrolled into two different age groups (Age Group 1: 6 years and older; Age 
Group 2: 1 to <6 years) in the OLE study. Subjects who turned 18 years old during the 
PANORAMA-HF double-blind study, and who qualify, are eligible to participate in the OLE 
study.
Age Groups 1 and 2 in the OLE have a target dose (dose level 4) of 3.1 mg/kg bid.
Subjects will be up titrated to the target dose of sacubitril/valsartan, dose level 4 (see Table 3-
2) according to their tolerability. Subjects have to meet all criteria in Table 3-1 during the up-
titration phase for safety monitoring before administering the next higher dose level.  
Visits 502, 503, 504 and 505, as applicable, are intended to be used for study drug up-titration 
and abbreviated safety follow-up at an interval of approximately 2 weeks between the visits. 
During that time, subjects should be up titrated to the maximum tolerated oral dose of 
sacubitril/valsartan with a goal of reaching the target dose of 3.1 mg/kg. (Refer to Table 3-2 for 
study-drug dose levels 1 to 4.)


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Table 3-1
Safety monitoring criteria for initiation/up-titration of study drug
Parameter
Description
Potassium level
Serum K ≤ 5.4 mmol/L (mEq/L) or plasma K ≤ 5.0 mmol/L (mEq/L)
Kidney function
eGFR (calculated using the modified Schwartz formula) ≥ 30% mean GFR for 
age (Appendix 3, Table 16-6) 
Kidney function
eGFR reduction < 35% compared to screening Visit 500. 
Blood pressure
SBP > than the calculated 5th percentile SBP for age as described in 
Appendix 6
AEs or conditions
No conditions that preclude continuation according to investigator’s judgment, 
including hypotension.
Table 3-2
Study drug dose levels for sacubitril/valsartan
age groups 1 and 2 *
Dose levels for pediatric formulation
Dose level 1
0.8 mg/kg bid.
Dose level 2
1.6 mg/kg bid.
Dose level 3
2.3 mg/kg bid.
Dose level 4
3.1 mg/kg bid.
Dose levels for adult formulation
Dose level 1
50 mg bid.
Dose level 2
100 mg bid.
Dose level 3
150 mg bid.
Dose level 4
200 mg bid.
*Note: sacubitril/valsartan target dose (dose level 4) for age groups 1 and  2 is 3.1 mg/kg bid. (see 
Section 4.2 for additional details).
If a subject is unable to tolerate up-titration to a higher sacubitril/valsartan dose level or at the 
discretion of the investigator, subjects may be maintained on lower dose levels of 
sacubitril/valsartan (dose level 1-3, see Table 3-2). In case of a consecutive 3-month 
interruption of study treatment, subject should be discontinued from the study and should 
complete Visit 599.
An outline of the study design is presented in Figure 3-1. Depending on when and where the 
patient is enrolled, the duration of the study varies from 1 to approximately 4.5 years.
The OLE study drug starting dose will depend either upon the dose of ACEI/ARB that the 
subject was transitioned to after completion of the PANORAMA-HF or the dose the subject 
was on at the End of Study visit for the core study PANORAMA-HF prior to screening (Visit 
500; refer to Table 3-2).
At Visit 501, subjects who meet eligibility criteria will start the study drug at dose level 1 or 2 
(Table 3-2). Subjects who were on dose level 1 at the PANORAMA-HF End of Study 
(PANORAMA-HF visit 416) or who are on a low dose of ACEI/ARB (dose levels 1; Table 3-
3) or not on an ACEI/ARB prior to screening (Visit 500) should start at dose level 1 at Visit 
501.


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Subjects who were on dose level 2, 3 or 4 at PANORAMA-HF visit 416 or who are on a higher 
dose of ACEI/ARB (dose levels 2, 3 or 4; Table 3-3) prior to screening (Visit 500) should start 
at dose level 2 at Visit 501 (Table 3-2) or at dose level 1 at investigator’s discretion.
During the study, visits to assess safety will be conducted at Visit 501 and at 3-months intervals 
until the conclusion of the study (except for titration visits, which are at 2-week intervals). 
Unscheduled visits are allowed for subject’s safety and for dose adjustment purposes
Table 3-3
Total daily dose levels of commonly prescribed ACEI/ARBs for the 
purpose of comparing to dose levels of study drug
Dose levels for 
pediatric formulation
Enalapril/Lisinopril 
total daily dose
Captopril total daily 
dose
Dose level 1
0.1 mg/kg
0.3 mg/kg
Dose level 2
0.2 mg/kg
0.6 mg/kg
Dose level 3
0.3 mg/kg
1.2 mg/kg
Dose level 4
0.4 mg/kg
1.5 mg/kg
Dose levels for adult 
formulation
Enalapril/Lisinopril 
total daily dose
Captopril total daily 
dose
Cilazapril total daily 
dose
Dose level 1
5 mg
18.75 mg
0.5 mg
Dose level 2
10 mg
37.5 mg
1.0 mg
Dose level 3
15 mg
75 mg
2.5 mg
Dose level 4
20 mg
150 mg
5.0 mg
Dose levels for 
pediatric formulation
Valsartan total daily 
dose
Losartan total daily 
dose
Candesartan total 
daily dose
Dose level 1
0.7 mg/kg
0.4 mg/kg
0.2 mg/kg
Dose level 2
1.4 mg/kg
0.7 mg/kg
0.25 mg/kg
Dose level 3
2.0 mg/kg
1.0 mg/kg
0.32 mg/kg
Dose level 4
2.7 mg/kg
1.4 mg/kg
0.64 mg/kg
Dose levels for adult 
formulation
Valsartan total daily 
dose
Losartan total daily 
dose
Candesartan total 
daily dose
Dose level 1
40 mg
25 mg
4 mg
Dose level 2
80 mg
50 mg
8 mg
Dose level 3
160 mg
75 mg
16 mg
Dose level 4
320 mg
100 mg
32 mg


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Figure 3-1
Study Design
4
Rationale
4.1
Rationale for study design
The purpose of this open-label extension study of PANORAMA-HF is to further evaluate the 
long-term safety and tolerability and to provide post-trial access of sacubitril/valsartan to 
eligible 
patients 
that 
successfully 
completed 
the 
PANORAMA-HF
study 
(see 
Inclusion/Exclusion criteria Section 5.1).
4.2
Rationale for dose/regimen and duration of treatment
The starting dose will be dose level 1 or 2, based on the dose level the subject was on at the 
final visit of PANORAMA-HF or the dose levels of ACEI/ARBs to which the subject was 
transitioned after completion of the double-blind core study, PANORAMA-HF. The respective 
starting dose levels were chosen to ensure a smooth transition to the open-label study 
medication taking safety and tolerability aspects into account. Subjects will be up-titrated to 
next dose level at approximately 2-week intervals, per investigator judgement, until the target 
dose of 3.1 mg/kg or the maximum tolerated dose is reached.
The duration of the study will continue up to 2 years from LPLV of part 2 of the core study (i.e., 
until approximately Dec-2023), receipt of local marketing authorization and commercial 
availability, or reaching maximum limit allowed by local regulations, whichever occurs first.  
In countries where the sacubitril/valsartan is already authorized for pediatric use during the core 
study, patients may participate in the study for up to 1 year before being transitioned to 
commercially available product. If the formulation the patient is taking is not yet commercially 
available at the end of 1 year, the patient may continue in the study until the formulation 
becomes commercially available or any of the above conditions are met (also see details in 
Section 6.1.4).
This timeframe will allow for meaningful capture of long-term safety data and will ensure 
sufficient access to study drug, which patients have relied on for their treatment, for an extended 
period until they can obtain it using normal local commercial process. In addition the results of 
w=weeks; m=months; DL=LCZ696 dose level
* ≥36 hour of ACEI or double-blind study medication-free washout before starting OLE study medication at Visit 501
** The starting dose at V501 can vary according to prior dose of AECI/ARBs or PANORAMA-HF study drug


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the PANORAMA-HF core study results will be available during this time frame and will 
determine whether patients in PANORAMA-HF derived benefit from treatment with LCZ696. 
[* The following text applies to subjects enrolled in the OLE in Germany: Each eligible subject 
enrolled in Germany has a maximum study duration of 4 years. The treatment duration may be 
re-evaluated at a later time point as needed.]
4.3
Rationale for choice of control drugs 
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
This is an extension study for subjects who have successfully completed the double-blind 
PANORAMA-HF trial, with a goal to further evaluate long-term safety and tolerability of
sacubitril/valsartan in pediatric heart failure subjects. 
Details regarding preclinical data from sacubitril/valsartan juvenile animal studies are described 
in the Sacubitril/Valsartan Investigator’s Brochure (IB), which is provided to every 
participating study site.
Sacubitril/valsartan has proven to have a significant mortality and morbidity benefit compared 
to the standard of care enalapril for the treatment of adult HF with reduced systolic function 
(HFrEF) in the PARADIGM-HF study (CLCZ696B2314). Continuous treatment with 
sacubitril/valsartan over a median follow-up time of 27 months led to a 20% RRR in the primary 
endpoint of CV death or first HF hospitalization over optimized enalapril treatment. Clinical 
trial data in adults demonstrate that sacubitril/valsartan has an overall safety profile generally 
comparable to other RAS inhibiting agents. Hypotension, hyperkalemia, renal impairment, and 
angioedema have been identified as possible safety risks in sacubitril/valsartan studies. While 
the incidence rate of hypotension in Study CLCZ696B2314 was higher for sacubitril/valsartan
compared with enalapril, hypotension assessed as severe or serious was not higher in the 
sacubitril/valsartan group compared to the enalapril group. In addition, no major difference was 
observed for hypotension leading to study drug discontinuation. In contrast, the incidence of 
hyperkalemia, renal impairment and cough was numerically lower in the sacubitril/valsartan
group compared to the enalapril group.
Data are not yet available from the double-blind study PANORAMA-HF. An external 
independent Data Monitoring Committee (DMC) monitors the safety of the PANORAMA-HF 
study participants in an unblinded manner. DMC findings (safety and/or efficacy) and 
recommendations may impact the conduct of PANORAMA-HF as well as this open-label-
extension study.
Although the DMC regularly monitors ongoing data in the core study PANORAMA-HF, one 
risk for patients enrolling in the open-label study is that, they are doing so without knowing the 
results of the double-blind core study PANORAMA-HF. It should also be noted that the long-
term exposure to sacubitril/valsartan on cognitive function is not known.


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Risks to subjects in this trial (e.g. renal dysfunction, blood pressure, and hyperkalemia) can be 
minimized by rigorous compliance with the inclusion and exclusion criteria and study 
procedures, as well as clinical safety monitoring (vital signs, physical exam, hematology, blood 
chemistry and urinalysis tests). Recommended guidelines for prophylactic or supportive 
management of study drug-induced adverse events are provided in Appendix 4, Appendix 6, 
and Appendix 7 (guidelines for the management of renal dysfunction, blood pressure, and 
hyperkalemia, respectively).
Women of childbearing 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 outlined in the 
exclusion criteria. If there is any concern that the subject will not reliably comply, they should 
not be entered or continue in the study.
4.6
Rationale for Public Health Emergency mitigation procedures
In the event of a Public Health emergency as declared by Local or Regional authorities i.e. 
pandemic, epidemic or natural disaster, mitigation procedures may be required to ensure 
patients safety and trial integrity are listed in relevant sections of the study protocol. Notification 
of the Public health emergency should be discussed with Novartis prior to implementation of 
mitigation procedures, and permitted/approved by Local or Regional Health Authorities and 
Ethics Committees as appropriate. 
5
Population
The study population consists of pediatric HF patients ≥ 13 months, in-patients or outpatients. 
Subjects will be divided into two age groups, Age Group 1, ≥6 years old and Age Group 2, 13 
months to <6 years old). All patients who safely tolerated study drug in PANORAMA-HF, who 
were receiving study drug at Visit 416 of the double-blind study or discontinued from study 
drug treatment early due to implementation of the USM and who successfully completed the 
double-blind study, and fulfilled the Inclusion/Exclusion criteria for the OLE (Section 5.1 and 
Section 5.2), can be considered for this open-label study. Patients in the double-blind study for 
whom study medication had been temporarily interrupted during the study, may be considered 
for the OLE if they were receiving study medication at Visit 416 and they meet all entry criteria. 
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent as well as assent at an appropriate age based on country 
regulations must be obtained prior to participation in the study.
2. Patient was on study medication at the PANORAMA-HF Part 2 End of Study visit (Visit 
416) or discontinued from the study drug treatment early due to the implementation of the 
USM and does not have any significant safety issue as determined by the investigator.  
Based on the investigator judgement, the patient is able to safely enroll in the OLE study.


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5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Patient who only participated in Part 1 of the PANORAMA-HF study or was a screen 
failure in PANORAMA-HF or permanently discontinued study drug in Part 2 of the 
PANORAMA-HF study for reasons other than the implementation of the USM.
2. Use of investigational drugs within 5 half-lives of enrollment or within 30 days whichever 
is longer; or longer if required by local regulations – with the exception of PANORAMA-
HF study drug. For PANORAMA-HF study drug (sacubitril/valsartan/placebo; 
enalapril/placebo), a minimum of 36-hour washout period is required before the initiation 
of study treatment (Visit 501).
3. History of hypersensitivity or allergy to any of the study treatments or its excipients or to 
drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or 
suspected contraindications to sacubitril/valsartan.
4. Renal vascular hypertension (including renal artery stenosis).
5. Patients with significant renal (eGFR calculated using the modified Schwartz formula < 
30% mean GFR for age, Appendix 3, Table 16-6); hepatic (serum aspartate 
aminotransferase or alanine aminotransferase > 3 times upper limit of normal); 
gastrointestinal or biliary disorders (that could impair absorption, metabolism, or excretion 
of orally administered medications).
6. Patients with a history of angioedema.
7. Patients who have parents or legal guardians who do not give consent or allow the child to 
give assent, or inability of the patient or the parents/legal guardians to follow instructions 
or comply with follow-up procedures.
8. Pregnant or nursing (lactating) women.
9. Any medical condition(s) that may put the patient at risk in the investigator’s opinion, or 
that the investigator deems unsuitable for the study.
10. Patient breastfed by a mother taking ACEI.
11. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 5 days of sacubitril/valsartan 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 screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 


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(failure rate <1%), for example, hormone vaginal ring or transdermal hormone 
contraception.
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 child bearing 
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
Table 6-1
Open-label sacubitril/valsartan formulations
Formulation
Strength
Comments
capsule containing 4 granules
(3.125 mg/granule)
12.5 mg
capsules in bottles
capsule containing 10 granules
(3.125 mg/granule)
31.25 mg 
capsules in bottles
tablets
50 mg
tablets in bottles
tablets
100 mg
tablets in bottles
tablets
200 mg
tablets in bottles
liquid suspension
please refer to OLE Pharmacy Manual
The sacubitril/valsartan study medication is available in 3 formulations: tablets, granules (mini-
tablets) or liquid formulation (Table 6-1). For liquid formulation, please refer to the OLE 
Pharmacy Manual. 
All pediatric formulations of study medication (sacubitril/valsartan granules or liquid) will be 
made available to all age groups. The adult tablet formulations of sacubitril/valsartan will be 
available for subjects based on the subject’s dosing and ability to swallow adult tablets (refer to 
OLE Pharmacy Manual). The dispensing of medication to the subjects will be controlled by an 
Interactive Response Technology (IRT) system based on the dose level, subject’s body weight 
and ability to swallow tablets/granules.
An overview of available sacubitril/valsartan formulations is illustrated in Table 6-1. Capsules 
of LCZ696 containing 4 granules or 10 granules per capsule will be provided for oral use. The 
granules can be swallowed by the subject, after the removal of the outer capsule. Subjects who 


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cannot use tablets or granules can use the liquid formulation. Sacubitril/valsartan liquid 
formulation will be compounded by the site / pharmacy (please refer to OLE Pharmacy Manual). 
Sufficient medication will be provided for treatment according to the study protocol. 
Medication labels will be in the local language and comply with the legal requirements of the 
country. The labels will include storage conditions for the drug and the medication number, and 
will not include information about the subject.
Subjects taking the liquid formulation of sacubitril/valsartan will need to have a resupply every 
4 weeks. Given the burden of traveling to the site for study visits for subjects and families, the 
parent/caregiver can come to the site without the subject for dispensation of study drug between 
scheduled study visits (see Table 8-1). Delivery of study drug to the subject can also be used, 
where possible and where allowed by local regulations. 
6.1.2
Additional study treatments
No other study treatments beyond the investigational treatment (sacubitril/valsartan) are 
planned for this trial.
6.1.3
Treatment arms/group
There is 1 treatment arm in this open-label study. All subjects will receive open-label 
sacubitril/valsartan.
6.1.4
Treatment duration
The study will continue up to 2 years from LPLV of part 2 of the core study (i.e., until 
approximately Dec-2023), receipt of local marketing authorization and commercial availability, 
or reaching maximum limit allowed by local regulations, whichever occurs first.  
In countries where the sacubitril/valsartan is already authorized for pediatric use during the core 
study, patients may participate in the study for up to 1 year before being transitioned to 
commercially available product. If the formulation the patient is taking is not yet commercially 
available at the end of 1 year, the patient may continue in the study until the formulation 
becomes commercially available or until the maximum limit allowed by local regulations or 
until Dec-2023, whichever occurs first.
6.2
Other treatment(s)
Subjects may be on a HF regimen throughout the study duration on the investigator’s discretion,
except for the use of ACEI, ARBs and renin inhibitors, which are strictly prohibited. Prohibited 
and important concomitant medications during the conduct of the clinical trial are listed below.
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject 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.


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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
enrolling a subject or allowing a new medication to be started. If the subject is already enrolled, 
the investigator should contact Novartis to determine if the subject should continue participation 
in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
The active metabolites of sacubitril (sacubitrilat) and valsartan are OATP1B1, OATP1B3 and 
OAT3 substrates; valsartan is also a Multidrug resistance protein 2 (MRP2) substrate. Therefore, 
co-administration of sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. 
rifampin, cyclosporine) or MPR2 (e.g. ritonavir) may increase the systemic exposure to 
sacubitrilat or valsartan, respectively. The investigator should exercise appropriate care when 
initiating or ending concomitant treatment with such drugs.
The co-administration of sacubitril/valsartan has increased maximum plasma concentration of 
atorvastatin. These effects may potentially be due to the OATP1B1 and OATP1B3 inhibitory 
effects of sacubitril. Therefore, caution is recommended when co-administering 
sacubitril/valsartan with atorvastatin and other statins that are substrates of OATP1B1 and 
OATP1B3.
Antihypertensive medication should be co-administered with caution due to blood pressure 
lowering characteristics of the study medication sacubitril/valsartan. 
Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium 
supplements) should be used with caution. In case of hyperkalemia adequate measures should 
be considered, e.g. reduce dietary potassium and/or adjust the dose of concomitant 
medication(s). Monitoring of serum potassium is recommended especially in subjects with risk 
factors.
In subjects with compromised renal function, concomitant use of sacubitril/valsartan and Non-
steroidal anti-inflammatory drugs (NSAIDs) may lead to an increased risk of worsening of renal 
function. Therefore, monitoring of renal function is recommended when initiating or modifying 
treatment in subjects on sacubitril/valsartan who are taking NSAIDs concomitantly.
Guidelines for the management of hyperkalemia, hypotension and renal dysfunction are 
provided in Appendix 7, Appendix 6, and Appendix 4, respectively.


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6.2.2
Prohibited medication
Use of the treatments included in the below table are not allowed while taking study drug due 
to safety reasons. If the medication included in Table 6-2 must be administered, study drug must 
be discontinued and the actions specified below must be taken.
Table 6-2
Prohibited medications
Medication
Prohibition 
period
Action taken
any ACEI
36 hour washout 
period
Discontinue study drug. ACEI must be stopped
for 36 hours prior to re-initiation of study drug. 
any ARB
Discontinue study drug. ARB must be stopped for prior to 
re-initiation of study drug.
renin inhibitor 
(aliskiren)
Discontinue study drug. Renin inhibitor must be stopped 
prior to re-initiation of study drug. 
ACEIs, ARBs, and renin inhibitors
The concomitant use of open-label ACEI, ARB, or renin inhibitor is strictly prohibited while 
the subject is receiving study drug. If the investigator believes the addition of an ACEI, ARB 
or renin inhibitor is required, the study drug must be temporarily discontinued. Study drug must 
be stopped 36 hours prior to starting open-label ACEI. Study drug must be stopped prior to 
starting open-label ARB or renin inhibitor. Similarly, if study drug is to be restarted, the open-
label ACEI must be stopped ≥ 36 hours prior to resuming study drug. Open-label ARB or renin 
inhibitor must be stopped prior to resuming study drug.
6.2.3
Rescue medication
If in the opinion of the investigator, the subject does not tolerate the assigned study medication, 
the investigator should consider whether non-disease-modifying medication [e.g. calcium 
channel blockers (CCBs), diuretics, α-blockers] could be adjusted to rectify the situation. 
Guidance on handling renal dysfunction, hypotension, and hyperkalemia are provided to 
investigators in Appendix 4, Appendix 6, and Appendix 7, respectively. 
The investigator may prescribe any medications and/or supportive care during the study based 
on clinical needs (excluding use of the prohibited medications described above). Use of rescue 
medication and/or supportive care must be recorded on the Concomitant medications eCRF.
6.3
Subject numbering and treatment assignment
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 subject number 
suffixed to it, so that each subject is numbered uniquely across the entire database. Upon signing 


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the informed consent form, the subject will be assigned the same Subject Number as he/she had 
in the PANORAMA-HF core study.
Upon signing the informed consent form, the investigator or his/her staff will contact the IRT 
and provide the requested identifying information to register the subject into the IRT system.
If the subject fails to be treated for any reason, the IRT must be notified as soon as possible that 
the subject was not treated. The reason for not being treated will be entered on the Screening 
Disposition eCRF.
6.3.2
Treatment assignment
This is an open-label study and subjects will not be randomized to treatment in this trial. All 
eligible subjects previously treated with sacubitril/valsartan or enalapril in PANORAMA-HF 
will be treated with open-label sacubitril/valsartan at maximally tolerated doses up to the target 
dose that has been determined for each age group. The target dose of sacubitril/valsartan will 
be 3.1 mg/kg bid for Age Group 1. The target dose for Age Group 2 is 3.1 mg/kg bid (see 
Section 4.2 for additional details).
An Interactive Response Technology (IRT) system will be used to enroll subjects into the study 
and dispense study drug. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all of the inclusion/exclusion criteria. The IRT system will 
prompt the investigator to enter the subject’s Subject Number into the system and will then 
assign a uniquely numbered medication kit for the first investigational treatment to be dispensed 
to the subject (at the time of completing Visit 501).
The IRT will be used to assign additional uniquely numbered medication kits at subsequent 
visits throughout the duration of the trial (except End of Study visit).
6.4
Treatment blinding
Not applicable. Treatment will be open to subjects, investigator staff, persons performing the 
assessments, and the Clinical Trial Team (CTT).
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
The study drug is up titrated every 2 weeks as tolerated to target dose (dose level 4) as outlined 
in Table 3-2 and based on the safety monitoring criteria (Table 3-1). Following up titration, the 
maximum tolerated or target dose will then be maintained for the duration of the study. Both 
scheduled and unscheduled visits can be utilized for up-titration and/or down-titration 
throughout the study based on investigator judgment.
For subjects who are unable to tolerate the protocol-specified dosing scheme, dose level 
adjustments and temporary interruptions of less than 3 months of study treatment are permitted. 
The following guidelines should be followed:

The investigator should adjust/interrupt/discontinue doses of concomitant medications if it 
is believed that they are the most likely cause of an adverse event.


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
If adjustment/elimination of concomitant medications is not possible or does not alleviate 
the adverse event of concern, the investigator may down titrate to the next lower study 
drug dose level (Table 3-2) to temporary or permanent discontinuation of study drug. 

The subject may reinitiate the higher dose when the investigator feels it is appropriate to 
do so per the directions provided below in this section.

If the study drug is permanently discontinued, the subject should be discontinued from the 
study (Visit 599).
Subjects may be seen at any time for unscheduled visits during the study for re-evaluation of 
safety criteria parameters. Study drug dose level adjustments should mainly be based on overall 
safety and tolerability with focus on a) hyperkalemia, b) symptomatic hypotension and c) renal 
dysfunction. Laboratory assessments of serum sodium, potassium, creatinine, and eGFR 
(calculated based on the modified Schwartz formula (Schwartz and Work 2009) will be utilized. 
Refer to Appendix 4, Appendix 6, and Appendix 7 for treatment guidelines for renal dysfunction, 
management of hypotension and hyperkalemia, respectively.
Adjustment of study-drug dose level
During the study, down titration of the study drug at any time is allowed based on the safety 
and tolerability criteria defined in Table 3-1 and per the Investigator’s clinical judgement. 
The investigator may down titrate the study drug to the next lower dose level or may down 
titrate 2 or 3 dose levels (e.g. from dose level 4 to dose level 1), based on their clinical judgement. 
If the tolerability issues are not alleviated despite down titration by multiple dose levels, the 
investigator may temporarily discontinue study drug. Once the subject’s condition is stable, the 
subject can be up titrated to the next higher dose level using unscheduled visits in an attempt to 
bring back the subject gradually to the target study drug dose level. The investigator may select 
the next dose level for down- or up-titration according to his or her judgment (Table 3-2). 
All changes should be recorded on the Drug Administration Record (DAR) eCRF. In addition, 
IRT should be contacted to register any changes in the subject’s study-drug dose level, in cases 
of temporary and permanent discontinuation of the study drug, and to obtain the medication 
numbers of the study drug supplies required for the new study-drug dose level.
Study drug restart after temporary treatment interruption
Subjects who have temporarily discontinued study drug should be restarted as soon as possible 
as deemed appropriate by the investigator. The investigator should restart the subject on the 
study drug at the most appropriate dose level (Table 3-2) as per the investigator’s clinical 
judgment. If the subject does not tolerate the newly restarted study-drug dose level, they may 
be down titrated again (if appropriate) or the study medication may be temporarily discontinued 
again. 
Subjects restarted on the study drug will retain their original study identification numbers.
Investigators may discontinue a subject's study drug due to serious or intolerable AEs suspected 
to be causally related to study drug. If study drug is discontinued for any reason, this must be 
recorded on the DAR eCRFs. In addition, subjects who permanently discontinued study drug 
should be scheduled for the discontinuation study Visit 599.


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If during study treatment interruption a subject requires treatment with an ACEI a ≥36 hours 
washout should be observed before the ACEI is initiated. The ACEI must be discontinued ≥36 
hours prior to restarting study drug. Subjects who have temporarily discontinued study drug and 
are presently taking an ARB or a renin inhibitor must discontinue their current ARB or renin 
inhibitor on the day study drug is restarted.
Note that after a consecutive 3-month interruption of study treatment, subject should be 
discontinued from the study and should be seen at the site for Visit 599).
If the subject becomes pregnant during the course of the study, the subject has to discontinue 
study drug immediately and should be seen at the site for Visit 599 and evaluated for transition 
to alternative treatment per the Investigator’s clinical judgement.  
Refer to (Section 8.4.2) for further details on pregnancies and reporting guidelines.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject/parent/guardian to 
take/administer the study treatment exactly as prescribed and by stating that compliance is 
necessary for the subject’s safety and the validity of the study. The subject/parent/guardian must 
also be instructed to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed.
6.6.2
Emergency breaking of assigned treatment code
This is an open-label study therefore emergency breaking of treatment assignment is not 
applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
Medication will be provided as tablets, granules (mini-tablets) or liquids. Tablets and granules 
(mini-tablets) will be provided by Novartis to the study site. Liquid preparation will be provided 
either by the site or by the pharmacy according to local regulations. For liquid preparation, 
please refer to OLE Pharmacy Manual.
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label). Before dispensing the medication kit to the subject, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document.


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6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study drug must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designees have 
access. Upon receipt, all study drugs must be stored according to the instructions specified on 
the labels and in the Investigator’s Brochure. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective Novartis 
CO 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 drug but no information about the 
subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study drug 
in a drug accountability log. Monitoring of drug accountability will be performed by monitors 
during site visits or remotely and at the completion of the trial. Subjects will be asked to return 
all unused study drug and packaging at the end of the study or at the time of discontinuation of 
study drug.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study drug, 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.
Where applicable and as per local regulations, the study medication can be shipped from the 
study site or pharmacy to subject’s home. Pharmacy to home operating procedures will be 
provided to the site/pharmacy by the sponsor.
6.7.1.2
Handling of additional treatment
The investigator should instruct the subject/parent/guardian to notify the study site about any 
new medications he/she/their child takes after the subject 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. 
The subject should be receiving optimal standard of medical care or surgical treatment for their 
HF and comorbidities. 
6.7.2
Instruction for prescribing and taking study treatment
Novartis will supply the investigators with all study medications required for the course of the 
study. Subjects will be provided with bottles containing study drug corresponding to their 
assigned dose level, sufficient to last until the next scheduled visit ( Table 8-1). Study drug will 
be supplied to subjects as:

sacubitril/valsartan tablets: 50 mg, 100 mg or 200 mg 

sacubitril/valsartan granules: 3.125 mg/granule (packaged in capsule containing either 4 or 
10 granules) supplied in a bottle


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
sacubitril/valsartan liquid formulation (compounded by site / pharmacy) (refer to OLE 
Pharmacy Manual) 
Details regarding preparation of liquid formulation for sacubitril/valsartan are provided in the 
OLE Pharmacy Manual.
Subjects will be instructed to take their morning study drug doses between 6:00 and 09:00 (6 -
9 AM) and their evening study drug dose between 18:00 and 21:00 (6 - 9 PM). The study drugs 
(tablets) should be taken with a glass of water with or without food. For granules and liquid 
administration, see OLE Pharmacy Manual. 
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the Dosage Administration Record (DAR) eCRF. All kits of study treatment 
assigned by the IRT will be recorded in the IRT system.
The investigator must promote compliance by instructing the subject/parent/guardian to take 
the study treatment exactly as prescribed and by stating that compliance is necessary for the 
subject’s safety and the validity of the study. The subject/parent/guardian must also be 
instructed to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed.
7
Informed consent procedures
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), Institutional Review Board /Independent Ethics 
Committee (IRB/IEC)-approved informed consent, or, if incapable of doing so, after such 
consent has been provided by a legally acceptable representative(s) of the patient. In cases 
where the patient’s representative gives consent, the patient must be informed about the study 
to the extent possible given his/her level of understanding. If the patient is capable of doing so, 
he/she must indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (e.g. the procedures described in the protocol). The process of 
obtaining informed consent and adolescent/child assent where applicable must be documented 
in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
and age appropriate assent forms that comply with the International Council for Harmonization 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good 
Clinical Practices (GCP) guideline and regulatory requirements and is considered appropriate 
for this study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC, and a copy of the approved version 
must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential 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 requirement for the duration of 
the study as outlined in the exclusion criteria. If there is any concern that the patient will not 
reliably comply, they must not be entered in the study.


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As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, if re-consenting 
the patient on amended informed consent form, the Investigator may conduct the informed 
consent discussion remotely (e.g. telephone, videoconference) if allowable by a local Health 
Authority. Guidance issued by local regulatory bodies on this aspect prevail and must be 
implemented and appropriately documented (e.g. the presence of an impartial witness, 
sign/dating separate ICFs by trial patients and person obtaining informed consent, etc.).
Informed consent at study entry will need to be conducted face-to-face with patients/ caregivers 
following the standard guidelines.
8
Visit schedule and assessments
After identifying a potential subject, an informed consent form (ICF) and assent (if applicable) 
must be signed by the parent(s)/legal guardian(s) and by the subject (as applicable) before 
performing any study-related procedures that are not considered standard of care for pediatric 
HF subjects at that site. Procedures that are part of a site‘s standard of care for a pediatric subject 
or that were done as part of core study PANORAMA-HF End of Study visit 416 may pre-date 
the signed ICF for the OLE. The AE and SAE reporting period will begin at the time the ICF is 
signed (e.g. screening visit– Visit 500). 
Following the start of sacubitril/valsartan treatment (at Visit 501), initial visits for up titration 
(i.e. Visits 502, 503, 504 and 505) will be scheduled approximately 2 weeks apart.  The number 
of up-titration visits that a subject requires may vary depending upon the starting dose at visit 
501 and the maximally tolerated/target dose. After the subject’s target dose is reached, one more 
visit can be scheduled approximately 2 weeks later for a safety evaluation.
Three (3) months after Visit 501, a telephone visit will occur (Visit 506). The subsequent site 
visits will occur at intervals of 6 months beginning at Visit 507, which is scheduled 6 months 
after starting study treatment. There will be telephone visits every 3 months in between the in-
person visits. 
Subjects should take their scheduled dose of sacubitril/valsartan in the morning of their study 
visits. Subjects are not required to fast overnight on the day prior to or the day of the study visit. 
Subjects, who discontinue sacubitril/valsartan for 3 consecutive months, will be discontinued 
from the study and are to attend Visit 599. 
The Assessment Schedule table ( Table 8-1) lists all of the assessments when they are performed 
(indicated with an “x”). All data obtained from these assessments must be supported in the 
subject’s source documentation.
The table indicates which data remain in the source documents only (S). Assessments that 
generate data for database entry are recorded on eCRFs.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. If one visit is postponed or brought forward, it 
should not result in the next visit being postponed or brought forward. The next visit, if at all 
possible, should adhere to the original schedule in relation to Visit 501. Missed or rescheduled 


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visits should not lead to automatic discontinuation. Specific circumstances surrounding missed 
or rescheduled visits must be discussed with the study monitor. Subjects who prematurely 
discontinue the study for any reason should be scheduled for a final visit as soon as possible, at 
which time all of the assessments listed for the final visit (Visit 599) will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the eCRF.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. In case of missed visits/ assessments due to any such events/ disruptions, 
the site must refer to the “Panorama-HF OLE Patient visit guide during Public Health 
Emergencies” document and discuss with the site monitor for guidance on the steps that need 
to be followed for collection of missed data.  


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Table 8-1
Assessment Schedule
Visit
500
501
**
502
*
503
*
504
*
505
*
50
6†
507
508
†
509
510
†
511
512
†
513
514
†
515
516
†
517
518
520
522
†
519 
521
523
U
N
S
599
Week/Month
Scree
ning
Wk
0
Wk
2
Wk
4
Wk
6
Wk
8
Mo 
3
Mo 
6
Mo 
9
Mo
12
Mo
15
Mo
18
Mo
21
Mo
24
Mo
27
Mo
30
Mo
33
Mo
36
Mo 
39 
Mo 
45 
Mo 
51
Mo 
42 
Mo 
48 
Mo 
54
EO
S6 
Obtain 
Informed 
Consent 
(parent 
(s)-legal guardian 
(s)/consent-
assent (patient, as 
applicable)1
x S
Demography
x
Inclusion/Exclusio
n Criteria
x
x4
Medical History
x
Pediatric 
Heart 
Failure History
S
Concomitant 
Medications5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Vital Signs (BP 
and pulse)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Height
x
x
S
x
S
x
S
x
S
x
Weight
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


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Visit
500
501
**
502
*
503
*
504
*
505
*
50
6†
507
508
†
509
510
†
511
512
†
513
514
†
515
516
†
517
518
520
522
†
519 
521
523
U
N
S
599
Week/Month
Scree
ning
Wk
0
Wk
2
Wk
4
Wk
6
Wk
8
Mo 
3
Mo 
6
Mo 
9
Mo
12
Mo
15
Mo
18
Mo
21
Mo
24
Mo
27
Mo
30
Mo
33
Mo
36
Mo 
39 
Mo 
45 
Mo 
51
Mo 
42 
Mo 
48 
Mo 
54
EO
S6 
Head 
Circumference (≤ 
3 years old)
x
x
x
x
x
x
Physical 
Examination 
(complete)
S
S
S
S
S
S
S
Physical 
Exam 
(abbreviated)
S
S
S
S
S
S
S
S
S
Urinalysis
x4
x
x
x
x
(x)
x
Serum/Urine 
Pregnancy Test2
x4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete 
Laboratories
x4
x
x
x
x6
(x)
x
Abbreviated 
Laboratories3
x4
x
x
x
x
x
x
x
x6
(x)
AEs/SAEs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dosage 
Administration 
Record
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
(x)
x
Study Medication 
Compliance
S
S
S
S
S
S
S
S
S
S
S
(S
)
S


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Visit
500
501
**
502
*
503
*
504
*
505
*
50
6†
507
508
†
509
510
†
511
512
†
513
514
†
515
516
†
517
518
520
522
†
519 
521
523
U
N
S
599
Week/Month
Scree
ning
Wk
0
Wk
2
Wk
4
Wk
6
Wk
8
Mo 
3
Mo 
6
Mo 
9
Mo
12
Mo
15
Mo
18
Mo
21
Mo
24
Mo
27
Mo
30
Mo
33
Mo
36
Mo 
39 
Mo 
45 
Mo 
51
Mo 
42 
Mo 
48 
Mo 
54
EO
S6 
Contact IRT
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense 
Study 
Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
(x)
End 
of 
Study 
Treatment 
Discontinuation 
x
UNS = Unscheduled visit
S = assessment to be recorded on source documentation only
X = assessment to be recorded in the clinical database or received electronically from a vendor
PSD = Premature subject discontinuation
(x) / (S) = parentheses  indicate that this is an optional assessment
† Visit numbers 506, 508, 510, 512, 514, 516, 518, 520, 522 are telephone visits. 
1 Patient Assent document is captured as a source document and is not stored in the clinical database.
2 For child bearing potential females (CHBP) only. Urine pregnancy test is analyzed locally and done at all in-person scheduled/unscheduled visits on all female subjects 
≥11 years of age and all female subjects who are <11 years of age if they are menstruating. A serum pregnancy test is performed and analyzed at Visit 500 (if >14 days 
after PANORAMA-HF EOS visit) and at Visit 599 respectively.  Additionally, for all CHBP, a urine pregnancy test will be performed at monthly intervals during the study. 
The monthly urine pregnancy test can be performed either via: 1) monthly study site visits for urine pregnancy tests, or 2) providing the subject with urinary pregnancy tests 
for home monthly tests. See Section 8.4.2 for additional details. 
3 Abbreviated laboratories consist of serum sodium, potassium, creatinine, eGFR (modified Schwartz formula). 


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Visit
500
501
**
502
*
503
*
504
*
505
*
50
6†
507
508
†
509
510
†
511
512
†
513
514
†
515
516
†
517
518
520
522
†
519 
521
523
U
N
S
599
Week/Month
Scree
ning
Wk
0
Wk
2
Wk
4
Wk
6
Wk
8
Mo 
3
Mo 
6
Mo 
9
Mo
12
Mo
15
Mo
18
Mo
21
Mo
24
Mo
27
Mo
30
Mo
33
Mo
36
Mo 
39 
Mo 
45 
Mo 
51
Mo 
42 
Mo 
48 
Mo 
54
EO
S6 
4 If Visit 500 is scheduled within 14 days of the PANORAMA-HF End of Study visit (Visit 416) and lab results from Visit 416 are available at Visit 500, the assessment results 
from PANORAMA-HF End of Study visit can be used for Visit 500 instead, except these discontinued study drug treatment early due to the implementation of the USM. Visit 
501 is the visit for first drug administration. The inclusion/exclusion criteria and the abbreviated local lab at Visit 501 may be performed per the investigator’s clinical 
judgement (e.g., if it is believed that the patient’s health status may have changed since the screening visit) (See Section 8.1 for details). Note: In addition to the scheduled 
complete and abbreviated laboratories per the Assessment Schedule, laboratory evaluations may also be performed at any scheduled or unscheduled visit based on the 
investigator’s clinical judgement.
5 Includes Prior and Concomitant Heart Failure Medications 
6 Complete labs at V521 and abbreviated labs at V519 and V523. If the EOS coincides with a scheduled visit, the assessments of EOS visit will take precedence. 
* Visits 502 (Week 2), 503 (week 4), 504 (week 6) and 505 (week 8) are for up-titration purposes and safety evaluation. Number of visits can vary dependent on starting 
dose (DL1 or DL2) and maximal tolerated/target dose. After subject’s target dose is achieved, one more visit can be scheduled approximately within the next 2 weeks for 
safety evaluation, subsequent visits are optional up to visit 506 (3 months).
** Visit 501 must occur within 30 days following completion of PANORAMA-HF core study Visit 416 (See Section 8.1 for details).


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8.1
Screening
Please refer to Table 8-1, Assessment Table, for the information to be collected during the 
Screening visit. All consenting subjects will be assessed for eligibility at the screening (Visit 
500). 

Complete laboratory tests at Visit 500 as indicated in Table 8-11 & Table 8-3 should be 
conducted to assess eligibility.  

The Investigator can use complete lab results from Visit 416 of PANORAMA-HF, except 
those who discontinued study drug treatment early due to the implementation of the USM, 
for Visit 500 to evaluate the OLE screening criteria when: 1) Visit 500 is conducted within 
14 days from Visit 416, and 2) when Visit 416 results are available at the time of Visit 500.

In the case where a safety laboratory value at screening is outside of the range specified in 
the exclusion criteria, the assessment may be repeated once prior to Visit 501 (please see
details for re-screening in Section 8.1.1). If the repeat value remains outside of the specified 
ranges, the subject must be excluded from the study.
Visit 501 is the visit for first drug administration. The inclusion/exclusion criteria and the 
abbreviated local lab at Visit 501 may be performed per the investigator’s clinical judgement 
(e.g., if it is believed that the patient’s health status may have changed since the screening visit 
laboratory assessment was performed).  
Visits 500 and 501 and all their procedures, including all required screening procedures and 
safety labs, must be completed such that the study medication is initiated no later than 30 days 
after Visit 416 of the core study. 
Before starting OLE study medication at Visit 501, a 36-hour double-blind study 
medication/ACEI-free washout is required after the last dose of study medication taken in the 
PANORAMA-HF study (Visit 416) and for those that have transitioned to an ACEI after 
completion of PANORAMA-HF, the core study.
8.1.1
Information to be collected on screening failures
Subjects or parents/guardians who sign an informed consent form for themselves or for their 
child, respectively, and who (i.e. the subject) are subsequently found to be ineligible for this 
study, will be considered a screen failure. The reason for screen failure should be entered on 
the applicable Case Report Form. The baseline characteristics, demographic information, 
informed consent, and Inclusion/Exclusion pages must also be completed for screen failure 
subjects. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a serious adverse event during the screening phase (see 
SAE section for reporting details).
Subjects or parents/guardians who sign an informed consent for themselves or for their child, 
respectively, and who are considered eligible but fail to be started on treatment for any reason 
will have to discontinue the study and will be considered an early study termination. The reason 
for early study termination should be captured on the appropriate disposition Case Report Form 
at Visit 599. 


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Re-screening:
The investigator may consider re-screening a screen failure subject if he/she believes that the 
subject’s condition has changed and they may potentially be eligible. Re-screening should be 
arranged as soon as possible to ensure initiation of study treatment (Visit 501) within 30 days 
after Visit 416 of the PANORAMA-HF core study. The subject (if applicable) /parent(s)/legal 
guardian(s) for the subject must provide new written informed consent before when the subject 
is re-screened. Subjects required to provide assent must also provide new assent before being 
re-screened.
8.2
Subject demographics/other baseline characteristics
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF.
Subject demographic and baseline characteristic data will be collected including: year of birth 
(where allowed)  age in years (age in months for subjects < 2 years, where allowed), sex, race 
and ethnicity, as well as the Identification Number (ID No.) the subject was formerly assigned 
in the PANORAMA-HF study (CLCZ696B2319). Additionally, vital signs, weight and height 
will be collected. Relevant medical history/current medical condition data includes data until 
the start of study drug. (Information regarding pediatric heart failure history will be recorded 
only in source documentation.) HF medications will be recorded on the Concomitant 
Medications eCRF.
8.3
Efficacy
Efficacy will not be measured in this study.
8.4
Safety/Tolerability
The Sponsor may request additional information on specific adverse events or laboratory events 
of interest and may make requests to perform additional diagnostic tests to further assess the 
safety profile of sacubitril/valsartan. Such information may include diagnostic procedure 
reports, discharge summaries, autopsy reports, and other relevant information that may help in 
assessing the reported adverse event. All additional information will be de-identified prior to 
collection by Novartis or its agents.
In addition to AE/SAEs, the following safety-related evaluations will be done:

Physical examinations (data recorded only in source)

Vital signs

Height, weight, and head circumference (head circumference is only collected in subjects 
who are ≤3 years of age at enrollment)

Laboratory evaluations

Pregnancy

Angioedema
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.


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For details on AE collection and reporting, refer to AE section (Section 10.1).
Table 8-2
Physical Assessments
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed.
An abbreviated physical exam will include the examination of general 
appearance and vital signs (systolic and diastolic blood pressure [SBP and 
DBP] and pulse)as well as other examinations based on the investigator’s 
discretion. . 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present 
prior to signing informed consent must be recorded as medical history on the 
appropriate eCRF. Significant findings made after signing informed consent 
which meet the definition of an Adverse Event must be recorded as an adverse 
event on the corresponding eCRF.
Vital sign
Vital signs include BP and pulse measurements and are assessed when a 
complete or abbreviated physical examination is performed. After the subject 
has been sitting for approximately 5 minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be measured 
using an automated validated device, e.g. OMRON, or a standard 
sphygmomanometer with an appropriately sized cuff on the non-dominant arm.
Supine BP instead of sitting BP will be measured in subjects who are infants or 
who cannot sit comfortably. Clinically notable vital signs are defined in 
Appendix 1.
Height, weight 
and head 
circumference
Height/ length in centimeters (cm). It is recommended to measure standing 
height using a stadiometer without shoes.
Body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without 
shoes) will be measured at every site visit. Body weight during hospitalization 
is to be recorded only if available as per standard of care.
For subjects ≤ 3 years, head circumference in centimeters (cm) is measured.
8.4.1
Laboratory evaluations
Complete laboratory evaluations (hematology, blood chemistry, and urine) as outlined in Table 
8-3 are performed at screening (Visit 500), and subsequently every 12 months from Visit 501
(Week 0) until End of Study (Visit 599). Complete laboratory evaluations will be performed at 
central laboratory facilities.
Abbreviated safety laboratory evaluation consists of serum sodium, potassium, creatinine, and 
eGFR (Table 8-3). Abbreviated laboratory evaluations are to be performed every 12 months 
starting from month 6 (Visit 507) at the central laboratory when possible, as indicated in Table 
8-1. 
In addition, abbreviated laboratory assessments should be performed at up-titration visits (Visits 
502, 503, 504 and 505, as applicable), and unscheduled visits with planned dose level changes 
and should be performed locally. Local laboratory results will allow investigators to proceed 


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with study visit procedures without the need to wait for central laboratory results. The local
laboratory results must be recorded in the appropriate eCRF. Given limitations of blood volume, 
the local laboratory assessments will be a priority for urgent medical decision-making 
(including for study-drug dose titration).
Details on the collections, shipment of samples and reporting of results by the central laboratory 
will be provided to the investigators in the Laboratory Manual. If the central laboratory is 
unavailable and/or when dose level changes are intended (either for abbreviated or complete 
labs), the local laboratory should be used.
Local and central laboratory results need not agree in reported results and reference ranges. The  
Investigator should use his/her clinical judgement on how to best manage the safety of the 
patient when making decisions. 
Clinically notable laboratory findings are defined in Appendix 1. These findings must be 
commented on by the investigator in the source documents and additional laboratory 
evaluations may be required, as judged appropriate by the investigator.
If the laboratory abnormality induces clinical signs or symptoms, or requires therapeutic 
intervention, and satisfies the criteria defined in Section 10 Safety reporting, then the diagnosis 
or medical condition must be entered on the AEs page of the subject's eCRF and any treatment 
necessary should be documented. If the laboratory abnormality is the primary reason for an 
unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then the 
procedure for rapid notification of SAEs must be followed.
Likewise, if the laboratory abnormality leads to discontinuation of the study drug, the subject 
must be followed until the abnormality resolves or until it is judged to be permanent. This 
investigation may include continued monitoring by repeat laboratory testing or by performing 
additional laboratory tests as deemed necessary by the investigator or the Sponsor’s medical 
monitor.
For child bearing potential females only, serum pregnancy testing will be performed at 
screening (visit 500), and End of Study visit (Visit 599). Please see details in Section 8.4.2. 
A table, which provides the maximum, allowable blood-draw volumes by weight, can be found 
in Appendix 8.
There are countries where plasma potassium is used instead of serum potassium for routine 
clinical care. Plasma potassium can be used instead of serum potassium in this study. Serum 
potassium thresholds in the study protocol, including those values cited in Appendix 1 and 
Appendix 7 can be converted to plasma potassium thresholds for the study by subtracting 0.4 
mmol/L from the serum potassium threshold.


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Table 8-3
Laboratory Assessments
Hematology
Biochemistry
Urine measurements**
Hematocrit 
Alanine aminotransferase (ALT)
Specific gravity
Hemoglobin
Albumin (Alb)
pH
Platelet count
Alkaline phosphatase (ALP)
Glucose
Red blood cell count (RBC)
Aspartate aminotransferase 
(AST)
Protein (Total)
White blood cell count (WBC)
Blood urea nitrogen (BUN)
Ketones
WBC differential
Calcium
Bilirubin
Magnesium
Urobilinogen
Phosphate
Hemoglobin (blood)
Red blood cell distribution width 
(RDW)
Chloride
Leukocyte esterase
Mean corpuscular volume 
(MCV)
Creatinine*
Nitrite
Mean corpuscular hemoglobin 
concentration (MCHC)
Glucose
WBC
Potassium*
RBC sediments
Sodium*
Hyaline casts
Bicarbonate
Granular casts
Total bilirubin (TBL)
Waxy casts
Fractionated bilirubin (if total 
bilirubin >2 x ULN)
WBC casts
Total protein
RBC casts
Uric acid
eGFR*
*Abbreviated laboratory evaluations must include these parameters. eGFR should be calculated based 
on most recently available height.
**Urinalysis with dipstick includes specific gravity, pH, glucose, total protein, bilirubin, ketones, 
urobilinogen, nitrite, leukocytes esterase and hemoglobin (blood). Other urine measurements listed are 
not required. If a urine dipstick is positive, other urine measurements such as a qualitative microscopic 
determination of WBC, RBC sediments (and casts) should also be measured.
8.4.2
Pregnancy and assessments of fertility
Pregnancy 
All child-bearing potential female subjects who are not surgically sterile will have pregnancy 
testing. Additional pregnancy testing might be performed if requested by local requirements.
Serum pregnancy testing will be performed at screening (Visit 500), and End of Study visit 
(Visit 599). Childbearing potential females (CHBP) are defined as all female subjects ≥ 11 years 
of age and all female subjects who are <11 years of age if they are menstruating. Pre-menarchal 
girls <11 years of age should notify the study site if they start menstruating after the study has 
started so pregnancy testing can be initiated. Urine pregnancy test is analyzed locally and done 
at all in-person scheduled/unscheduled visits on all CHBP female subjects. If screening visit 
(Visit 500) is scheduled within 14 days after PANORAMA-HF End of Study visit for the 


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subject, no serum pregnancy test will be performed, only urine pregnancy test will be needed 
(see Table 8-1 for additional details regarding pregnancy testing). A positive urine pregnancy 
test should be confirmed with a serum pregnancy test. Subjects with a positive serum pregnancy 
at any time in the study must be discontinued immediately from the study and should be seen 
at the site for Visit 599. 
For child-bearing potential females, a urine pregnancy test will also be performed at monthly 
intervals between study visits, during the study. Based on local regulatory requirements and/or 
cultural differences across participating countries, the between-study-visit monthly urine 
pregnancy test can be performed either via: 1) monthly study site visits for urine pregnancy 
tests, or 2) providing the subject with urinary pregnancy tests for home monthly tests. 
If monthly home urine pregnancy tests are utilized, child-bearing potential female subjects will 
be given a urine pregnancy test kit for each month between study visits and will be instructed 
to perform a urine pregnancy test at home, once per month (approximately every 30 days). 
Subjects will be given a Pregnancy Test Diary in which they are to record the date and the 
results of their pregnancy tests that are done at home, each time they run the test. Where possible, 
Study Site personnel will contact the subject on a monthly basis to check that the subject has 
completed the urine pregnancy test and has recorded the result in the Pregnancy Test Diary. 
The Study Site personnel may also ask for the result of the pregnancy test. The contact by the 
Study Site personnel and the result of the pregnancy test will be documented in the source 
documentation for the subject. The Pregnancy Test Diary will be part of the source 
documentation for the subject. If the pregnancy test is positive, the subject/parents/guardian 
must contact the investigator immediately. The aforementioned pregnancy testing (i.e. done at 
home or at the study site) will be maintained during treatment and until the end of relevant 
systemic exposure.
All menarchal girls and their parents/caregivers should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. It is important to be sensitive in 
introducing this issue, as understanding and comprehension of puberty, sexual activity, 
pregnancy and contraception is influenced by age; as well as, factors such as precocity, socio-
educational economic and familial background. These discussions are therefore best performed 
by investigators familiar with the pediatric subject and her family and should be guided by 
requirements of the local regulatory authorities. These discussions should take into account the 
socio-economic, cultural factors and religious beliefs of the adolescent participant and her 
family. The investigator should also discuss the management of the pregnancy test results with 
the subject and her parents/caregivers. The privacy of the subject should be considered in 
accordance with the local law and ethics.
Any subject with a positive pregnancy test must discontinue study drug immediately, should be 
discontinued from the study, and should be seen at the site for Visit 599 .
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.


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In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH)
testing is required of any female subject regardless of reported reproductive/menopausal status 
at screening/baseline.
8.4.3
Other safety evaluations
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 subjects. If such an 
event occurs, the investigator will complete angioedema case report forms to summarize the 
event, its treatment, and its ultimate outcome. This report along with the requisite medical 
documentation must be submitted to Novartis as soon as possible. Follow-up reports must be 
communicated to Novartis as soon as new information regarding the event becomes available. 
All hospital records related to the event must be communicated to Novartis.
The investigator may also be contacted by Novartis and be instructed to complete specific forms 
regarding AEs that may resemble an angioedema-like event. 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 by Novartis to an external independent Angioedema 
Adjudication Committee for assessment. Information regarding this committee is outlined in 
Section 10.2.3. Details on the procedures for reporting angioedema events will be provided to 
investigators in a manual.
The study duration will provide at least 1 year of growth and safety data in growing children, 
and this will be additional to the 1 year of data provided by the PANORAMA-HF study.
8.4.4
Appropriateness of safety measurements
The safety and clinical laboratory assessments performed in this study are similar to those used 
in the core study PANORAMA-HF (CLCZ696B2319). These assessments are appropriate for 
an investigational drug with the mechanism(s) of action of sacubitril/valsartan (angiotensin 
receptor neprilysin inhibitor), the safety profile described in the sacubitril/valsartan Investigator 
Brochure, and the indication/subject population under study.
8.5
Additional assessments
No additional tests will be performed on subjects entered into this study.


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment 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.
In this study, if the study treatment is permanently discontinued, the subject should be 
discontinued from the study and EOS visit (Visit 599) should be conducted (Section 6.5.1).
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section

Any situation in which study participation might result in a safety risk to the subject

Any laboratory abnormalities that in the judgment of the investigator prevents the subject 
from continuing participation in the study

A consecutive 3-month interruption of study treatment
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.
Subjects who discontinue study treatment 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 withdraw of informed consent section,). 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
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.


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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 table.
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.
For the United States (US) and Japan: All biological samples not yet analyzed at the time of 
withdrawal may still be used for further testing/analysis in accordance with the terms of this 
protocol and of the informed consent form.
For European Union (EU) and Rest of World (RoW): All biological samples not yet analyzed 
at the time of withdrawal will no longer be used, unless permitted by applicable law. They will 
be stored according to applicable legal requirements.
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 due 
diligence has been completed or 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. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final visit) 
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.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 

Discontinuation of study drug development

The results of the PANORAMA-HF core study do not support local registration
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from study drug or refer them for appropriate ongoing care.


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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 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.
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 severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment and other investigational treatment. For example, if 
the event is due to progression of the study indication, the assessment of causality will 
usually be ‘Not suspected.’ The rationale for this guidance is that progression of 
underlying illness are not caused by the trial drug, they happen in spite of its 
administration and 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
4. whether it constitutes an SAE (see Section 10.1.2 for definition of SAE) and which 
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5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Study drug dose not changed

Study drug dose Reduced/increased

Study drug interrupted/withdrawn
6. its outcome
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.
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, any potential 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 
Appendix 1.
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

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).


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
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: 
a. routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
b. 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
c. social reasons and respite care in the absence of any deterioration in the subject’s 
general condition
d. 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 immediately, without undue delay, but under no circumstances later than within
24 hours of obtaining knowledge of the events (Note: If more stringent, local regulations 
regarding reporting timelines prevail). Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site.
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.


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Investigators will report events that are commonly seen in the study population, but they will 
not be reported as Suspected Unexpected Serious Adverse Reactions (SUSARs) to regulatory 
agencies, ethics committees (ECs), or investigators during the study ( Table 10-1).
Table 10-1
Events commonly seen in study population
Cardiovascular events 
Non-cardiovascular events 
Worsening HF 
Bronchitis 
Influenza 
Edema 
Vomiting 
Nasopharyngitis 
Hypotension 
Cough 
Nausea 
Renal impairment 
Diarrhea 
Pneumonia 
Failure to thrive 
Upper respiratory infection 
Fatigue 
Weight change 
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 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information. (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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 (new occurrence) and 
is thought to be related to the study treatment, a 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.
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01, Food Drug Administration (FDA)
Guidance 2012 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30-day period following end of study visit should only be 
reported to Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
Should a pregnancy be discovered during the course of study, the following procedure must be 
followed. In case of pregnancy discovered during the screening period, the patient will be 
withdrawn from the study immediately.
To ensure patient 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 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.


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Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to study treatment any 
pregnancy outcome.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
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. Please refer to the 
Guidance for capturing the study treatment errors including misuse/abuse in Table 10-2.
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 10-2
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
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 
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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 16-3 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-3 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 16-4. Repeat liver chemistry tests (i.e. ALT, AST, Albumin, 
TBL, PT/INR, ALP and 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 be performed and evaluations may include 
additional investigations:

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.
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with TBL increase may be indicative of potential 
DILI and should be considered as clinically important events.
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below:

For subjects with normal ALT and AST and TBL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis.


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Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury.
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat Liver Function Tests (LFT) testing as soon as possible, preferably within 
48 hours from the awareness of the abnormal results. The evaluation should include laboratory 
tests, detailed history, physical assessment, and the possibility of liver metastasis or new liver 
lesions, obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR, and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing 
liver conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.


Additional testing for other hepatotropic viral infection [Epstein-Barr virus (EBV), 
cytomegalovirus (CMV), or herpes simplex virus (HSV)], autoimmune hepatitis or liver 
biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of a serious adverse event (SAE) and should reported 
as SAE using the term “potential drug-induced liver injury.” All events should be followed up 
with the outcome clearly documented.
10.2.2
Renal safety monitoring
Every renal laboratory trigger or renal event as defined in Table 16-5 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Appendix 3.
10.2.3
Angioedema Adjudication committee
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis). Details 
on the process of reporting angioedema and angioedema-like events are outlined in a manual 
provided to investigators.
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
If an angioedema-like event satisfies the definition of an SAE, the investigator must submit an 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event.
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 CFR Part 11 requirements, investigator site staff will not 
be given access to the Electronic 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.
11.2
Database management and quality control
Novartis personnel [or designated Clinical Research Organization (CRO)] 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 members are required to respond promptly to queries and to make any necessary 
changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Data about all study treatment (s) dispensed to the subject and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines.
Once the database has been declared to be complete and accurate, it will be locked and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO 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. 


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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 visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/delegated CRO/Clinical Research Associate (CRA)
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis/sponsor 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, 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 analysis sets will be used for the statistical analyses:

Screened set (SCR): All patients who signed the informed consent for the extension open-
label study.

Safety Set (SAF): All SCR patients who received at least one dose of open-label study 
treatment during the extension open-label study.
12.2
Subject demographics and other baseline characteristics
In the following, the term “age group” refers to the two age groups. Summary statistics will be 
provided by age group (6 years and older, 1 year to < 6 years) and for overall for demographics 
and baseline characteristics, including age, age group (only for overall), sex, race, ethnicity, 
weight, height and vital signs.
Continuous variables will be summarized using n, mean, standard deviation, median, minimum, 
and maximum. Categorical variables will be summarized using frequencies and percentages.


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Relevant medical histories will be summarized, by system organ class and preferred term, for 
overall and for each age group.
The SAF will be used for the above analyses.
12.3
Treatments
Duration of exposure to the study treatment will be summarized for each age group and for 
overall, using mean, standard deviation, median, minimum, and maximum. Additionally, the 
number and percentage of patients in meaningful duration categories will be summarized for 
each age group and for overall. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by anatomical therapeutic classification (ATC), preferred 
term, for overall and for each age group.
The SAF will be used for the above analyses.
12.4
Analysis of the primary endpoint(s)
The primary objective is to evaluate safety and tolerability of LCZ696 in eligible heart failure 
patients from PANORAMA-HF receiving open-label investigational drug.
The primary safety assessment will be based on adverse events, which will be analyzed using 
frequencies and percentages.
The following adverse events will be summarized by primary system organ class, preferred 
term, and maximum severity as appropriate, for each age group and for overall, using numbers 
and percentages of patients with at least one adverse event in the corresponding class.

Any adverse event (treatment emergent or not)

Any serious adverse event (treatment emergent or not)

Treatment emergent adverse event (TEAE)

Treatment emergent serious adverse event

Treatment emergent adverse event of special interest, i.e. hyperkalemia, hypotension, 
angioedema, renal impairment

TEAE leading to dose adjustment, temporary dose interruption, or permanent 
discontinuation (including death) of study treatment

TEAE leading to permanent discontinuation (including death) of study treatment
For overall and for each age group, death during the treatment period and the primary cause of 
death will be summarized using frequencies and percentages.
For overall and for each age group, the vital signs and the laboratory evaluations will be 
summarized by visit.
Adverse events (including SAEs), laboratory assessments, vital signs, and duration of drug 
exposure are considered primary endpoints.


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12.4.1
Definition of primary endpoint(s) 
Adverse events, laboratory assessments, vital signs, and duration of drug exposure are 
considered primary endpoints.
12.5
Analysis of secondary endpoints
Not applicable. There are no secondary endpoints.
12.6
Analysis of exploratory endpoints
Not applicable. There are no exploratory endpoints.
12.7
Interim analyses
No interim analysis is planned. However, the safety will be monitored through regular review 
of adverse events and related data.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
All patients who have completed the double-blind phase of the study PANORAMA-HF, as 
defined in the Inclusion Criteria (Section 5.1), and who meet all other Inclusion and Exclusion 
criteria (Section 5.1 and Section 5.2), are eligible for the extension study.
There is no specific sample size required for the study.
12.8.2
Secondary endpoint(s)
Not applicable.
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 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/sponsor monitors, auditors, Novartis/sponsor Quality Assurance representatives, 


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designated agents of Novartis/sponsor, 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/sponsor 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 (defined as last patient last visit) 
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.).
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 Operating 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.


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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
Andrews RE, Fenton MJ, Ridout A, et al. (2008) New onset heart failure due to heart muscle 
disease in childhood: A prospective study in the United Kingdom and Ireland. Circulation; 
117:79-84.
CVAL489K2304 (2011) Physician survey of clinical management and uses of medicinal 
products in paediatric patients with heart failure survey protocol. Diovan pediatric heart 
failure survey. Novartis Internal Document.
Howie SR (2011) Blood sample volumes in child health research: review of safe limits. Bull 
World Health Organ; 89:46-53.
Hsu DT, Pearson GD (2009) Heart failure in children Part I: History, etiology and 
pathophysiology. Circulation Heart Failure; 2:63-70.
Kantor PF, Mertens LL (2010) Clinical practice: Heart failure in children. Part II: current 
maintenance therapy and new therapeutic approaches. Eur J Pediatr; 169:403-410.
Kleinman ME, Chameides L, Schexnayder SM, et al. (2010) Part 14: PALS (Pediatric 
Advanced Life Support): 2010 American Heart Association guidelines for cardiopulmonary 
resuscitation and emergency cardiovascular care. Circulation; 122:S876-S908.
Mah D, Singh TP, Thiagarajan RR, et al. (2009) Incidence and risk factors for mortality in 
infants awaiting heart transplantation in the USA. J Heart Lung Transplant; 12: 1292-8.
McMurray JJV, Packer M, Akshay S, et al. (2014) Angiotensin-neprilysin inhibition versus 
enalapril in heart failure. N Engl J Med; 371(11):993-1004.
Peters A, Gordon I (1999) Quantitative Assessment of the Urinary Tract with Radionuclides. 
In Barratt T. M, Avner E, Harmon W (eds), Pediatric Nephrology, fourth edition, pp 365-735. 
Lippincott Williams & Wilkins, Maryland.
Sharma M, Nair M, Jatana SK, et al. (2003) Congestive heart failure in infants and children. 
MJAFI; 59:228-233.
Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and 
adolescents. Clin J Am Soc Nephrol; 4:1832–1843.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Table 16-1
Clinically notable laboratory values
Parameter
Conventional
Alert Value
Conventional
Units
SI Alert
Value
SI
Units
Hematology
Red Blood Cell 
Count 
>50% 
increase, >30% 
decrease
x10E6/uL
>50% 
increase, >30% 
decrease
x10E12/L
Hemoglobin
>50% 
increase, >30% 
decrease, or any 
value <7
g/dL
>50% 
increase, >30% 
decrease, or any 
value <70
g/L
Hematocrit
>50% 
increase, >30% 
decrease
%
>50% 
increase, >30% 
decrease
L/L
White Blood Cell 
Count 
>50% 
increase, >50% 
decrease
x10E3/uL
>50% 
increase, >50% 
decrease
x10E9/L
Platelet Count
>75% 
increase, >50% 
decrease
x10E3/uL
>75% 
increase, >50% 
decrease
x10E9/L
Chemistry
BUN
>50% increase
mg/dL
>50% increase
mmol/L
Creatinine
>50% increase
mg/dL
>50% increase
umol/L
Albumin
<2
g/dL
<20
g/L
Glucose
>50% 
increase, >50% 
decrease, or any 
value <60
mg/dL
>50% 
increase, >50% 
decrease, or any 
value <3.3
mmol/L
Total Bilirubin
>100% increase
mg/dL
>100% increase
umol/L
AST (SGOT)
>150% increase
U/L
>150% increase
U/L
ALT (SGPT)
>150% increase
U/L
>150% increase
U/L
Sodium
>5% increase, or 
any value >150
mEq/L
>5% increase, or 
any value >150
mmol/L
Potassium
>20% 
increase, >20% 
decrease, or any 
value >5.3 
mEq/L
>20% 
increase, >20% 
decrease, or any 
value >5.3 
mmol/L
Chloride
>10% 
increase, >10% 
decrease
mEq/L
>10% 
increase, >10% 
decrease
mmol/L
Calcium
>10% 
increase, >10% 
decrease
mg/dL
>10% 
increase, >10% 
decrease
mmol/L
Uric Acid
>50% increase
mg/dL
>50% increase
mmol/L


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Table 16-2
Criteria for clinically notable vital signs
Age
HR [min-1]
SBP [mmHg]
DBP [mmHg]
RR [min-1]
1-3 years
<60, >120
<76, >115
<45, >75
<14, >35
3-6 years
<55, >120
<82, >120
<50, >80
<12, >30
6-12 years
<50, >105
<90, >130
<50, >80
<10, >27
>12 years
<45, >95
<90, >145
<55, >90
<8, >23


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16.2
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements
Table 16-3
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS
3 × ULN < ALT / AST ≤5 × ULN
1.5 × ULN < TBL ≤2 × 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 16-4
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

Complete liver eCRF
ALT, AST, TBL, Albumin (Alb), 
PT/INR, ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver eCRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver eCRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more 
than 2 weeks, discontinue the 
study drug

Establish causality

Complete liver eCRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver eCRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver eCRF
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

Complete liver eCRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 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

Complete liver eCRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially 
indicative of a 
liver toxicity

Consider study treatment 
interruption or discontinuation 

Hospitalization if clinically 
appropriate

Establish causality
Investigator discretion


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Criteria
Actions required
Follow-up monitoring

Complete liver eCRF
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.


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16.3
Appendix 3: Specific renal alert criteria and actions
Table 16-5
Specific renal alert criteria and actions
Serum event
Estimated GFR* decrease
≥ 25% compared to baseline AND eGFR  
< 90 mL/min/1.73m2 
Confirm ≥ 25% decrease AND eGFR*
< 90 mL/min/1.73m2 after 24-48 hours (h). 
If it persists, follow up with repeat, if possible, 
within 2-5 days. 
Then do some frequent monitoring (preferably 
weekly) until event resolves or stabilizes. 
If event does not resolve or stabilize, consider 
consulting nephrologist and/or drug interruption.
Acute Kidney Injury: Serum estimated GFR* 
decrease ≥50% compared to baseline in the 
PANORAMA-HF core study (i.e. Visit 301 for Part 
2)
Follow up within 24-48h if possible.
If value persists, consider consulting nephrologist 
and/or drug interruption.
Urine event
Confirm by urinary protein creatinine ratio. 
If it persists, consider consulting nephrologist 
and/or drug interruption.
New dipstick proteinuria ≥ 1+
Confirm value after 24-48 h, if possible.
If dipstick value confirmed: 
a) perform urinary protein/creatinine ratio (PCR) 
within 2-5 days, if possible. If PCR > 0.2 then:
b) perform urine microscopy and evaluate.
If PCR > 0.2 and /or urine microscopy has 
findings (e.g. crystals, casts, dysmorphic RBC, 
leukocytes), consider consulting nephrologist or 
drug interruption or discontinuation
New dipstick glucosuria ≥ 1+ not due to diabetes
Confirm value after 24-48 h, if possible.
If it persists: 
a) perform, blood glucose (fasting)
b) perform urinary protein/creatinine ratio. 
If PCR ratio > 0.2 and blood glucose abnormal 
consider consulting nephrologist and /or drug 
interruption or discontinuation
New dipstick hematuria ≥ 1+ not due to trauma
Confirm value after 24-48 h, if possible.
If it persists:
a) perform urinary protein creatinine ratio (PCR) 
within 2-5 days on a first morning urine collection 
b) perform urine microscopy and evaluate.
If PCR > 0.2 and /or urine microscopy has 
findings (e.g. crystals, casts , dysmorphic RBC, 
leukocytes) consider consulting nephrologist or 
drug interruption or discontinuation
* eGFR is calculated using a modified Schwartz formula for subjects <18 years: 
eGFR (ml/min/1.73m2) = 0.413 x height (cm) / serum creatinine (mg/dl). The most recently available 
height should be used for calculation.


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Urine samples for testing for renal monitoring, and particularly those for the PCR ratio determination, 
must be collected at the first morning void.
Document contributing factors in the eCRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed. 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: estimated GFR within 20% of baseline and > 90 mL/min/1.73m2 or PCR < 0.2; 
Event stabilization: estimated GFR within 20% of baseline OR > 90 mL/min/1.73m2 or PCR < 0.3.
Table 16-6
GFR by age for initiation/up-titration and exclusion criteria
Age range*
≥ 30% mean GFR for 
age (mL/min/1.73m2)**
< 30% mean GFR for 
age (mL/min/1.73m2)***
12 months to < 19 months (1 year, 7 months) 
≥ 31
< 31
19 months to < 18 years
≥ 38
< 38
≥ 18 years 
≥ 30
< 30
* Age rounded to nearest whole number
** Initiation/up-titration criteria
*** Exclusion criteria
Source: (Peters and Gordon 1999)


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16.4
Appendix 4: Guidelines for the management of renal dysfunction
General principles:
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, renal 
dysfunction may develop or may deteriorate in some patients after study drug administration. 
These recommendations have been developed to guide the investigators in managing patients 
with renal dysfunction after OLE enrollment and the first OL dose of LCZ696.
Two types of response to serum creatinine increase are described:
Surveillance situation
If, at any time after OLE enrollment and the first open-label dose of LCZ696, eGFR%* 
decreases by ≥ 50% from baseline in the PANORAMA-HF core study (i.e. Visit 301 for Part 
2), 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 cause 
creatininemia

volume decrease, including that resulting from excessive dosing of diuretics

urinary infection

urinary tract obstruction

study medication
Action situation
If a patient eGFR* decreases by ≥ 50% from baseline of the core study (i.e. Visit 301 for Part 
2) (or if serum creatinine concentration rises above 3 mg/dL (265 μmol/L), the investigator will 
check for potentially reversible causes of renal dysfunction (see above). If the investigator 
judges that study medication has to be stopped, he/she will have to contact the Novartis medical 
monitor or his/her designee. Thereafter, serum creatinine assessments will have to be repeated 
at least each week until levels return to acceptable values. If study medication was stopped, 
every effort will be done to restart it again, according to clinical conditions.
*eGFR is calculated using a modified Schwartz formula for subjects <18 years.
For subjects ≥18 years, an adult formula for eGFR will be utilized (Reference: Novartis 
Nephrology Guidance document)


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16.5
Appendix 5: American heart association (AHA) pediatric 
advanced life support (PALS) guidelines
Table 16-7
5th percentile systolic blood pressure (SBP) table
Age
SBP percentile
SBP (mmHg)
1 month to < 1 year
5th
70
1 year
5th
72
2 years
5th
74
3 years
5th
76
4 years
5th
78
5 years
5th
80
6 years
5th
82
7 years
5th
84
8 years
5th
86
9 years
5th
88
10 years
5th
90
11 years
5th
90
12 years
5th
90
13 years
5th
90
14 years
5th
90
15 years
5th
90
16 years
5th
90
17 years
5th
90
* AHA PALS guidelines 2010 (Kleinman et al 2010) are widely used criteria for hypotension in acute 
HF patients. The formula (for 1 year and older: 70 mmHg + 2 x Age, up to age 10) is understood to 
provide the 5th SBP percentile up to 10 years. For children 1 month to < 1 year and >10 years, the 
AHA PALS guidelines 2010 5th percentile is set at 70 mmHg and 90 mmHg respectively. NOTE: 


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This formula approximates the population-based 5th percentile BP data; however, the margin of 
error increases with increasing age, with the PALS formula value generally providing a lower value.


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16.6
Appendix 6: Guidelines for the management of blood pressure
1. Investigator should monitor blood pressure closely.
2. If symptomatic hypotension occurs:

Correct any treatable cause, e.g. hypovolemia

If hypotension persists, any antihypertensive drug and non-disease-modifying drugs, 
such as diuretics, calcium channel blockers (CCBs), nitrates, and α-blockers, should 
be down-titrated or stopped first before down-titration of the study drug is considered

If hypotension persists, the study drug should be down titrated or even temporarily
withdrawn.


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16.7
Appendix 7: Treatment guidelines for elevated potassium and 
hyperkalemia (serum potassium ≥5.3 mmol/L)
General principles
Elevation of potassium levels on a non-hemolyzed specimen above the predefined values 
should be repeated and confirmed before any action, if appropriate based on investigator’s 
medical judgment.
For assessment of potassium, no blood sample should be drawn by finger or heel stick. Also 
note that pH can affect potassium values, and that abnormal potassium values should include
assessment of pH. Each 0.1 increase in pH represents a 0.6 mEq/L change in the opposite 
direction of the pH change.
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 elevated potassium and hyperkalemia
Serum potassium > 5.2 and ≤5.4 mmol/L
Confirm potassium concentration in a non-hemolyzed sample.
Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. 
orange juice, melon, bananas, low-salt substitutes etc.).
Review medical regimen (including dietary supplements and over-the-counter medications) for 
agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of these 
agents:

Aldosterone antagonists (if they are believed to be the most likely cause of hyperkalemia)

Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics

Potassium supplements, e.g. potassium chloride

Salt substitutes

Non-steroidal anti-inflammatory drugs (NSAIDs)

Cyclo-oxygenase-2 (COX-2) inhibitors

Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and 
Septra® (trimethoprim/sulfamethoxazole fixed combination)

Herbal Supplements: For example, Noni juice, alfalfa (Medicago sativa), dandelion 
(Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, 
lily of the valley, Siberian ginseng, hawthorn berries.
Repeat serum potassium measurement within 3 to 5 days. If serum potassium remains > 5.2 and 
≤ 5.4 mmol/L, regularly monitor serum potassium levels to ensure stability suggested once 
monthly.
Consider down-titration of study medication, according to investigator’s medical judgment.


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Serum potassium > 5.4 and < 6.0 mmol/L
Confirm potassium concentration in a non-hemolyzed sample.
Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment.
Apply all measures outlined for serum potassium > 5.2 and ≤ 5.4 mmol/L.
Repeat serum potassium measurement after 2-3 days.

If serum potassium < 5.4 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days.
Serum potassium ≥6.0 mmol/L
Confirm potassium concentration in a non-hemolyzed sample.
Urgently evaluate patient and treat hyperkalemia as clinically indicated.
Apply all measures outlined for serum potassium > 5.4 and < 6.0 mmol/L.
Study drug should be immediately interrupted or discontinued if the serum potassium is greater 
than or equal to 6.0 mmol/L.
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee.


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16.8
Appendix 8: Reference table – blood volume by weight
Table 16-8
Reference table – blood collection volumes by body weight (kg)
2.5% and 5% Blood volume table by weight (up to 35 kg)1
Body 
Weight 
(Kg)
Total blood 
volume of the 
patient (mL)
Maximum allowable volume 
(mL) in one blood draw 
(= 2.5% of total blood volume 
of the patient)
Total maximum volume (mL) 
drawn in a 28-day period 
( = 5% of total blood volume 
of the patient)
2.5
200
5
10
3
240
6
12
3.5
280
7
14
4
320
8
16
4.5
360
9
18
5
400
10
20
5.5
440
11
22
6
480
12
24
6.5
520
13
26
7
560
14
28
7.5
600
15
30
8
640
16
32
8.5
680
17
34
9
720
18
36
9.5
760
19
38
10
800
20
40
10.5
840
21
42
11
880
22
44
11.5
920
23
46
12
960
24
48
12.5
1000
25
50
13
1040
26
52
13.5
1080
27
54
14
1120
28
56
14.5
1160
29
58
15
1200
30
60
15.5
1240
31
62
16
1280
32
64
16.5
1320
33
66
17
1360
34
68
17.5
1400
35
70
18
1440
36
72
18.5
1480
37
74
19
1520
38
76
19.5
1560
39
78


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2.5% and 5% Blood volume table by weight (up to 35 kg)1
Body 
Weight 
(Kg)
Total blood 
volume of the 
patient (mL)
Maximum allowable volume 
(mL) in one blood draw 
(= 2.5% of total blood volume 
of the patient)
Total maximum volume (mL) 
drawn in a 28-day period 
( = 5% of total blood volume 
of the patient)
20
1600
40
80
20.5
1640
41
82
21
1680
42
84
21.5
1720
43
86
22
1760
44
88
22.5
1800
45
90
23
1840
46
92
23.5
1880
47
94
24
1920
48
96
24.5
1960
49
98
25
2000
50
100
25.5
2040
51
102
26
2080
52
104
26.5
2120
53
106
27
2160
54
108
27.5
2200
55
110
28
2240
56
112
28.5
2280
57
114
29
2320
58
116
29.5
2360
59
118
30
2400
60
120
30.5
2440
61
122
31
2480
62
124
31.5
2520
63
126
32
2560
64
128
32.5
2600
65
130
33
2640
66
132
33.5
2680
67
134
34
2720
68
136
34.5
2760
69
138
35
2800
70
140
Blood volume drawn for the purpose of this study is limited to a maximum of 2.5% of the circulating 
blood volume per sampling session and to a maximum of 5% over a 4-week period (Howie 2011).
Investigators may further limit the volume of blood withdrawn based on local institutional guidelines 
and if the clinical condition of the patient may be adversely affected by removal of the blood volumes 
stated above. Details about blood volume requirement for safety samples are provide in the laboratory 
manual. 
1 For body weights >35 kg, use the following formulas to calculate 2.5% and 5% of total blood volume:
2.5% of total blood volume = body weight (in kg to the closest 0.5 kg) X 2


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2.5% and 5% Blood volume table by weight (up to 35 kg)1
Body 
Weight 
(Kg)
Total blood 
volume of the 
patient (mL)
Maximum allowable volume 
(mL) in one blood draw 
(= 2.5% of total blood volume 
of the patient)
Total maximum volume (mL) 
drawn in a 28-day period 
( = 5% of total blood volume 
of the patient)
5% of total blood volume = body weight (in kg to the closest 0.5 kg) X 4

SAP_001.pdf: 
Clinical Development 
Sacubitril/Valsartan 
CLCZ696B2319E1 / NCT03785405
A multicenter study to evaluate long-term safety and 
tolerability of open label sacubitril/valsartan in pediatric 
patients with heart failure due to systemic left ventricle 
systolic dysfunction who have completed study 
CLCZ696B2319 
Statistical Analysis Plan (SAP), Amendment 2 
Author:         
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
2023-05-12 
Number of pages: 
24 
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 and title 
impacted (Current) 
06-May-
2019 
Prior to FPFV 
Initial 
N/A 
N/A 
12-Dec-
2021 
Prior to FPFV 
Extending study duration  
Changing 
Figure 
1-1 
according 
to 
protocol 
version 
2 
of 
CLCZ696B2319 
 
Section 1.1 
Section 2.1 
Section 2.8.3 
02-Mar-
2023 
Prior to LPLV 
Adding/modifying 
general 
definitions for the study 
(e.g., 
study 
completer, 
treatment 
period, 
study 
period) 
 
Section 2.1 
03-April-
2023 
Prior to LPLV 
Removing the eligible set 
(ELG) 
 
Section 2.2 
03-April-
2023 
Prior to LPLV 
Modifying 
analysis 
for 
patient disposition  
 
Section 2.3.1 
03-April-
2023 
Prior to LPLV 
Modifying 
analysis 
for 
demographics and baseline 
characteristics 
(e.g., 
adjusted 
percentile 
for 
weight and height, z-score 
for height) 
 
Section 2.3.2 
02-Mar-
2023 
Prior to LPLV 
Adding analyses for study 
treatment 
 
Section 2.4.1 
03-April-
2023 
Prior to LPLV 
Adding analysis for patients 
who 
undergo 
heart 
transplant 
 
Section 2.4.2 
03-April-
2023 
Prior to LPLV 
 
Modifying 
definition 
for 
TEAE and TEAE of special 
interest 
 
Section 2.8.1 
03-April-
2023 
Prior to LPLV 
Modifying analysis for renal 
impairment in Table 2-1 
 
Section 2.8.1 
02-Mar-
2023 
Prior to LPLV 
Specifying data convention 
and algorithms for missing 
central lab data and imputed 
them with local lab data 
 
Section 2.8.3 
03-April-
2023 
Prior to LPLV 
Changing Table 2-3 as per 
Table 2-19 in the SAP of 
CLCZ696B2319 
Adding formula for eGFR 
calculation for patients <18 
years 
 
Section 2.8.3 
15-April-
2023 
Prior to LPLV 
Changing threshold of SBP 
for patients aged 1 to <3 
years 
 
Section 2.8.4.2 


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SAP 
 
CLCZ696B2319E1 
 
Date 
Time point 
Reason for update 
Outcome for 
update 
Section and title 
impacted (Current) 
17-April-
2023 
Prior to LPLV 
Adding analysis of height for 
patients in the age range of 
2-9 years throughout the 
OLE study 
 
Section 2.8.4.3 
28-Aug-
2023 
Prior to LPLV 
Removing analysis of lab 
data for study period and 
use a window to include lab 
data within 5 days after 
treatment discontinuation 
 
Section 2.8.3 
21-Sept-
2023 
Prior to LPLV 
Considering patients who 
switch 
to 
commercial 
entresto 
as 
censored 
patients for Kaplan-Meier 
analysis 
 
Section 2.4.1 
14-Dec-
2023 
Prior to LPLV 
Changing 
summary 
statistics for duration on 
each dose level from mean 
and standard deviation to 
median 
and 
interquartile 
range 
 
Section 2.4.1 
14-Dec-
2023 
Prior to LPLV 
Changing 
the 
rule 
for 
counting 
treatment 
emergent adverse event 
 
Section 2.8.1 
22-Dec-
2023 
Prior to LPLV 
Adding Table 2-2 to further 
clarify tablet use for patients 
 
Section 2.4.1 
30-Jan-
2024 
Prior to DBL 
Adding clarification for the 
analysis of clinically notable 
laboratory abnormality 
 
Section 2.8.3 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
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 
2.2.1 
Subgroup of interest ................................................................................ 9 
2.3 
Patient disposition, demographics and other baseline characteristics ..................... 9 
2.3.1 
Patient disposition ................................................................................... 9 
2.3.2 
Demographics and baseline 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, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective .......................................................................... 14 
2.5.1 
Primary endpoint ................................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.5.4 
Supportive analyses ............................................................................... 14 
2.6 
Analysis of the key secondary objective ............................................................... 15 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 15 
2.8 
Safety analyses ....................................................................................................... 15 
2.8.1 
Adverse events (AEs) ............................................................................ 15 
2.8.2 
Deaths .................................................................................................... 17 
2.8.3 
Laboratory data ..................................................................................... 18 
2.8.4 
Other safety data ................................................................................... 21 
2.9 
Pharmacokinetic endpoints .................................................................................... 22 
2.10 
PD and PK/PD analyses......................................................................................... 22 
2.11 
Patient-reported outcomes ..................................................................................... 22 
2.12 
Biomarkers ............................................................................................................. 22 
2.13 
Other Exploratory analyses .................................................................................... 22 
2.14 
Interim analysis ...................................................................................................... 23 


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3 
Sample size calculation ..................................................................................................... 23 
4 
Change to protocol specified analyses .............................................................................. 23 
5 
Appendix ........................................................................................................................... 23 
5.1 
Imputation rules ..................................................................................................... 23 
5.1.1 
Study drug ............................................................................................. 23 
5.1.2 
AE date imputation ............................................................................... 23 
5.1.3 
Concomitant medication date imputation ............................................. 23 
5.2 
Rule of exclusion criteria of analysis sets.............................................................. 23 
6 
Reference ........................................................................................................................... 24 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Dose administration record 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PDS 
Programming datasets specifications 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que die / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This document describes details of the analyses as outlined in section 12 of the study protocol. 
Results will be summarized in the clinical study report (CSR). However, since this is an open-
label study with regular review of safety outcomes, selected outputs may also be generated 
during the course of the study. 
1.1 
Study design 
This trial is a multicenter, open-label long-term extension (OLE) study for subjects who have 
successfully completed Part 2 of the PANORAMA-HF trial. Subjects will be enrolled into two 
different age groups (Age Group 1: 6 years and older; Age Group 2: 1 to < 6 years) in the OLE 
study. Age Groups 1 and 2 in the OLE have a target dose (dose level 4) of 3.1 mg/kg bid. 
Subjects will be up titrated to the target dose of sacubitril/valsartan, dose level 4, according to 
their tolerability, in 2-weeks intervals. An outline of the study design is presented in Figure 1-
1.  
No specific sample size is required for the study. However, all patients who have completed the 
double-blind phase of the study PANORAMA-HF, and fulfill all inclusion/exclusion criteria, 
are eligible for the study. 
The primary analysis will be conducted when all patients who are still ongoing (i.e., did not 
prematurely discontinue) have had their end of study visit (EoS).  
No interim analysis is planned. However, the safety will be monitored through regular review 
of adverse events and related data. 
Figure 1-1 
Study design 
 
w=weeks; m=months; DL=LCZ696 dose level 
* ≥36 hour of ACEI or double-blind study medication-free washout before starting OLE study medication at Visit 501 
** The starting dose at V501 can vary according to prior dose of AECI/ARBs or PANORAMA-HF study drug 
 


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1.2 
Study objectives and endpoints 
This study has only primary objective as described in Table 1-1.  
Table 1-1 
Objectives and related endpoints 
Primary Objective  
Endpoint(s) for primary objective 
• 
To further evaluate long-term safety and 
tolerability of sacubitril/valsartan in eligible 
PANORAMA-HF subjects receiving open-label 
sacubitril/valsartan 
• 
AEs, SAEs, laboratory values, vital signs, and 
duration of drug exposure 
 
2 
Statistical methods 
2.1 
Data analysis general information 
Unless otherwise specified, the data will be analyzed according to the study protocol using SAS 
9.4 or higher and R 3.4.3 or higher, by Novartis personnel.  
In general, continuous variables will be summarized using number of observations, mean, 
standard deviation, median, quartiles, minimum and maximum. Categorical variables will be 
summarized using frequencies and percentages. Unless otherwise specified, the by age group 
summaries will include: summary for the two age groups (6 years and older, 1 year to < 6 years) 
and summary for the entire analysis set.  
Study completion is defined as having reached the end of study visit (December 2023 from 
Protocol Amendment V.01 and later versions or December 2022 for Protocol V.00) while on 
treatment, or having completed 12 months of study while being on treatment and being 
transitioned to commercial Entresto.  
Data from all study centers will be combined. 
2.1.1 
General definitions  
Study treatment is sacubitril/valsartan. 
The date of first administration of study treatment is the day of the first dose of 
sacubitril/valsartan. 
The date of last administration of study treatment is the day of the last non-zero dose of 
sacubitril/valsartan. 
Study day is defined as actual date – date of first administration of study treatment + 1. 
Baseline is defined as last non-missing value before starting treatment, where for the same 
parameter, central laboratory result takes precedence over local laboratory result; in general 
values are obtained at the baseline visit (501), with the exception of urinalysis and complete 
laboratory, which are obtained at the screening visit (500). In case these two visits happened on 
the same day, results from the central laboratory will be considered as baseline values. Note 
that per protocol, in the case that visit 500 and, if applicable visit 501, is scheduled within 14 


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days of the PANORAMA-HF End of Study visit (Visit 416), the assessment results from 
PANORAMA-HF End of Study visit can be used as screening/baseline.  
The study period starts with the date of screening visit (500) and ends with the date of end-of-
study (EOS) or premature study discontinuation (PSD) visit (599).  
Treatment period starts with the date when the first dose of study treatment is given (visit 501, 
unless no dose is given at that visit) and ends with the date of treatment disposition. In the case 
that no EOS visit was undertaken (e.g., because the patient died or withdrew from the study 
without such a visit), the treatment period ends with the death/withdrawal date or the last dose 
taken as reported in the DAR page. Subjects who permanently discontinued study drug should 
be scheduled for the discontinuation study Visit 599. Note that after a consecutive 3-month 
interruption of study treatment, subject should be discontinued from the study and should be 
seen at the site for Visit 599. 
2.2 
Analysis sets 
The following analysis sets will be used: 
• Screened set (SCR): All patients who signed the informed consent for the extension 
open-label study. 
• Safety Set (SAF): All SCR patients who received at least one dose of open-label study 
treatment during the extension open-label study. 
2.2.1 
Subgroup of interest 
The patients satisfying the criterion of being within the age range of 2-9 years at each 12-month 
visit (e.g., patients aged 8 years at baseline will only be included in the analysis of height at 
their first 12-month visit) starting from baseline until EOS will be investigated, other than the 
age groups specified in Section 2.1. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number and percentage of patients who completed the screening phase will be provided by 
age group. In addition, the primary reason for not completing the screening phase will be 
summarized by age group using the numbers and percentages of patients not qualifying for such 
reasons and criteria leading to exclusion from the analysis will be provided by age group.  For 
patients who are screen failures and re-screened, the rescreening visit will be used. These 
summaries will be performed for the SCR.  
The number and percentage of patients who complete the treatment, who discontinue from the 
treatment and the primary reasons for discontinuation will be summarized by age group. In 
addition, the number and percentage of patients with protocol deviations will be provided by 
age group. These summaries will be performed based on the SAF. 


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2.3.2 
Demographics and baseline characteristics 
Summary statistics will be provided by age group and for overall for demographics and baseline 
characteristics, including age, age group (only for overall), sex, race, ethnicity, weight, height, 
head circumference (for subjects ≤ 3 years old), BMI, vital signs, age adjusted percentile for 
weight, height and body mass index (BMI = weight (kg) / height2 (m2)), z-score for height . 
Continuous variables will be summarized using n, 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 MedDRA dictionary. Medical history includes heart failure history and other 
medical history in this study, which are collected at screening (Visit 500). The number and 
percentage of patients with each medical condition will be provided by age group and for overall, 
by system organ class (SOC), high level group term (HLGT) and preferred term (PT).  
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 
All analyses in this section will use the SAF. 
The study drug administration is recorded on the CRF page: “Dosage Administration Record” 
using start date-time, end date-time 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 
of the dose. For subject with gaps and/or overlaps among dosing interval (e.g., when the patient 
takes the previous dispensing level in the morning and starts a different dispensing level in the 
evening, the end date of a dosing interval is the same as the start date of the next dosing interval), 
a conventional data imputation algorithm will be applied to the start date and end date. The 
detailed algorithm will be provided in the study programming datasets specifications (PDS). 
For patients who permanently discontinue study treatment, there should be a dosing interval 
with its start date equal to the date of the permanent discontinuation of the study drug, its end 
date equal to the study discontinuation date, and its dispensing level equal to “No treatment”. 
Patients who complete the treatment are defined as receiving study treatment as reported in the 
DAR page until the day of EoS or the date marked as “treatment complete” in the disposition 
page. 
The specific doses based on the dispensing dose levels are defined in Table 2-1 for both the 
pediatric and adult formulation.  If the dispensing level is no treatment, the dose level is defined 
as 0. 


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For a dosing interval with a pediatric dose level, the daily dose (mg/day) during the interval is 
defined as the product of the weight based daily dose (mg /kg/day) during the interval and the 
weight during the interval, where the weight based daily dose (mg /kg/day) during the interval 
is defined in Table 2-1 and Table 2-2 and the weight during the interval is defined as the weight 
from the last non-missing assessment (scheduled or unscheduled) prior to or equal to the start 
dose time of the study drug of the interval.  
Table 2-1 
Study drug dose levels and doses for sacubitril/valsartan 
Age groups 1 and 2 * 
Dispensing dose levels for pediatric 
formulation 
Weight based daily dose 
Dose level 1 
0.8 mg/kg bid. 
1.6 mg/kg/day 
Dose level 2 
1.6 mg/kg bid. 
3.2 mg/kg/day 
Dose level 3 
2.3 mg/kg bid. 
4.6 mg/kg/day 
Dose level 4 
3.1 mg/kg bid. 
6.2 mg/kg/day 
Dispensing dose levels for adult formulation 
Weight based daily dose 
Dose level 1 
50 mg bid. 
1.6 mg/kg/day 
Dose level 2 
100 mg bid. 
3.2 mg/kg/day 
Dose level 3 
150 mg bid. 
4.6 mg/kg/day 
Dose level 4 
200 mg bid. 
6.2 mg/kg/day 
*Note: sacubitril/valsartan target dose (dose level 4) for age groups 1 and 2 is 3.1 mg/kg bid.  
Table 2-2 
Tablet use for sacubitril/valsartan (43 to < 57 kg patients) 
Study drug 
Pediatric dose level 
Patient weight (kg) 
Pediatric dose 
Tablet dose 
LCZ696 
Dose level 4 
43 to < 57 kg 
>= 133 to < 177 mg 
150 mg 
Dose level 3 
43 – 54 kg 
>= 98 to <125 mg 
100 mg 
Dose level 3 
>54 to <57 kg 
>= 125 to < 131 mg 
150 mg 
 
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 dose level and weight based daily dose (mg/ kg/day) at the visit are defined as the dose 
level and weight based daily dose (mg/kg/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 dose level will be summarized by visit, for overall and for each age group, using the number 
and percentage of patients on each level; and further be summarized using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum; the weight 
based daily dose (mg /kg/day) will be summarized by visit, for overall and for each age group, 
using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum.  


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The summary will include all scheduled visits in the study or until treatment discontinuation 
date. 
Duration of treatment exposure 
Duration of exposure to treatment regardless of temporary interruptions is defined as: date of 
last dose of study treatment – date of first dose of study treatment + 1. 
Conversion for treatment exposure durations is as follows: 
• 1 week = 7 days 
• 1 month = 30.4375 days 
• 1 year = 365.25 days 
Total (sum of patient-years) and per-patient duration of exposure to the study treatment will be 
summarized for each age group and for overall in years, using mean, standard deviation, median, 
Q1, minimum, Q3 and maximum.  
The duration (day) of treatment exposure excluding study drug interruptions is defined as the 
sum of the duration (day) on dose level 1 to 4 during the study without counting any days that 
patients are not taking the treatment. 
The analyses specified in the Section “Dispensing level (dose level) and daily dose at each visit” 
will be used here. In addition, the duration of study drug exposure with and without study drug 
interruptions, respectively, will be categorized into: 
• < 6 months  
• 6 months to < 1 year  
• 1 to < 2 years  
• 2 to < 3 years 
• 3 to < 4 years 
• >=4 years. 
The number and percentage of patients within each category by age group and overall will be 
tabulated.   
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 of 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 median and interquartile range will be presented for duration on each dose level. The 
number of patients who have ever been on a specific dose level will be reported.  


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Time to permanent discontinuation of the study drug 
The time (day) to permanent discontinuation of the study drug during the study (excluding death) 
will be summarized for each age group and overall by duration categories (refer to the Section 
“Duration of study drug exposure” for specific categories) using the Kaplan-Meier curves, 
considering time-to-death, completion of the study and switch to commercial entresto as 
independent censoring. 
Mean weight based daily dose and mean dose level 
For each patient, the mean weight based daily dose (mg/kg/day) during the study is defined as 
the weighted mean of the weight based daily dose (mg/kg/day) among dose level 0 to 4 using 
the duration (day) on each dose level as the weight, i.e. 
 
 
the mean dose level is defined as the weighted mean of the dose level among dose level 0 to 4 
using the duration (day) on each dose level as the weight, i.e., 
 
 
The mean weight based daily dose (mg /kg/day) and the mean dose level during the study will 
be summarized for each age group and overall, using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum. 
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 during the study will be summarized by each age group and overall, 
using the numbers and percentages of patients with at least one down-titration dosing interval 
during the study. 
Dose interruption 
A dose-interruption dosing interval is defined as a dosing interval with “NO TREATMENT”. 
The numbers and percentages of patients with at least one dose-interruption greater than 24-
hour dosing interval during the study will be provided by age group and the overall. 
The numbers and percentages of patients having at least one dose-interruption dosing interval 
with duration (day) of dose-interruption larger than 14 days will be provided by each age group 
and overall. 
2.4.2 
Prior, concomitant and post therapies 
Missing or partially missing start/end dates for prior/concomitant therapies will be imputed 
using the Novartis ADaM Governance Board (AGB) global standard approach. 
∑
Weight Based Daily Dose (mg/kg/day) for Dose Level 𝑘𝑘× Duration (day) on Dose Level 𝑘𝑘
4
𝑘𝑘=0
∑
Duration (day) on Dose Level 𝑘𝑘
4
𝑘𝑘=0
∑
𝑘𝑘× Duration (day) on Dose Level 𝑘𝑘
4
𝑘𝑘=0
∑
Duration (day) on Dose Level 𝑘𝑘
4
𝑘𝑘=0
. 


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Prior and concomitant medications/non-drug therapies will be identified based on recorded or 
imputed start and end dates. Details will be provided in the study programming datasets 
specifications (PDS). 
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 start date (recorded or imputed) prior to or 
equal to the end date of the treatment period.  
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 start date (recorded or imputed) prior to or equal to the end date of the 
treatment period. Whereas patients who undergo heart transplant will also be listed for  the 
treatment period and the study period together.  
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by anatomical therapeutic classification (ATC 3) and 
preferred term, for overall and for each age group. 
Concomitant heart failure medications (including ACE-inhibitors, ARBs, renin inhibitors, beta-
blockers, calcium antagonists, diuretics, aldosterone antagonists, cardiac glycocytes, aspirin, 
oral anticoagulants, antiarrhythmics agents, nitrates) will be summarized by ATC and preferred 
term, for overall and for each age group. 
The SAF will be used for the above analyses. 
 
2.5 
Analysis of the primary objective 
The primary objective is to evaluate safety and tolerability of LCZ696 in eligible heart failure 
patients from PANORAMA-HF receiving open-label investigational drug. 
2.5.1 
Primary endpoint 
Adverse events, laboratory assessments, vital signs, and duration of drug exposure are 
considered primary endpoints.  
2.5.2 
Statistical hypothesis, model, and method of analysis 
Refer to Section 2.8.1, Section 2.8.2, Section 2.8.3 and Section 2.8.4.  
2.5.3 
Handling of missing values/censoring/discontinuations 
Refer to Section 2.8.1, Section 2.8.2, Section 2.8.3 and Section 2.8.4.  
2.5.4 
Supportive analyses 
Not applicable, there are no supportive analyses. 


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2.6 
Analysis of the key secondary objective 
Not applicable, there is no key secondary objective. 
 
2.7 
Analysis of secondary efficacy objective(s) 
Not applicable, there are no secondary objectives. 
 
2.8 
Safety analyses 
The SAF will be used for all safety analyses, unless specified otherwise. 
2.8.1 
Adverse events (AEs) 
All AEs will 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. 
Treatment emergent adverse events (TEAEs) are defined as any recorded AE with its start date-
time (recorded or imputed) on or after the start date-time of the treatment period and end date 
as the end date of the treatment period or the date of last dose taken as reported in the DAR 
page + 30 days. Any AE happening after treatment discontinuation +30 days but still within the 
study period (e.g., where patient did not discontinue the study on the same date of treatment 
discontinuation) would not be considered as a TEAE and will be reported in the listing of AE.  
The following adverse events will be summarized by primary system organ class, preferred 
term, and maximum severity as appropriate, for each age group and for overall, using numbers 
and percentages of patients with at least one adverse event in the corresponding class (see list 
below). Outputs will be produced for AEs regardless of study-drug relationship, and for study-
drug related AEs. Study drug related AEs are defined as any recorded AE with “Reasonable 
possibility that AE is related to study treatment” answered as “YES”. Serious adverse events 
(SAEs) are defined as any recorded AE with “Does AE meet the definition of an SAE” answered 
as “Yes”. 
Adverse events summaries 
• Any adverse event (treatment emergent or not) 
• Any serious adverse event (treatment emergent or not) 
• Treatment emergent adverse event (TEAE) 
• Treatment emergent serious adverse event 
• Treatment emergent adverse event (TEAE) occurred in >5% of patients 
• Treatment emergent serious adverse event (TESAE) occurred in >5% of patients 


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• Treatment emergent adverse event of special interest, e.g. angioedema (both, 
adjudicated and non-adjudicated), change in bone growth and density, cognitive 
impairment (narrow SMQ), embryo-fetal toxicity or lethality, hepatotoxicity, 
hyperkalemia, hypersensitivity, hypotension, malignancy. neonatal or infantile toxicity 
through exposure from breast milk, renal impairment (narrow SMQ), and/or statin drug 
interaction as defined in the Case Retrieval Sheet for LCZ696 (see Section 2.8.1.1) 
• TEAE and TESAE leading to dose adjustment, temporary dose interruption, or 
permanent discontinuation (including death) of study treatment 
• TEAE and TESAE leading to permanent discontinuation (including death) of study 
treatment 
• TEAE and TESAE leading to death 
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. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Most common TEAEs are defined as any recorded TEAE corresponding to a PT with at least 
5% of patients having at least one TEAE of this PT. Most common TEAEs will be derived 
overall and by age group and will be summarized by age group and for overall, by SOC and PT, 
in descending frequency according to incidence, starting from the most common event. 
Table 2-1 shows the identified and potential risks for LCZ696 and the specifically specified 
analyses for each risk. In addition, the following standard analyses will be applied to all risks. 
• Numbers and percentages of patients with any TEAE within the risk category (or 
SOC/PT within risk category) by age group and risk category, SOC, PT and maximum 
severity. 
• Exposure adjusted incidence rates per 100 patient-years for TEAEs within the risk 
category by age group and risk category. 
• Listing of patient numbers per risk. 
Table 2-3 
Identified and potential risks 
Risk 
Analysis 
Hyperkalemia 
1. Standard analyses; 
2. Numbers and percentages of patients with treatment emergent hyperkalemia 
among patients with/without hyperkalemia at baseline by age group and overall 
3. Numbers and percentages of patients with any post-baseline serum 
potassium ≥5.5 mEq/L, >6.0 mEq/L and >6.5 mEq/L by age group and overall 
Hypotension 
1. Standard analyses; 


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Risk 
Analysis 
2. Blood pressures and change from baseline in blood pressures will be 
summarized by visit, time point, age group and overall using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum; 
3. Numbers and percentages of patients with the following events during the 
treatment period will be provided by age group and overall: 
• 
Post-baseline systolic blood pressure (SBP) < 5th percentile per age 
(Table 16-7 in the protocol); 
• 
At least 20 mmHg drop in SBP (post-baseline assessments comparing 
to baseline); 
• 
Simultaneous treatment emergent symptomatic hypotension and 
postbaseline SBP < 5th percentile per age (Table 16-7 in the protocol); 
• 
Simultaneous treatment emergent symptomatic hypotension and at 
least 20 mmHg drop in SBP (post-baseline assessments comparing to 
baseline); 
• 
Simultaneous post-baseline SBP < 5th percentile per age (Table 16-7 in 
the protocol) and at least 20 mmHg drop in SBP (post-baseline 
assessments comparing to baseline). 
Angioedema 
(positively 
adjudicated events) 
Standard analyses; 
Renal impairment 
1. Standard analyses; 
2. For serum creatinine and eGFR, the test values and changes from baseline 
will be summarized by visit, age group and overall using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum; the summaries will be provided for local and central lab separately; 
3. Numbers and percentages of patients with the following events will be 
provided by age group and overall (the summaries will be provided for local and 
central lab together and if both central lab and local lab data are available, 
central lab result will take precedence over local lab result): 
• 
eGFR decline by >25%, >40%, >50%, and/or >30 mL/min/1.73 m2 
(postbaseline assessments comparing to baseline) and <LLN; 
• 
eGFR < 45 mL/min/1.73 m2 and/or eGFR < 30 mL/min/1.73 m2 
• 
Serum creatinine increase by >50% (post-baseline assessments 
comparing to baseline) and >ULN; 
• 
Serum creatinine increase by >0.5 mg/dL and >ULN (post-baseline 
assessments comparing to baseline),  
• 
serum creatinine post-baseline >2.0 mg/dL, >2.5 mg/dL, >3.0 mg/dL ; 
• 
Standard analyses within the subgroups additionally if possible: patients 
with baseline eGFR ≤170 mL/min/1.73 m2 and >170 mL/min/1.73 m2. 
For safety topics of special interest defined in the CRS, the standard analyses will be performed. 
 
2.8.2 
Deaths 
For overall and for each age group, death (including both cardiovascular and non-CV deaths) 
during the treatment period and the primary cause of death will be summarized using 
frequencies and percentages. 


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A listing of all deaths and heart transplant will also be provided for the SAF. 
2.8.3 
Laboratory data 
Complete and abbreviated laboratory evaluations are described in Table 2-2. Complete 
laboratory evaluations (hematology, blood chemistry, and urine) are performed at screening 
(Visit 500), and subsequently every 12 months from Visit 501 until End of Study (Visit 599); 
these analyses are performed at central laboratory. 
Abbreviated safety laboratory evaluation consists of serum sodium, potassium, creatinine, and 
eGFR. Abbreviated laboratory evaluations are performed every 12 months starting from visit at 
6 months (Visit 507). In addition, abbreviated laboratory assessments are performed at up-
titration visits (visits 501, 502, 503, 504 and 505, as applicable), and unscheduled visits with 
planned dose level changes; these analyses can be performed at central or local laboratories. 
Laboratory data will be reported for the treatment period. Note that a window of 5-day will be 
used to include laboratory data performed within 5 days after the discontinuation of treatment.  
Table 2-4 
Laboratory Assessments 
Hematology  
Biochemistry  
Urine measurements** 
Hematocrit 
Alanine aminotransferase (ALT) 
Specific gravity 
Hemoglobin 
Albumin (Alb) 
pH 
Platelet count 
Alkaline phosphatase (ALP) 
Glucose 
Red blood cell count (RBC) 
Asparate aminotransferase 
(AST) 
Protein (Total) 
White blood cell count (WB) 
Blood urea nitrogen (BUN) 
Ketones 
WBC differential 
Calcium 
Magnesium 
Phosphate 
Bilirubin 
Urobilinogen 
Hemoglobin (blood) 
Red blood cell distribution width 
(RDW) 
Chloride 
Leukocyte esterase 
Mean corpuscular volume 
(MCV) 
Creatinine* 
Nitrite 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Glucose 
WBC 
 
Potassium 
Sodium 
Bicarbonate 
Total bilirubin (TBL) 
Fractionated bilirubin (if total 
bilirubin > 2x ULN) 
Total protein 
Uric acid 
eGFR* 
RBC sediments 
Hyaline casts 
Granular casts 
Waxy casts 
WBC casts 
 
RBC casts 
*Abbreviated laboratory evaluations must include these parameters 
**Urinalysis with dipstick includes specific gravity, pH, glucose, total protein, bilirubin, ketones, 
urobilinogen, nitrite, leukocytes esterase and hemoglobin (blood). Other urine measurements listed are 
not required. If a urine dipstick is positive, other urine measurements such as a qualitative microscopic 
determination of WBC, RBC sediments (and casts) should also be measured. 


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Both complete laboratory evaluations and abbreviated laboratory evaluations will be included 
in the summaries for laboratory data. In general, local lab and central lab data will be analyzed 
separately. However, for shift tables, where only abnormal/normal values are used, they may 
be summarized together. Here, “summarized together” means the following:  
1) For each patient, the shift will be calculated either within local lab, or within central lab. 
2) In the shift table, these shifts will be presented together. If shifts within both, local lab 
and central lab are available, at the same visit, only shifts within the central lab will be 
shown. 
Test values and change from baseline based on the local laboratory assessments and the central 
laboratory assessments will be summarized by laboratory parameter, age group (and overall) 
and visit, using number of observations, mean, standard deviation, median, minimum, Q1, Q3, 
and maximum.  
The shift from baseline will be summarized by laboratory parameter, age group and visit, using 
the numbers and percentages of patients in each category (low/normal/high). 
For missing lab data at a given visit (except for lab performed after IMP discontinuation), the 
missing data will be taken from an unscheduled visit between two scheduled visits if they are 
available. Otherwise will leave them as missing. The data from the unscheduled visit for the 
missing data imputation will use the central lab data for tables reporting central lab analyses, 
and local lab data for table reporting local lab analyses. 
Clinically notable laboratory abnormality 
Table 2-3 provides criteria for clinically notable laboratory abnormalities. 
The clinically notable laboratory abnormalities during the treatment period based on the local 
laboratory assessments and the central laboratory assessments will be summarized together (the 
definition of “summarized together” is the same as that for the shift tables described above) by 
criteria and age group, using the numbers and percentages of patients satisfying such criteria. 
Table 2-5 
Clinical notable criteria for laboratory values 
Parameter 
Conventional 
Units 
SI Alert 
Value 
SI 
Units 
Hematology 
Red Blood Cell 
Count  
x10E6/uL 
>50% increase and >ULN; 
>30% decrease and <LLN. 
x10E12/L 
Hemoglobin 
g/dL 
>50% increase and >ULN; 
(>30% decrease and <LLN) or any value <70. 
g/L 
Hematocrit 
% 
>50% increase and >ULN; 
>30% decrease and <LLN. 
L/L 
White Blood Cell 
Count  
x10E3/uL 
>50% increase and >ULN; 
>50% decrease and <LLN. 
x10E9/L 
Platelet Count 
x10E3/uL 
>75% increase and >ULN; 
>50% decrease and <LLN. 
x10E9/L 
Chemistry 


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BUN 
mg/dL 
>50% increase and >ULN 
mmol/L 
Creatinine 
mg/dL 
>50% increase and >ULN 
umol/L 
Albumin 
g/dL 
<20 
g/L 
Glucose 
mg/dL 
>50% increase and >ULN;  
(>50% decrease and <LLN) or any value <3.3. 
mmol/L 
Total Bilirubin 
mg/dL 
>100% increase and >ULN 
umol/L 
AST (SGOT) 
U/L 
>150% increase and >ULN 
U/L 
ALT (SGPT) 
U/L 
>150% increase and >ULN 
U/L 
Sodium 
mEq/L 
(>5% increase and >ULN) or any value >150; 
(>5% decrease and <LLN) or any value <125 
mmol/L 
Potassium 
mEq/L 
(>20% increase and >ULN) or any value >6; 
(>20% decrease and <LLN) or any value <3.  
mmol/L 
Chloride 
mEq/L 
>10% increase and >ULN; 
>10% decrease and <LLN 
mmol/L 
Calcium 
mg/dL 
>10% increase and >ULN; 
>10% decrease and <LLN. 
mmol/L 
Uric Acid 
mg/dL 
>50% increase and >ULN 
mmol/L 
 
Liver events 
Table 2-4 provides criteria for liver laboratory triggers and liver events. 
The liver laboratory triggers and liver events during the treatment period based on the local 
laboratory assessments and the central laboratory assessments will be summarized together by 
criteria and age group, using the numbers and percentages of patients satisfying such criteria. 
Table 2-6 
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* 
 


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Definition / threshold 
*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 
Renal events 
Renal events are defined using the following two categories of criteria.  
1. Serum event: 
a. Serum estimated GFR* decrease ≥ 25% compared to baseline AND eGFR < 90 
mL/min/1.73m2 
b. Serum estimated GFR* decrease ≥ 50% compared to baseline  
Note that *eGFR is calculated using a modified Schwartz formula for patients <18 years:  
eGFR (ml/min/1.73m2) = 0.413 x height (cm) / serum creatinine (mg/dl). 
2. Urine event: 
a. New onset (≥1+) proteinuria 
b. New onset (≥1+) hematuria 
c. New onset (≥1+) glucosuria 
The renal events during the treatment period based on the local laboratory assessments and the 
central laboratory assessments will be summarized together by criteria and age group (and 
overall), using the numbers and percentages of patients satisfying such criteria. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable, there are no ECG/cardiac imaging data. 
2.8.4.2 
Vital signs 
The test values and the changes from baseline in vital signs (sitting/supine pulse rate, 
sitting/supine systolic blood pressure, sitting/supine diastolic blood pressure) will be 
summarized by vital sign parameter, age group and visit, using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum. By-visit summaries will only 
include scheduled assessments.  
The number (percentage) of patients with clinically notable vital signs (Table 2-5) during the 
treatment period will be summarized by visit, separately by criteria and age group. 
Table 2-7 
Criteria for clinically notable vital signs 
Age (years) 
HR [min-1]  
SBP [mmHg]  
DBP [mmHg] 
1- <3 
<60, >120 
<76, >115 
<45, >75 
3- <6 
<55, >120 
<82, >120 
<50, >80 
6- <12 
<50, >105 
<90, >130 
<50, >80 


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Age (years) 
HR [min-1]  
SBP [mmHg]  
DBP [mmHg] 
≥ 12 
<45, >95 
<90, >145 
<55, >90 
2.8.4.3 Changes in height, weight and head circumference 
Summary statistics and change from baseline will be provided for weight, height, and head 
circumference (patients ≤ 3 years) by visit and age group (and overall). Subgroup analysis of 
height (i.e., height, z-score for height and age-adjusted percentile for height) will be performed 
for patients satisfying the criterion of being within the age range of 2-9 years at each 12-month 
visit throughout the OLE study and for overall group. Summary statistics by yearly visit will be 
provided.  
In addition, age-adjusted percentile will be calculated for height, weight and BMI; Z-score will 
be calculated for height, as done by the WHO to assess child growth. For more details, see 
World Health Organization (WHO) 1997.  
The same summaries as for the raw values will be produced for these Z-scores. In addition, shift 
tables will be produced using the following rules for severe low/moderate low/normal 
classification (Dibley et al, Mei Z and Grummer-Strawn LM, World Food Programme): 
• Z-score < -3: severe low 
• -3 ≤ Z-score < -2: moderate low 
• Z-score ≥ -2: normal 
2.9 
Pharmacokinetic endpoints   
Not applicable. There are no PK analyses. 
 
2.10 
PD and PK/PD analyses 
Not applicable. There are no PD and PK/PD analyses. 
 
2.11 
Patient-reported outcomes 
Not applicable, there are no patient-reported outcomes. 
2.12 
Biomarkers 
Not applicable, there are no biomarkers. 
 
2.13 
Other Exploratory analyses 
Not applicable. There are no other exploratory analyses. 
 


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2.14 
Interim analysis 
No interim analysis is planned. However, the safety will be monitored through regular review 
of adverse events and related data. 
3 
Sample size calculation 
There is no specific sample size required for the study. All patients who have completed the 
double-blind phase of the study PANORAMA-HF, as defined in the protocol Inclusion Criteria, 
and who meet all other Inclusion and Exclusion criteria, are eligible for the extension study. 
4 
Change to protocol specified analyses 
None. 
5 
Appendix 
5.1 
Imputation rules 
The missing or partially missing start/end date for AEs and prior/concomitant therapies will be 
imputed using the Novartis AGB global standard approach. Details will be provided in the study 
PDS. 
If the visit date is missing, the scheduled date (per protocol) of the visit will be used. 
5.1.1 
Study drug 
If the study drug start date is missing, then the planned start date will be used. If only the study 
start day is missing (but the month is known), then the study start day will be the 1st day of that 
month, unless the planned date of the first dose is in the same month, then it will be the planned 
date of the first dose. 
5.1.2 
AE date imputation 
See Section 5.1. 
5.1.3 
Concomitant medication date imputation 
See Section 5.1. 
5.1.3.1 
Prior therapies date imputation 
See Section 5.1. 
5.2 
Rule of exclusion criteria of analysis sets  
Table 5-1 
Protocol deviations that cause subjects to be excluded 
Deviation ID 
Description of Deviation 
Exclusion from analyses 
INCL01 
No informed consent. 
Excluded from all analyses. 
 


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Table 5-2 
Subject classification 
Analysis set 
PD ID that cause subjects to be 
excluded 
Non-PD criteria that cause subjects to 
be excluded 
SCR 
INCL01 
Not applicable. 
SAF 
INCL01A and INCL01B 
Not obtaining any study medication.  
 
6 
Reference 
WHO Global Database on Child Growth and Malnutrition (Internet) Available from: 
[https://apps.who.int/iris/bitstream/handle/10665/63750/WHO_NUT_97.4.pdf] (Accessed 02 
May 2019). 
Dibley M J, Staehling N, Nieburg P, Trowbridge F L, 1987. Interpretation of Z-score 
anthropometric indicators derived from the international growth reference. The American 
Journal of Clinical Nutrition. 46(5):749-762. 
World Food Programme, 2005. A manual: measuring and interpreting malnutrition and 
mortality. Rome, World Food Programme.  
Mei Z and Grummer-Strawn LM, 2007. Standard deviation of anthropometric Z-scores as a 
data quality assessment tool using the 2006 WHO growth standards: a cross country analysis. 
Bulletin of the World Health Organization, 85, pp. 441-448.