Clinical trial NCT06149104
Conditions: Heart Failure
Keywords: sacubitril/valsartan post-trial access pediatric heart failure
Sponsor: Novartis Pharmaceuticals
Start date: 2023-12-04; Completion date: 2024-08-14
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this open-label study was to collect additional safety information of sacubitril/valsartan and to provide post-trial access to sacubitril/valsartan for the eligible Japanese patients who completed CLCZ696B2319E1(NCT03785405) study until marketed product of pediatric formulation, film-coated granules in capsule, is available in Japan.

Detailed description:
This trial (CLCZ696B2319E2) was a multicenter, open-label extension study for Japanese patients who have successfully completed the CLCZ696B2319E1 study. Only Japanese patients who successfully completed CLCZ696B2319E1 study and fulfilled protocol requirements were eligible to participate in this study.

The first visit (Visit Day1) was the same day as the End of Study visit of CLCZ696B2319E1 study.

Arms: arm 1: The starting dose of study drug was determined by the investigator in consideration of the participant´s condition. The dose level at the end of study visit of CLCZ696B2319E1 study could remain the same, or the dose level could be changed at the discretion of the investigator.
Interventions: intervention 1: sacubitril/valsartan
Intervention descriptions: intervention 1: sacubiril/valsartan

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................5
List of figures.......................................................................................................................5
1
Protocol summary................................................................................................................6
1.1
Summary..................................................................................................................6
1.2
Schema.....................................................................................................................8
1.3
Schedule of activities (SoA) ....................................................................................8
2
Introduction........................................................................................................................12
2.1
Study rationale .......................................................................................................12
2.2
Background............................................................................................................12
2.3
Benefit/Risk assessment.........................................................................................13
3
Objectives, endpoints, and estimands................................................................................14
3.1
Primary estimands..................................................................................................14
3.2
Secondary estimands..............................................................................................14
4
Study design.......................................................................................................................15
4.1
Overall design ........................................................................................................15
4.2
Scientific rationale for study design.......................................................................16
4.3
Justification for dose..............................................................................................16
4.4
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................16
4.5
Rationale for public health emergency mitigation procedures ..............................16
4.6
Purpose and timing of interim analyses/design adaptations ..................................16
4.7
End of study definition...........................................................................................16
5
Study population................................................................................................................16
5.1
Inclusion criteria ....................................................................................................17
5.2
Exclusion criteria ...................................................................................................17
5.3
Screen failures........................................................................................................18
5.3.1
Participant numbering ...........................................................................18
6
Study treatment(s) and concomitant therapy .....................................................................19
6.1
Study treatment(s)..................................................................................................19
6.1.1
Additional study treatments...................................................................19
6.1.2
Treatment arms/group ...........................................................................20
6.1.3
Treatment duration ................................................................................20
6.2
Preparation, handling, storage, and accountability ................................................20
6.2.1
Handling of study treatment..................................................................20
6.2.2
Handling of other treatment...................................................................21


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6.2.3
Instruction for prescribing and taking study treatment..........................21
6.3
Study treatment compliance...................................................................................21
6.3.1
Recommended treatment of adverse events ..........................................22
6.4
Dose modification..................................................................................................22
6.4.1
Dose modifications................................................................................22
6.4.2
Follow-up for toxicities.........................................................................24
6.5
Continued access to study treatment after the end of the study.............................24
6.6
Treatment of overdose ...........................................................................................24
6.6.1
Reporting of study treatment errors including misuse/abuse ................24
6.7
Concomitant and other therapy..............................................................................24
6.7.1
Concomitant therapy .............................................................................24
6.7.2
Prohibited medication............................................................................26
6.7.3
Rescue medicine....................................................................................26
7
Discontinuation of study treatment and participant discontinuation/withdrawal ..............26
7.1
Discontinuation of study treatment........................................................................26
7.2
Participant discontinuation from the study ............................................................27
7.3
Withdrawal of informed consent and exercise of participants’ data privacy 
rights.......................................................................................................................27
7.4
Lost to follow-up....................................................................................................28
7.5
Early study termination by the Sponsor.................................................................28
8
Study Assessments and Procedures ...................................................................................29
8.1
Screening................................................................................................................30
8.2
Participant demographics/other baseline characteristics........................................30
8.3
Efficacy assessments..............................................................................................30
8.4
Safety assessments.................................................................................................30
8.4.1
Physical examinations ...........................................................................31
8.4.2
Vital signs..............................................................................................31
8.4.3
Height and weight..................................................................................31
8.4.4
Clinical safety laboratory tests ..............................................................31
8.4.5
Pregnancy testing...................................................................................32
8.4.6
Other safety evaluations ........................................................................34
8.4.7
Appropriateness of safety measurements ..............................................34
8.5
Additional assessments ..........................................................................................34
8.6
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting.................................................................................................................34
8.6.1
Adverse events.......................................................................................34
8.6.2
Serious adverse events...........................................................................36


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8.6.3
SAE reporting........................................................................................37
8.6.4
Pregnancy ..............................................................................................38
8.7
Pharmacokinetics ...................................................................................................38
8.8
Biomarkers.............................................................................................................38
8.9
Immunogenicity assessments.................................................................................39
8.10
Health economics OR Medical resource utilization and health economics...........39
9
Statistical considerations....................................................................................................39
9.1
Analysis sets...........................................................................................................39
9.2
Statistical analyses .................................................................................................39
9.2.1
General considerations ..........................................................................39
9.2.2
Participant demographics and other baseline characteristics ................39
9.2.3
Treatments.............................................................................................40
9.3
Primary endpoint(s)/estimand(s) analysis..............................................................40
9.3.1
Definition of primary endpoint(s) .........................................................40
9.3.2
Statistical model, hypothesis, and method of analysis ..........................40
9.3.3
Handling of intercurrent events of primary estimand (if applicable)....40
9.3.4
Handling of missing values not related to intercurrent event................40
9.3.5
Multiplicity adjustment (if applicable)..................................................41
9.3.6
Sensitivity analyses ...............................................................................41
9.3.7
Supplementary analysis.........................................................................41
9.4
Secondary endpoint(s)/estimand(s) analysis..........................................................41
9.5
Exploratory endpoint(s)/estimand(s) analysis........................................................41
9.6
(Other) Safety analyses..........................................................................................41
9.7
Other analyses........................................................................................................41
9.8
Interim analysis......................................................................................................41
9.9
Sample size determination .....................................................................................42
9.9.1
Primary endpoint(s)...............................................................................42
9.9.2
Secondary endpoint(s)...........................................................................42
10 Supporting documentation and operational considerations...............................................43
10.1
Appendix 1: Regulatory, ethical, and study oversight considerations...................43
10.1.1
Regulatory and ethical considerations...................................................43
10.1.2
Informed consent process......................................................................44
10.1.3
Data protection ......................................................................................45
10.1.4
Committees structure.............................................................................45
10.1.5
Data quality assurance...........................................................................45
10.1.6
Source documents..................................................................................46


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10.1.7
Publication policy..................................................................................47
10.1.8
Protocol adherence and protocol amendments......................................47
10.2
Appendix 2: Abbreviations and definitions ...........................................................49
10.2.1
List of abbreviations..............................................................................49
10.2.2
Definitions.............................................................................................50
10.3
Appendix 3: Clinical laboratory tests.....................................................................53
10.3.1
Clinically notable laboratory values and vital signs..............................53
10.4
Appendix 4: Participant Engagement ....................................................................55
10.5
Appendix 5: Renal safety monitoring....................................................................56
10.5.1
Specific Renal Alert Criteria and Actions and Event Follow-up ..........56
10.6
Appendix 6: Guidelines for the management of renal dysfunction .......................58
10.7
Appendix 7: American heart association (AHA) pediatric advanced life 
support (PALS) guidelines.....................................................................................59
10.8
Appendix 8: Guidelines for the management of hypotension................................61
10.9
Appendix 9: Treatment guidelines for elevated potassium and hyperkalemia 
(serum potassium ≥ 5.3 mmol/L)...........................................................................62
10.10 Appendix 10: Reference table – blood volume by weight.....................................64
11 References..........................................................................................................................66
List of tables
Table 1-1
Primary and secondary objectives, endpoints and estimands..................6
Table 1-2
Assessment Schedule.............................................................................10
Table 3-1
Objectives and related endpoints...........................................................14
Table 4-1
Study drug dose levels for sacubitril/valsartan......................................15
Table 6-1
Open-label sacubitril/valsartan formulation..........................................19
Table 6-2
Safety monitoring criteria for adjustment of study-drug dose level......23
Table 6-3
Prohibited medication............................................................................26
Table 8-1
Events commonly seen in study population..........................................37
Table 10-1
Clinically notable laboratory values......................................................53
Table 10-2
Criteria for clinically notable vital signs ...............................................53
Table 10-3
Specific renal alert criteria and actions .................................................56
Table 10-4
GFR by age for up-titration...................................................................57
Table 10-5
5th percentile systolic blood pressure (SBP) table.................................59
Table 10-6
Reference table – blood collection volumes by body weight (kg) ........64
List of figures
Figure 1-1
Study design ............................................................................................8


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1
Protocol summary
1.1
Summary
Protocol Title:
A multicenter, open-label study to collect the safety information of sacubitril/valsartan in 
Japanese pediatric patients with heart failure due to systemic left ventricle systolic dysfunction 
who have completed CLCZ696B2319E1 study
Brief Title:
A safety study of sacubitril/valsartan in Japanese pediatric patients with heart failure due to 
systemic left ventricle systolic dysfunction who have completed CLCZ696B2319E1 study
Purpose
The purpose of this open-label study is to collect additional safety information of 
sacubitril/valsartan and to provide post-trial access to sacubitril/valsartan for the eligible 
Japanese patients who completed CLCZ696B2319E1 study until marketed product of pediatric 
formulation, film-coated granules in capsule, is available in Japan.
Study Indication /Medical Condition:
Heart Failure
Treatment type
Drug
Study type
Interventional 
Objectives, Endpoints, and Estimands:
Table 1-1
Primary and secondary objectives, endpoints and estimands
Objectives
Endpoints
Primary
To collect additional safety information of sacubitril/valsartan in 
Japanese patients after long-term treatment of sacubitril/valsartan in 
CLCZ696B2319E1 study
Adverse events (AEs)
Secondary
Not applicable
Not applicable
Trial Design:
This trial (CLCZ696B2319E2) is a multicenter, open-label extension study for Japanese 
patients who have successfully completed the CLCZ696B2319E1 (PANORAMA-HF OLE) 


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study (Figure 1-1). PANORAMA-HF OLE study is an on-going Phase 3b study in pediatric 
patients with systemic left ventricular systolic dysfunction to evaluate long- term safety and 
tolerability of sacubitril/valsartan in eligible CLCZ696B2319 (PANORAMA-HF) participants.
Only Japanese patients who successfully completed PANORAMA-HF OLE study and fulfill 
protocol requirements (see Section 5) are eligible to participate in this study, and will be offered 
the option to initiate treatment with sacubitril/valsartan by enrolling into this study at the 
discretion of the Investigator. Participants who permanently discontinued study drug treatment 
during PANORAMA-HF OLE study are not eligible for this study (see Section 5.2).
For all consenting patients eligibility for this study will be assessed at the first visit (Visit Day1) 
and the study medication will be initiated (see Section 8 for details). The first visit (Visit Day1) 
is the same day as the End of Study visit (Visit 599) of PANORAMA-HF OLE study. The 
starting dose of study drug will be determined by the Investigator considering the participant’s 
condition The dose level at the end of study visit of PANORAMA-HF OLE study may remain 
the same, or the dose level may be changed at the discretion of the Investigator.
Brief Summary:
The purpose of this open-label study is to collect additional safety information of 
sacubitril/valsartan and to provide post-trial access to sacubitril/valsartan for the eligible 
Japanese patients who completed CLCZ696B2319E1 study until marketed product of pediatric 
formulation, film-coated granules in capsule, is available in Japan.
Study Duration:
Actual duration depends on the timing of sacubitril/valsartan formulation for pediatrics 
available on the market in Japan.
Treatment Duration:
Until marketed product of pediatric formulation is available in Japan
Visit Frequency:
Every 3 months (including telephone visits)
Treatment of interest
The investigational treatment sacubitril/valsartan
Number of Participants:
A maximum of 8 Japanese patients will be enrolled into the study.
Key Inclusion criteria
1.
Signed informed consent as well as assent at an appropriate age must be obtained prior to 
participation in the study.
2.
Male or female, inpatient or outpatient, and < 18 years of age (at the time of signing 
informed consent).
3.
Patients who have completed PANORAMA-HF OLE study and are able to be safely 
enrolled into this study as judged by the Investigator.


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Key Exclusion criteria
1.
Patients who permanently discontinued the study drug treatment during PANORAMA-
HF OLE study.
2.
Renal vascular hypertension (including renal artery stenosis).
3.
Patients with a history of angioedema.
4.
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.
5.
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.
Treatment Groups:
All participants will receive open-label sacubitril/valsartan.
Data Monitoring/Other Committee: 
No
Key words
Pediatric, Japanese, LCZ696, sacubitril/valsartan, heart failure, open-label study, angiotensin 
receptor neprilysin inhibitor (ARNI)
1.2
Schema
Figure 1-1
Study design
1.3
Schedule of activities (SoA)
The Assessment Schedule (Table 1-2) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. The “X” in the table denotes the assessments to be recorded in the clinical 


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database or received electronically from a vendor. The “S” in the table denotes the assessments 
that are only in the participant’s source documentation and do not need to be recorded in the 
clinical database.
Sacubitril/valsartan treatment will start at Visit Day1, which is the same day as the End of Study 
visit (Visit 599) of CLCZ696B2319E1 (PANORAMA-HF OLE) study. A telephone visit (Visit 
M3) and an on-site visit (Visit M6) will occur 3 months and 6 months after Visit Day1, 
respectively. The visits as same Visit M3 and Visit M6 will then be repeated every 3 months 
until the end of the study. When the pediatric formulation of sacubitril/valsartan becomes 
available in Japan, or this study is terminated by Novartis, any participants should return to the 
study site as soon as possible for End of Study (EOS) visit (Visit EOS) regardless of subsequent 
scheduled visit, and all of the assessments listed for Visit EOS will be performed.
Participants should take their scheduled dose of sacubitril/valsartan in the morning of their study 
visits. Participants are not required to fast overnight on the day prior to or the day of the study 
visit.
Participants 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 Day1. Missed or rescheduled 
visits should not lead to automatic discontinuation. Specific circumstances surrounding missed 
or rescheduled visits must be discussed with the study monitor. Participants who prematurely 
discontinue the study treatment, or prematurely withdraws from 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 EOS) will be performed. 
As per Section 4.5, 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. If allowable by a local health authority, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or visits by site 
staff/ off-site healthcare professional(s) staff to the participant´s home, can replace on-site study 
visits, for the duration of the disruption until it is safe for the participant to visit the site again. 
If the Investigator delegates tasks to an off-site healthcare professional, the Investigator must 
ensure the individual(s) is/are qualified and appropriately trained to perform assigned duties. 
The Investigator must oversee their conduct and remain responsible for the evaluation of the 
data collected.


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Table 1-2
Assessment Schedule
UNS= Unscheduled visit, EOS= End of study visit
X: Assessment to be recorded in the clinical database or received electronically from a vendor
S: Assessment to be recorded in the source documentation only
(X) / (S) = parentheses indicate that this is an optional assessment
# Visit Day1 is the same day as Visit 599 (EOS visit) of PANORAMA-HF OLE (CLCZ696B2319E1) study
† Visit M3 is a telephone visit.
* If the trial is extended, Visits M9, M12 to be performed at the same intervals and with same measurements as at Visits M3 and 
M6, respectively.
1.
Patients who permanently discontinued the study drug treatment during PANORAMA-HF OLE study cannot be enrolled in 
this study (Section 5.2), however, patients who temporally discontinued the study drug for any reason at the End of Study 
visit (Visit 599) in PANORAMA-HF OLE study may be enrolled in this study. In this case, the assessments specified for Visit 
Day1 should be performed at the visit when the study treatment starts. They will have to discontinue the study unless the 
study treatment starts within 3 months from Visit Day1, and will be considered an early study termination (Section 5.3).
2.
End of Study (EOS) visit will be completed when marketed product of sacubitril/valsartan pediatric formulation becomes 
commercially available in Japan, the study treatment is permanently discontinued based on the Investigator’s judgement, or 
participant prematurely withdraws from the study, whichever occurs first. 
3.
Signed informed consent as well as assent at an appropriate age must be obtained prior to participation in the study. Patient 
Assent document is captured as a source document and is not stored in the clinical database. 
4.
If the trial is extended 1 year or over, height at Visit M12 should be recorded in the electronic Case Report Form (eCRF)
5.
The data measured at the End of Study visit (Visit 599) in PANORAMA-HF OLE study will be utilized as the data at Visit 
Day1 for this study.


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6.
Serum sodium, potassium, creatinine, and estimated Glomerular Filtration Rate (eGFR, modified Schwartz formula) will be 
measured locally, and recored in the eCRF. Additional laboratory evaluation including hematology and urinalysis may be 
performed optionally by Investigator’s clinical judgement at any visits. There is no local assessment at Visit Day1, but the 
results of central laboratory at the End of Study visit (Visit 599) in PANORAMA-HF OLE study should be reviewed by the 
Investigator soon after the results are obtained.
7.
For child-bearing potential females (CHBP) only. Urine pregnancy test is analyzed locally and done at Visit M6 and 
unscheduled visits on all female participants ≥11 years of age and all female participants who are <11 years of age if they 
are menstruating. There is no assessment at Visit Day1, but the result of central laboratory (serum test) at the End of Study 
visit (Visit 599) in PANORAMA-HF OLE study should be reviewed by the Investigator soon after the result is obtained. 
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 
participant with urinary pregnancy tests for home monthly tests. See Section 8.4.5 for additional details. A serum pregnancy 
test is performed and analyzed locally at Visit EOS.  


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2
Introduction
2.1
Study rationale
The purpose of this open-label study is to collect additional safety information of 
sacubitril/valsartan and to provide post-trial access to sacubitril/valsartan for the eligible 
Japanese patients who completed CLCZ696B2319E1 study until marketed product of pediatric 
formulation, film-coated granules in capsule, is available in Japan.
2.2
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, 
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, Mertens 2010). The Diovan Pediatric Heart Failure Survey study confirmed that two 
factors; ‘efficacy shown in adult heart failure trials’ 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 (ARNI) treatment for chronic HF. 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 II 
type 1 (AT1) receptor. The resulting increase in natriuretic peptide activity due to NEP 


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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 study (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, 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).
PARALLEL-HF study (CLCZ696B1301) in Japanese adult patients with HFrEF showed no 
difference in efficacy for mortality and morbidity between sacubitril/valsartan group and 
enalapril group, but favorable results were obtained with sacubitril/valsartan in other clinical 
indices (Tsutsui et al 2021). 
Sacubitril/valsartan has been approved for adult use worldwide mainly based on the results of 
PARADIGM-HF study, and the results of both of PARADIGM-HF and PARALLEL-HF 
studies for Japan.
PANORAMA-HF study (CLCZ696B2319) was a large, multicenter, double-blind, active 
controlled pediatric HF trial and includes patients with systemic left ventricular systolic 
dysfunction <18 years of age (Shaddy et al 2017). PANORAMA-HF was 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. PANORAMA-HF study has been completed, and demonstrated a favorable benefit-
risk balance of sacubitril/valsartan in the treatment of HF in pediatric patients, and 
sacubitril/valsartan has been approved for pediatric HF (1 year and above) due to systemic left 
ventricle systolic dysfunction in the US and European Union. Regulatory approval was also 
received in countries referencing the US label. 
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. 
PANORAMA-HF Open-Label Extension (OLE) study (CLCZ696B2319E1) is ongoing to 
provide the opportunity to receive open-label sacubitril/valsartan for patients who successfully 
complete the 52 weeks double-blind treatment period of PANORAMA-HF study. Since 
PANORAMA-HF OLE study is going to end approximately December 2023 as planned, this 
study (CLCZ696B2319E2) was planned to provide an additional sacubitril/valsartan treatment 
opportunity to Japanese patients enrolled in PANORAMA-HF OLE study until marketed 
product of sacubitril/valsartan formulation for pediatrics is available in Japan.
2.3
Benefit/Risk assessment
This is an extension study for Japanese participants who have successfully completed 
PANORAMA-HF OLE study, with a goal to collect the safety information of 
sacubitril/valsartan in pediatric heart failure patients, and to provide post-trial access to 
sacubitril/valsartan until marketed product of pediatric formulation is available in Japan.


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Based on the results of PANORAMA-HF study, the benefit of sacubitril/valsartan treatment for 
pediatric HF due to systemic left ventricle systolic dysfunction has been proven, and 
sacubitril/valsartan has been approved in the US and European countries. Especially, extended 
treatment of sacubitril/valsartan from PANORAMA-HF OLE study is expected to be beneficial 
and safe since the eligible patients in this study have successfully completed long-term 
treatment of sacubitril/valsartan in PANORAMA-HF OLE study. 
Appropriate eligibility criteria (Section 5), as well as specific dose modification (Section 6.4) 
and stopping rules (Section 7.1), are included in this protocol. Recommended guidelines for 
prophylactic or supportive management of study-drug induced adverse events are provided in 
Appendix 6, Appendix 8, and Appendix 9 (guidelines for the management of renal dysfunction, 
blood pressure, and hyperkalemia, respectively).
Female participants of child-bearing potential must be informed that taking the study treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study they must adhere to the contraception requirements 
outlined in the exclusion criteria. If there is any concern that the participant will not reliably 
comply, they should not be entered or continue in the study.
3
Objectives, endpoints, and estimands
The primary objective is to collect additional safety information of sacubitril/valsartan in the 
eligible Japanese patients who completed CLCZ696B2319E1 study.
There are no secondary or exploratory objectives for this study.
Table 3-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
•
To collect additional safety information of 
sacubitril/valsartan in Japanese patients after 
long-term treatment of sacubitril/valsartan in 
CLCZ696B2319E1 study
Endpoint(s) for primary objective(s) 
• Adverse events (AEs)
Secondary Objective(s)
Not applicable
Endpoint(s) for secondary objective(s)
Not applicable
Exploratory Objective(s) 
Not applicable
Endpoint(s) for exploratory objective(s)
Not applicable
3.1
Primary estimands
Not applicable
3.2
Secondary estimands
Not applicable


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4
Study design
4.1
Overall design
This trial (CLCZ696B2319E2) is a multicenter, open-label extension study for Japanese 
patients who have successfully completed the PANORAMA-HF OLE study (Refer to 
Section 1.2 Schema for study design figure). PANORAMA-HF OLE study is an on-going Phase 
3b study in pediatric patients with systemic left ventricular systolic dysfunction to evaluate 
long- term safety and tolerability of sacubitril/valsartan in eligible PANORAMA-HF 
participants.
Only Japanese patients who successfully completed PANORAMA-HF OLE study and fulfill 
protocol requirements (see Section 5) are eligible to participate in this study, and will be offered 
the option to initiate treatment with sacubitril/valsartan by enrolling into this study at the 
discretion of the Investigator. Participants who permanently discontinued study drug treatment 
during PANORAMA-HF OLE study are not eligible for this study (see Section 5.2).
For all consenting patients eligibility for this study will be assessed at the first visit (Visit Day1) 
and the study medication will be initiated (see Section 8 for details). The first visit (Visit Day1) 
is the same day as the End of Study visit (Visit 599) of PANORAMA-HF OLE study. 
Participants who turned 18 years old during PANORAMA-HF OLE study, and who qualify, 
are eligible to participate in this study.
The starting dose of study drug will be determined by the Investigator considering the 
participant’s condition The dose level at the end of study visit of PANORAMA-HF OLE study 
may remain the same, or the dose level may be changed at the discretion of the Investigator.
All participants have a target dose (dose level 4) of 3.1 mg/kg bid. If a participant is unable to 
tolerate up-titration to a higher sacubitril/valsartan dose level or at the discretion of the 
Investigator, participants may be maintained on lower dose levels of sacubitril/valsartan (dose 
level 1-3, see Table 4-1). Please see Section 6.4.1 for dose adjustments. In case of a consecutive 
3-month interruption of study treatment, participant should be discontinued from the study and 
should complete the End of Study visit (Visit EOS).
Table 4-1
Study drug dose levels for sacubitril/valsartan
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.


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4.2
Scientific rationale for study design
The purpose of this open-label study is to collect additional safety information of 
sacubitril/valsartan and to provide post-trial access to sacubitril/valsartan for the eligible 
Japanese patients who completed CLCZ696B2319E1 study until marketed product of pediatric 
formulation, film-coated granules in capsule, is available in Japan. Open-label design is adopted 
to fulfill this purpose.
4.3
Justification for dose
This study is extended from PANORAMA-HF OLE study, with a similar study design as 
PANORAMA-HF OLE study. The starting dose of study drug will be determined by the 
Investigator considering the participant’s condition The dose level at the end of study visit of 
PANORAMA-HF OLE study may remain the same, or the dose level may be changed at the 
discretion of the Investigator. Maintaining the dose level at the end of study visit in 
PANORAMA-HF OLE study is considered appropriate, to ensure a smooth transition to this 
study medication taking safety and tolerability aspects into account. However, since it may not 
be appropriate to maintain the dose due to changes in the participant’s condition, etc., the dose 
level could be changed at the discretion of the Investigator.
4.4
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable
4.5
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 
participant safety and trial integrity and 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.
4.6
Purpose and timing of interim analyses/design adaptations
Not applicable
4.7
End of study definition 
Study completion is defined as when the last participant finishes their End of study 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.
5
Study population
The study population consists of Japanese pediatric HF patients, in-patients or outpatients. Only 
patients who successfully completed PANORAMA-HF OLE study and fulfill protocol 


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requirements (see Section 5.1 and Section 5.2) are eligible to participate in this study. Patients 
in PANORAMA-HF OLE study for whom study medication had been temporarily interrupted 
during the study (including at the study completion), may be considered for this study if they 
meet all entry criteria. A maximum of 8 Japanese patients will be enrolled into the study.
5.1
Inclusion criteria
Participants 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 must be obtained prior to 
participation in the study.
2. Male or female, inpatient or outpatient, and < 18 years of age (at the time of signing 
informed consent).
3. Patients who have completed PANORAMA-HF OLE study and are able to be safely 
enrolled into this study as judged by the Investigator.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Patients who permanently discontinued the study drug treatment during PANORAMA-HF 
OLE study.
2. Renal vascular hypertension (including renal artery stenosis).
3. Patients with a history of angioedema.
4. 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.
5. 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.
6. Patient breastfed by a mother taking ACEI.
7. Pregnant or nursing (lactating) female patients. 
8. Female patients of child-bearing potential, defined as all females physiologically capable 
of becoming pregnant, unless they are using highly effective methods of contraception 
while taking study treatment and for 7 days after stopping medication. Highly effective 
contraception methods include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception
•
Female bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks 
before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the female has been confirmed by follow up hormone level 
assessment.
•
Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant


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•
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 
(failure rate <1%), for example, hormone vaginal ring or transdermal hormone 
contraception.
In case of use of oral contraception, females should have been stable on the same pill for 
a minimum of 3 months before taking study treatment.
Females are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age-appropriate 
history of vasomotor symptoms). Females are considered not of child-bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to 
enrollment on study. In the case of oophorectomy alone, only when the reproductive 
status of the female has been confirmed by follow-up hormone level assessment is she 
considered to be not of child-bearing potential.
If local regulations are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the informed consent 
form (ICF).
5.3
Screen failures
Participants or parents/guardians who sign an informed consent form for themselves or for their 
child, respectively, and who (i.e. the participant) 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 electronic Case Report Form (eCRF). The baseline characteristics at Visit Day1, 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event (SAE) during the screening phase (see SAE section for reporting details).
Participants 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 on Visit Day1 
for any reason may be enrolled in this study. However, they will have to discontinue the study 
unless the study treatment starts within 3 months from Visit Day1 and will be considered an 
early study termination. The reason for early study termination should be captured on the 
appropriate disposition eCRF at Visit EOS. 
5.3.1
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.). The 
Participant No. consists of the Site Number (Site No.) (as assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each participant’s 
participation is numbered uniquely across the entire database. Upon signing the informed 
consent form, the participant will be assigned the same Participant Number as he/she had in the 
PANORAMA-HF OLE study.


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6
Study treatment(s) and concomitant therapy
6.1
Study treatment(s)
The sacubitril/valsartan study medication is available in 3 formulations: tablets, granules or 
liquid formulation (Table 6-1). For liquid formulation, please refer to the Pharmacy Manual.
Table 6-1
Open-label sacubitril/valsartan formulation
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
Prepared from tablets 100 mg
(please refer to Pharmacy Manual)
All pediatric formulations of study medication (sacubitril/valsartan granules or liquid) will be 
made available to all participants. The tablet formulations of sacubitril/valsartan will be 
available for participants based on the participant’s dosing and ability to swallow adult tablets 
(refer to Pharmacy Manual). 
An overview of available sacubitril/valsartan formulations is illustrated in Table 6-1. Capsules 
of sacubitril/valsartan containing 4 granules or 10 granules per capsule will be provided for oral 
use. The granules can be swallowed by the participant, after the removal of the outer capsule. 
Participants who cannot use tablets or granules can use the liquid formulation. 
Sacubitril/valsartan liquid formulation will be compounded by the site / pharmacy (please refer 
to 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 will not include information 
about the participant.
Participants 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 participants and 
families, the parent/caregiver can come to the site without the participant for dispensation of 
study drug between scheduled study visits (see Table 1-2). Delivery of study drug to the 
participant can also be used, where possible and where allowed by local regulations.
6.1.1
Additional study treatments
No other treatment beyond investigational drug is included in this trial.


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6.1.2
Treatment arms/group 
There is 1 treatment arm in this open-label study. All participants will receive open-label 
sacubitril/valsartan.
6.1.3
Treatment duration
The study will continue until marketed product of pediatric formulation is available in Japan.
6.2
Preparation, handling, storage, and accountability
Each study site will be supplied with study treatment in packaging as described under Table 
6-1.
Medication will be provided as tablets, granules or liquids. Tablets and granules will be 
provided by Novartis to the study site. Liquid preparation will be provided by the site For liquid 
preparation, please refer to Pharmacy Manual.
As per the treatment assigned to the participant, Investigator staff will select the study treatment 
to dispense to the participant. 
As per Section 4.5, 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, delivery 
of IMP directly to a participant’s home may be permitted (if allowed by local or regional health 
authorities and ethics committees, as appropriate) in the event the Investigator has decided that 
an on-site visit by the participant is no longer appropriate or possible, and that it is in the interest 
of the participant’s health to administer the study treatment even without performing an on-site 
visit. The dispatch of IMP from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 3-
months supply. In this case, regular phone calls or virtual contacts (every 4 weeks or more 
frequently if needed) will occur between the site and the participant for instructional purposes, 
safety monitoring, investigation of any adverse events, ensuring participants continue to benefit 
from treatment, and discussion of the participant's health status until the participants can resume 
visits at the study site.
6.2.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant.
The Investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 


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will be performed by field monitors during site or remote monitoring visits, and at the 
completion of the trial. The Investigator must provide accountability also for locally sourced 
materials used for administration (e.g. i.v. bags).
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the Investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the Investigator folder at each site.
6.2.2
Handling of other treatment 
The Investigator should instruct the participant/parent/guardian to notify the study site about 
any new medications he/she/their child takes after the participant was enrolled into the study. 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded. 
The participant should be receiving optimal standard of medical care or surgical treatment for 
their HF and comorbidities. 
6.2.3
Instruction for prescribing and taking study treatment
Novartis will supply the Investigators with all study medications required for the course of the 
study. Participants will be provided with bottles containing study drug corresponding to their 
assigned dose level, sufficient to last until the next scheduled visit (Table 1-2).  Study drug will 
be supplied to participants as:
Sacubitril/valsartan tablets: 50 mg, 100 mg or 200 mg 
Sacubitril/valsartan granules: 12.5 mg or 31.25 mg (3.125 mg/granule, either 4 or 10 granules 
packaged in capsule) supplied in a bottle
Sacubitril/valsartan liquid formulation (compounded by site / pharmacy) (refer to Pharmacy 
Manual) 
Details regarding preparation of liquid formulation for sacubitril/valsartan are provided in the 
Pharmacy Manual.
Participants 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 Pharmacy Manual. 
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded on the Dosage Administration Record (DAR) eCRF. 
See Section 6.3 for Study treatment compliance.
6.3
Study treatment compliance
The Investigator must promote compliance by instructing the participant/parent/guardian to 
take/administer the study treatment exactly as prescribed and by stating that compliance is 


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necessary 
for 
the 
participant’s 
safety 
and 
the 
validity 
of 
the 
study. 
The 
participant/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.
6.3.1
Recommended treatment of adverse events
Recommendations for handling Renal events, hypotension and hyperkalemia are described in 
Appendix 6, Appendix 8, and Appendix 9, respectively. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate eCRF.
6.4
Dose modification
6.4.1
Dose modifications
The maximum tolerated or target dose (dose level 4) will 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 participants who are unable to tolerate the study drug, 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.
•
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 4-1) to temporary or permanent discontinuation of study drug. 
•
The participant 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 participant should be discontinued from 
the study (Visit EOS).
Participants 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, Work 2009) will be 
utilized. Refer to Appendix 6, Appendix 8, and Appendix 9 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 6-2 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 participant’s condition is stable, 


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the participant can be up-titrated to the next higher dose level using unscheduled visits in an 
attempt to bring back the participant 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 4-1). For up-titration of the study drug, participants have to meet all criteria in 
Table 6-2 before administering the higher dose level.
Table 6-2
Safety monitoring criteria for adjustment of study-drug dose level
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 5, Table 10-4) 
Kidney function
eGFR reduction < 35% compared to Visit Day1. 
Blood pressure
Systolic blood pressure (SBP) > than the calculated 5th percentile SBP for age as 
described in Appendix 7
AEs or conditions
No conditions that preclude continuation according to Investigator’s judgment, 
including hypotension.
All changes should be recorded on the DAR eCRF.
Study drug restart after temporary treatment interruption
Participants who have temporarily discontinued study drug should be restarted as soon as 
possible as deemed appropriate by the Investigator. The Investigator should restart the 
participant on the study drug at the most appropriate dose level (Table 4-1) as per the 
Investigator’s clinical judgment. If the participant 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. 
Participants restarted on the study drug will retain their original study identification numbers.
Investigators may discontinue a participant’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, participants who permanently discontinued 
study drug should be scheduled for the discontinuation study Visit EOS. Note that after a 
consecutive 3-month interruption of study treatment, participant should be discontinued from 
the study and should be seen at the site for Visit EOS).
If during study treatment interruption a participant 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. Participants 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.
If the participant becomes pregnant during the course of the study, the participant has to 
discontinue study drug immediately and should be seen at the site for Visit EOS and evaluated 
for transition to alternative treatment per the Investigator’s clinical judgement.  
Refer to (Section 8.4.5) for further details on pregnancies and reporting guidelines.


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6.4.2
Follow-up for toxicities    
Refer to Appendix 5 and Appendix 6 (Section 10.5 and Section 10.6) for the follow-up of renal 
events.
6.5
Continued access to study treatment after the end of the study
Not applicable
6.6
Treatment of overdose
In the event of an overdose, the Investigator should:
•
Contact the medical monitor immediately.
•
Evaluate the participant to determine, in consultation with Novartis medical monitor, 
whether study treatment should be interrupted or whether the dose should be reduced.
•
Closely monitor the participant for any AE/SAE and laboratory abnormalities.
•
Document the quantity of the excess dose as well as the duration of the overdose.
6.6.1
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, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE. Study 
treatment errors and uses outside of what is foreseen in the protocol, 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. For more information on AE and SAE definition 
and reporting requirements, please see the respective sections.
6.7
Concomitant and other therapy
Participants 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.
6.7.1
Concomitant therapy
The Investigator must instruct the participant to notify the study site about any new medications 
he/she takes after the participant was enrolled into the study.


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All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate eCRFs.
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before enrolling a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
6.7.1.1
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. 
Concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), 
potassium supplements, or salt substitutes containing potassium may lead to increases in serum 
potassium, if co-medication is considered necessary, monitoring of serum potassium is advised. 
In volume depleted patients (including those on diuretic therapy), or patients 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 
participants on sacubitril/valsartan who are taking NSAIDs concomitantly.
The potential for a drug interaction between sacubitril/valsartan and lithium has not been 
investigated. Reversible increases in serum lithium concentrations and toxicity have been 
reported during concomitant administration of lithium with ACEI or ARBs. Therefore, careful 
monitoring of serum lithium levels is recommended during concomitant use with 
sacubitril/valsartan.
Guidelines for the management of renal dysfunction, hypotension, and hyperkalemia are 
provided in Appendix 6, Appendix 8, and Appendix 9, respectively.


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6.7.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed while taking study drug due 
to safety reasons. If the medication included in Table 6-3 is administered, study drug must be 
discontinued and the actions specified below must be taken.
Table 6-3
Prohibited medication 
Medication
Prohibition period
Action taken
any ACEI
36 hours 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 participant 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.
6.7.3
Rescue medicine
If in the opinion of the Investigator, the participant 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 6, Appendix 8, and Appendix 9, 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.
7
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration, and can be initiated by either the participant or the 
Investigator. In this study, if the study treatment is permanently discontinued, the participant 


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should be discontinued from the study and the end of study visit (Visit EOS) should be 
conducted (Section 6.4.1).
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant’s well-being.
Study treatment must be discontinued under the following circumstances:
•
Participant/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 participant
•
Any laboratory abnormalities that in the judgment of the Investigator prevents the 
participant 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 participant’s premature discontinuation of study 
treatment and record this information.
Participants 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). 
7.2
Participant discontinuation from the study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason.
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in Section 1.3 Schedule of Activities.
7.3
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant:
•
Explicitly requests to stop use of their data
and
•
No longer wishes to receive study treatment
and
•
Does not want any further visits or assessments (including further study-related contacts)
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation.
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 


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very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms.
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation.
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 participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3 Schedule of 
Activities.
Further details on withdrawal of consent or the exercise of participants’ data privacy rights are 
included in the corresponding informed consent form.
7.4
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show “due diligence” by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed or until the end of the study.
7.5
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 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.
Reasons for early termination (but not limited to)
•
Unexpected, significant, or unacceptable safety risk to participants enrolled in the study
•
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data
•
Discontinuation of study treatment development in this indication
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. 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. 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 


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participant’s interests. The Investigator or Novartis depending on local regulation will be 
responsible for informing Institutional Review Boards (IRBs) / Independent Ethics Committees 
(IECs) of the early termination of the trial.
8
Study Assessments and Procedures
After identifying a potential participant, an ICF and assent (if applicable) must be signed by the 
parent(s)/legal guardian(s) and by the participant (as applicable) before performing any study-
related procedures that are not considered standard of care for pediatric HF participants at that 
site. Procedures that are part of a site‘s standard of care for a pediatric participant or that were 
done as part of the End of Study visit (Visit 599) of PANORAMA-HF OLE study may pre-date 
the signed ICF for this study. The AE and SAE reporting period will begin at the time the ICF 
is signed. 
The Assessment Schedule (Table 1-2) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. The “X” in the table denotes the assessments to be recorded in the clinical 
database or received electronically from a vendor. The “S” in the table denotes the assessments 
that are only in the participant’s source documentation and do not need to be recorded in the 
clinical database.
Sacubitril/valsartan treatment will start at Visit Day1, which is the same day as the End of Study 
visit (Visit 599) of PANORAMA-HF OLE study. The data of some assessments (such as vital 
sign, height, and weight) at the End of Study visit (Visit 599) in PANORAMA-HF OLE study 
will be utilized as the data at Visit Day1 for this study.
A telephone visit (Visit M3) and an on-site visit (Visit M6) will occur 3 months and 6 months 
after Visit Day1, respectively. The visits as same Visit M3 and Visit M6 will then be repeated 
every 3 months until the end of the study. When the pediatric formulation of sacubitril/valsartan 
becomes available in Japan, or this study is terminated by Novartis, any participants should 
return to the study site as soon as possible for End of Study (EOS) visit (Visit EOS) regardless 
of subsequent scheduled visit, and all of the assessments listed for Visit EOS will be performed.
Participants should take their scheduled dose of sacubitril/valsartan in the morning of their study 
visits. Participants are not required to fast overnight on the day prior to or the day of the study 
visit. 
Participants, who discontinue sacubitril/valsartan for 3 consecutive months, will be 
discontinued from the study and are to attend Visit EOS. 
Participants 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 Day1. Missed or rescheduled 
visits should not lead to automatic discontinuation. Specific circumstances surrounding missed 
or rescheduled visits must be discussed with the study monitor. Participants who prematurely 
discontinue the study treatment, or prematurely withdraws from 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 EOS) will be performed. At this final visit, all dispensed investigational 


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product should be reconciled, and the adverse event and concomitant medications recorded on 
the eCRF.
As per Section 4.5, 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. If allowable by a local health authority, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or visits by site 
staff/ off-site healthcare professional(s) staff to the participant´s home, can replace on-site study 
visits, for the duration of the disruption until it is safe for the participant to visit the site again. 
If the Investigator delegates tasks to an off-site healthcare professional, the Investigator must 
ensure the individual(s) is/are qualified and appropriately trained to perform assigned duties. 
The Investigator must oversee their conduct and remain responsible for the evaluation of the 
data collected.
8.1
Screening
Participants or parents/guardians who sign an informed consent form for themselves or for their 
child, respectively, will be screened. The inclusion/exclusion criteria at Visit Day1 will be 
checked.  
8.2
Participant demographics/other baseline characteristics
Participant demographic and baseline characteristic data at Visit Day1 will be collected 
including: year of birth (where allowed) age in years (age in months for participants < 2 years, 
where allowed), sex, race and ethnicity, as well as the Identification Number (ID No.). 
Additionally, pediatric heart failure history, vital signs, weight and height will be collected. 
Relevant medical history/current medical condition data includes data until the start of study 
drug. HF medications will be recorded on the Concomitant Medications eCRF.
8.3
Efficacy assessments
Efficacy will not be measured in this study.
8.4
Safety assessments
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
•
Laboratory evaluations


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•
Pregnancy test
Safety assessments are specified below with Section 1.3 Schedule of Activities detailing when 
each assessment is to be performed.
For details on AE collection and reporting, refer to Section 8.6.
As per Section 4.5, 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, regular 
phone or virtual calls can occur (every 3 months or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again.
8.4.1
Physical examinations
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.
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 on the appropriate eCRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse Event must be recorded 
as an adverse event.
8.4.2
Vital signs
Vital signs include blood pressure (BP) and pulse measurements and are assessed when a 
physical examination is performed. After the participant 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 participants who are infants or who cannot sit 
comfortably. Clinically notable vital signs are defined in Appendix 3.
8.4.3
Height and weight 
Height 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.
8.4.4
Clinical safety laboratory tests
Laboratory assessments will be analyzed locally during the study. It is the responsibility of the 
Investigator to review all laboratory results and make an assessment of whether an abnormal or 
notable value is clinically significant, whether additional evaluations should be performed as 


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judged appropriate, and whether the patient may continue in the trial. Sample collection should 
be conducted according to the standards and requirements of the local laboratory.
Serum sodium, potassium, creatinine, and eGFR (modified Schwartz formula) will be evaluated 
locally at visits defined in Table 1-2, and recorded in the eCRF. Additional laboratory 
evaluation including hematology and urinalysis may be performed optionally by Investigator’s 
clinical judgement at any visits. There is no local assessment at Visit Day1, but the results of 
central laboratory at the End of Study visit (Visit 599) in PANORAMA-HF OLE study should 
be reviewed by the Investigator soon after the results are obtained.
Clinically notable laboratory findings are defined in Appendix 3 Table10-1. 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 8.6 Safety reporting, then the diagnosis 
or medical condition must be entered on the AEs page of the participant’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 
participant 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 the End 
of Study visit (Visit EOS). Please see details in Section 8.4.5. 
A table, which provides the maximum, allowable blood-draw volumes by weight, can be found 
in Appendix 10.
Plasma potassium may be used instead of serum potassium in this study.  Serum potassium 
thresholds in the study protocol, including those values cited in Appendix 3 and Appendix 9 
can be converted to plasma potassium thresholds for the study by subtracting 0.4 mmol/L from 
the serum potassium threshold.
As per Section 4.5, 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, if 
participants cannot visit the site for protocol-specified safety lab assessments, an alternative lab 
(local) collection site may be used.
8.4.5
Pregnancy testing
All child-bearing potential female participants who are not surgically sterile will have 
pregnancy testing. Additional pregnancy testing might be performed if requested by local 
requirements.


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Childbearing potential females (CHBP) are defined as all female participants ≥ 11 years of age 
and all female participants 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 (except for End of Study visit: Visit EOS) on all 
CHBP female participants. There is no assessment at Day1, but the result of central laboratory 
(serum test) at the End of Study visit (Visit 599) in PANORAMA-HF OLE study should be 
reviewed by the Investigator soon after the result is obtained. A positive urine pregnancy test 
should be confirmed with a serum pregnancy test. Participants 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 EOS. Serum pregnancy testing will be performed at Visit EOS.
For child-bearing potential females, a urine pregnancy test will also be performed at monthly 
intervals between study visits, during the study. 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 participant with urinary pregnancy tests for home monthly tests. 
If monthly home urine pregnancy tests are utilized, child-bearing potential female participants 
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). Participants 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. Study 
Site personnel will contact the participant on a monthly basis to check that the participant 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 participant. The Pregnancy Test Diary will be part of the source 
documentation 
for 
the 
participant. 
If 
the 
pregnancy 
test 
is 
positive, 
the 
participant/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 participant 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 participant and her parents/caregivers. The privacy of the participant should be considered 
in accordance with the local law and ethics.
Any participant 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 EOS .


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Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the female 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.
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female participant regardless of reported reproductive/menopausal 
status at screening/baseline.
8.4.6
Other safety evaluations
Not applicable
8.4.7
Appropriateness of safety measurements
The safety and clinical laboratory assessments performed in this study are similar to those used 
in PANORAMA-HF OLE study. 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 LCZ696 Investigator's Brochure (IB), and the 
indication/participant population under study.
8.5
Additional assessments 
No additional tests will be performed on participants entered into this study.
8.6
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
The definitions of AEs and SAEs can be found in Section 8.6.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up (see Section 7).
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 8.6.3.
8.6.1
Adverse events 
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical investigation 
participant 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.


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The Investigator has the responsibility for managing the safety of individual participant 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 participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant 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 8.6.2):
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. If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single participant
3. Its duration (start and end dates or ongoing) and the outcome must be reported
4. Whether it constitutes a SAE (see Section 8.6.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:
•
Dose not changed
•
Dose Reduced/increased
•
Drug interrupted/permanently discontinued
6. Its outcome
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
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 not recovered/not resolved (e.g. continuing at the end of the study), and assessment must be 


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made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 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 participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.3.
8.6.2
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 participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).
•
results in persistent or significant disability/incapacity
•
constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or 
birth defect
•
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
•
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
•
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
•
social reasons and respite care in the absence of any deterioration in the participant’s 
general condition
•
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
•
is medically significant, e.g. defined as an event that jeopardizes the participant 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 


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life-threatening or result in death or hospitalization but might jeopardize the participant 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 new 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.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective of whether a clinical event has occurred. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
8.6.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
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. Information 
about all SAEs is collected and recorded on the eSAE (electronic Serious Adverse Event) with 
paper backup Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report.
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis.
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, or Investigators during the study (Table 8-1).
Table 8-1
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 


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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 or Package Insert (new 
occurrence) and is thought to be related to the study treatment, the Novartis Chief Medical 
Office and Patient Safety and Pharmacovigilance (PS & PV) 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 with the exception of those terms listed in Table 8-1 will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30-day period following end of study should only be reported 
to Novartis Safety using the paper SAE form provided to the site if the Investigator suspects a 
causal relationship to study treatment, unless otherwise specified by local law/regulations. 
8.6.4
Pregnancy
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant 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. After informed consent is provided, the pregnancy reporting 
will occur up to one year after the estimated date of delivery. Post-natal follow up should occur 
at 1, 3 and 12 months after delivery.
Pregnancy should be recorded and reported by the Investigator to the Novartis PS&PV. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment with any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
8.7
Pharmacokinetics
PK parameters are not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.


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8.9
Immunogenicity assessments
Immunogenicity is not evaluated in this study.
8.10
Health economics OR Medical resource utilization and health 
economics
Health economics OR Medical resource utilization and health economics parameters are not 
evaluated in this study.
9
Statistical considerations
9.1
Analysis sets
The following analysis sets will be used for the statistical analyses:
•
Enrolled set (ENR): All patients who signed the informed consent for the extension open-
label study.
•
Safety Set (SAF): All ENR patients who received at least one dose of open-label study 
treatment during the extension open-label study.
9.2
Statistical analyses
9.2.1
General considerations
•
The study treatment is sacubitril/valsartan.
•
The date of first administration of study treatment during this study is the day of the first 
non-zero dose of sacubitril/valsartan.
•
The date of last administration of study treatment is the day of the last non-zero dose of 
sacubitril/valsartan.
•
The study period starts with the date of the signature on informed consent (Visit Day 1, 
the same day as Visit 599 (EOS visit) of PANORAMA-HF OLE study) and ends with the 
date of end-of-study or premature study discontinuation visit (Visit EOS). 
•
The treatment period starts with the date of first administration of study treatment and 
ends with the date of treatment disposition. In the case that no EOS visit is undertaken 
(e.g., because the participant died or withdrew from the study without such a visit), the 
treatment period ends with the death/withdrawal date, or the last dose taken.
•
In general, continuous variables will be summarized using number of observations, mean, 
standard deviation, median, minimum and maximum. Categorical variables will be 
summarized using frequencies and percentages. 
9.2.2
Participant demographics and other baseline characteristics
Demographic and other characteristics at Visit Day1, including age, age group (6 years and 
older, < 6 years), sex, weight, height, body mass index (BMI), vital signs, and age adjusted 
percentile for weight and height, and z-score for height will be summarized descriptively.


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BMI will be calculated as weight (kg) / height2 (m2) using the collected height and weight at 
Visit Day1.
Relevant medical histories at Visit Day1 will be summarized, by system organ class and 
preferred term.
The SAF will be used for the above analyses.
9.2.3
Treatments
Duration of exposure to the study treatment will be summarized for continuous variable. 
Dose levels will be summarized for continuous variable by visit.
Concomitant medications and significant non-drug therapies prior to and after Visit Day1 will 
be summarized by anatomical therapeutic classification (ATC), preferred term.
The SAF will be used for the above analyses.
9.3
Primary endpoint(s)/estimand(s) analysis
The primary objective is to collect additional safety information of sacubitril/valsartan in 
eligible heart failure patients from PANORAMA-HF OLE study receiving open-label 
investigational drug.
The primary safety information to analyze will be based on adverse events, which will be 
analyzed using frequencies and percentages.
Adverse events will be summarized by primary system organ class and preferred term, using 
numbers and percentages of patients with at least one adverse event in the corresponding class.
9.3.1
Definition of primary endpoint(s)
Any adverse events (treatment emergent or not) are considered primary endpoints.
9.3.2
Statistical model, hypothesis, and method of analysis
Not applicable. There are no statistical hypotheses to be tested in this study and no model 
analyses will be performed.
9.3.3
Handling of intercurrent events of primary estimand (if applicable)
Not applicable
9.3.4
Handling of missing values not related to intercurrent event
The missing value for laboratory assessments, vital signs, height, weight, and other assessments 
will be not imputed.
The missing or partially missing start/end date for AEs, prior/concomitant therapies, and study 
drug will be imputed according to the imputation rules specified in the Statistical Analysis Plan 
(SAP).


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9.3.5
Multiplicity adjustment (if applicable)
Not applicable. No statistical tests will be performed in this study.
9.3.6
Sensitivity analyses
Not applicable
9.3.7
Supplementary analysis
Not applicable
9.4
Secondary endpoint(s)/estimand(s) analysis
Not applicable. There are no secondary endpoints.
9.5
Exploratory endpoint(s)/estimand(s) analysis
Not applicable. There are no exploratory endpoints.
9.6
(Other) Safety analyses
The following adverse events will be summarized by primary system organ class, and preferred 
term as appropriate using numbers and percentages of patients with at least one adverse event 
in the corresponding class.
•
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. events of important identified 
risks and important potential risks defined in the Risk Management Plan (RMP)
*TEAEs is any adverse events (new or worsened) occurring on or after Visit Day 1.
Descriptive statistics of vital signs (raw values) and the number of patients and percentages with 
clinically notable vital signs during the treatment period will be provided by visit (Day1, M3, 
M6, EOS). Criteria of clinically notable vital signs are given in the Appendix 3 Table 10-2.
Descriptive statistics (raw values) will be provided for weight, height, BMI, age adjusted 
percentile for weight and height, and z-score for height by visit.
BMI will be calculated as weight (kg) / height2 (m2) using the collected height and weight at 
each visit.
9.7
Other analyses
Not applicable
9.8
Interim analysis
Not applicable


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9.9
Sample size determination
9.9.1
Primary endpoint(s)
All patients who have completed PANORAMA-HF OLE study and who meet all Inclusion and 
Exclusion criteria (Section 5.1 and Section 5.2), are eligible for this extension study. 
There is no specific sample size required for the study. A maximum of 8 Japanese patients will 
be enrolled into the study.
9.9.2
Secondary endpoint(s)
Not applicable


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10
Supporting documentation and operational considerations
10.1
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines
•
Applicable ICH Good Clinical Practice (GCP) guidelines
•
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following:
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority
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 or European Clinical Trial 
Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the Declaration 
of Helsinki.


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10.1.2
Informed consent process  
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative and answer all questions 
regarding the study.
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents.
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative.
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document.
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant upon obtaining consent and also 
during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate, 
for example, via an Investigator notification or an aggregate safety finding. New information 
might require an update to the informed consent and then must be discussed with the participant.
The following informed consents and assents are included in this study:
•
Main study consent and assent, which also included: 
•
A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study
•
Optional consent for activities that may be done outside of the study site
•
As applicable, Pregnancy Outcomes Reporting Consent for female participants 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.


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As per Section 4.5, 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, 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 participant and person obtaining informed consent, etc.).
10.1.3
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws.
10.1.4
Committees structure 
Not applicable
10.1.5
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis.
10.1.5.1 Data collection 
Data not requiring a separate written record will be defined in the protocol and Section 1.3 
Schedule of Activities and can be recorded directly on the eCRFs. All other data captured for 


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this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source
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 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 participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
10.1.5.2 Database management and quality control 
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated Investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments 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.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. Any changes to 
the database after that time can only be made after written agreement by Novartis development 
management.
10.1.6
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available.


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The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 
informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in monitoring guidelines.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements.
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/ 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 clinical teams to assist with trial oversight.
10.1.7
Publication policy 
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 participant 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.
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation.
10.1.8
Protocol adherence and protocol amendments 
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 participants 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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10.1.8.1 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 participant 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 participant 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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10.2
Appendix 2: Abbreviations and definitions
10.2.1
List of abbreviations
ACEI
Angiotensin Converting Enzyme (inhibitor)
AE
Adverse Event
AHA
American Heart Association
AKI
Acute Kidney Injury
ARB
Angiotensin Receptor Blocker
ARNI
Angiotensin Receptor Neprilysin Inhibitor 
AT1
Angiotensin II Type 1
ATC
Anatomical Therapeutic Classification
bid
bis in die/twice a day
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CCB
Calcium Channel Blocker
CHBP
Child Bearing Potential Females
CIOMS
Council for International Organizations of Medical Sciences
COX
Cyclo-oxygenase
Cr
Creatinine
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical Study Report
CV
Cardiovascular
DAR
Dosage Administration Record
DBP
Diastolic Blood Pressure
eCRF
electronic Case Report/Record Form
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
ENR
Enrolled Set
EOS
End of Study
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
HF
Heart Failure
HFrEF
HF with Reduced Ejection Fraction
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
IRB
Institutional Review Board
IUD
Intrauterine Device
IUS
Intrauterine System


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KDIGO
Kidney Disease: Improving Global Outcomes
LLN
Lower Limit of Normal
MedDRA
Medical Dictionary for Regulatory Activities 
MRP2
Multidrug resistance protein 2
NEP
Neprilysin
NSAID
Non-steroidal Anti-Inflammatory Drug
PALS
Pediatric Advanced Life Support
PCR
Protein-Creatinine Ratio
PK
Pharmacokinetic(s)
PS
Patient Safety
PV
Pharmacovigilance
OLE
Open Label Extension
RAAS
Renin-Angiotensin-Aldosterone System
RMP
Risk Management Plan
RRR
Relative Risk Reduction
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SoA
Schedule of Activities
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment- Emergent Adverse Event
ULN
Upper Limit of Normal
UNS
Unscheduled
WHO
World Health Organization
10.2.2
Definitions
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
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant
Cohort
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time
Discontinuation 
from study
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or data.
Discontinuation 
from study 
treatment
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study intervention 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the use 
of their samples or data.


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Dosage
Dose of the study treatment given to the participant 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 source data/documents 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 participant.
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained. The action of enrolling one or more participants
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 participants with established disease and 
in those with newly-diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
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
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Screen Failure
A participant 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 eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Treatment 
arm/group
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.


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Withdrawal of 
consent
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation.
This request should be distinguished from a request to discontinue the study. 
Other study participant's privacy rights are described in the corresponding 
informed consent form.


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Protocol No. CLCZ696B2319E2
10.3
Appendix 3: Clinical laboratory tests 
10.3.1
Clinically notable laboratory values and vital signs 
Table 10-1
Clinically notable laboratory values
Parameter
Conventional
Units
SI Alert
Value
SI
Units
Hematology
Red Blood Cell 
Count 
x10E6/uL
>50% increase and > Upper limit of normal 
(ULN);
>30% decrease and < Lower limit of normal 
(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
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
Increase and decrease are defined as compared to the baseline value of PANORAMA-HF OLE 
study (i.e. Visit 500).
Table 10-2
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


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Age
HR [min-1]
SBP [mmHg]
DBP [mmHg]
RR [min-1]
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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Protocol No. CLCZ696B2319E2
10.4
Appendix 4: Participant Engagement 
The following participant engagement initiative is included in this study and will be provided, 
as available for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis.
•
Plain language trial summary - after clinical study report (CSR) publication 


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Protocol No. CLCZ696B2319E2
10.5
Appendix 5: Renal safety monitoring
10.5.1
Specific Renal Alert Criteria and Actions and Event Follow-up
Table 10-3
Specific renal alert criteria and actions
Renal Event
Actions
eGFR decrease 25 – 49%
•
Consider causes and possible interventions
•
Repeat laboratory values within 48 hrs of receipt of abnormal 
test results. Assess patient for signs and symptoms of illness, 
acute kidney injury (AKI), etc.
eGFR decrease ≥ 50% *
OR if <18 years old, eGFR < 
35 mL/min/1.73 m2
•
Consider causes and possible interventions
•
Repeat assessment within 24-48h if possible
•
Repeat laboratory values within 48 hrs of receipt of abnormal 
test results. Assess patient for signs and symptoms of illness, 
AKI, etc.
•
Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected
•
Consider referral to nephrologist for diagnosis and management
•
Consider patient hospitalization and specialized treatment
New onset dipstick 
proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) 
≥ 1g/g creatinine (Cr)
•
Confirm presence of true proteinuria by quantification: 
protein:creatinine on first morning void
•
Consider causes and possible interventions
•
Assess serum albumin & serum total protein
•
Repeat assessment to confirm
•
Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected
•
Consider referral to a nephrologist
New onset hematuria ≥ 3+ on 
urine dipstick
•
Obtain urine microscopy to distinguish hemoglobinuria or 
myoglobinuria from hematuria
•
Assess serum Cr
•
Exclude infection, trauma, calculi, bleeding from the distal 
urinary tract/bladder, menstruation
•
Consider bleeding disorder
* Corresponds to KDIGO criteria for Acute Kidney Injury
eGFR is calculated using a modified Schwartz formula for participants <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. 
eGFR decrease are defined as compared to the baseline value of PANORAMA-HF OLE study (i.e. 
Visit 500).
Urine samples for testing for renal monitoring, and particularly those for the PCR ratio determination, 
must be collected at the first morning void.


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Table 10-4
GFR by age for up-titration
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
** up-titration criteria
Source: (Peters, Gordon 1999)


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Protocol No. CLCZ696B2319E2
10.6
Appendix 6: 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 enrollment and the first dose of sacubitril/valsartan.
Two types of response to serum creatinine increase are described:
Surveillance situation
If, at any time after enrollment and the first open-label dose of sacubitril/valsartan, eGFR%* 
decreases by ≥ 50% from baseline in PANORAMA-HF OLE study (i.e. Visit 500), 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 PANORAMA-HF OLE study (i.e. 
Visit 500) (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 participants <18 years.
For participants ≥18 years, an adult formula for eGFR will be utilized (Reference: Novartis 
Nephrology Guidance document)


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Protocol No. CLCZ696B2319E2
10.7
Appendix 7: American heart association (AHA) pediatric 
advanced life support (PALS) guidelines
Table 10-5
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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Protocol No. CLCZ696B2319E2
10.8
Appendix 8: Guidelines for the management of hypotension
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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Protocol No. CLCZ696B2319E2
10.9
Appendix 9: 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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Protocol No. CLCZ696B2319E2
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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Protocol No. CLCZ696B2319E2
10.10
Appendix 10: Reference table – blood volume by weight
Table 10-6
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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Clinical Trial Protocol (Version No. v00)
Protocol No. CLCZ696B2319E2
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. 
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
5% of total blood volume = body weight (in kg to the closest 0.5 kg) X 4


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11
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(1):79-84.
CVAL489K2304 (2011) Physician survey of clinical management and uses of medicinal 
products in paediatric patients with heart failure. Valsartan 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(1):46-53.
Hsu DT, Pearson GD (2009) Heart failure in children Part I: History, etiology and 
pathophysiology. Circulation Heart Failure; 2(1):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(4):403-10. 
Kleinman ME, Chameides L, Schexnayder SM, et al (2010) Part 14: pediatric advanced life 
support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and 
Emergency Cardiovascular Care. Circulation; 122(18 Suppl 3):S876-908.
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; 28(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. pp. 365-735 Fourth edition.  
Lippincott Williams & Wilkins: Maryland.
Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and adolescents. 
Clin J Am Soc Nephrol; 4(11):1832–43.
Shaddy R, Canter C, Halnon N, et al (2017) Design for the sacubitril/valsartan (LCZ696) 
compared with enalapril study of pediatric patients with heart failure due to systemic left 
ventricle systolic dysfunction (PANORAMA-HF study). Am Heart J; 193:23-34.
Sharma M, Nair M, Jatana SK, et al (2003) Congestive heart failure in infants and children. 
Med J Armed Forces India; 59(3):228-33. 
Tsutsui H, Momomura SI, Saito Y, et al (2021) Efficacy and Safety of Sacubitril/Valsartan in 
Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction
- Results From 
the PARALLEL-HF Study. Circ J; 85(5):584-94.

SAP_001.pdf: 
Clinical Development 
LCZ696/ Sacubitril Valsartan Sodium Hydrate /Entresto® 
CLCZ696B2319E2 / NCT06149104
A multicenter, open-label study to collect the safety information of 
sacubitril/valsartan in Japanese pediatric patients with heart failure 
due to systemic left ventricle systolic dysfunction who have 
completed CLCZ696B2319E1 study 
Statistical Analysis Plan (SAP)  
Author: 
Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
30-August-2024
Number of pages: 
24 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 6.0, Effective from 23-Nov-2022 


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Page 2 of 24 
SAP v2 
 
Study No. CLCZ696B2319E2 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
27-
Nov-
2023 
Prior to 
DB lock 
Creation of final 
version 
N/A - First version 
NA 
30-
August 
2024 
Prior to 
DB lock 
To Add software 
used for analysis 
Unless otherwise specified, the 
data will be analyzed according 
to the study protocol using 
SAS® 9.4 or higher and current 
version R® at time of analysis, 
by Novartis personnel. 
2.1
 
Data 
analysis 
general 
information 
30-
August 
- 2024 
Prior to 
DB lock 
To 
clear 
the 
definition 
of 
each scheduled 
visit  
Each scheduled visit is defined 
using the study day as follows: 
•Visit 3M = day 91 
•Visit 6M = day 183 
2.1.1 General 
definitions 
30-
August 
- 2024 
Prior to 
DB lock 
To correct a typo  The z-score formula is 
corrected. 
2.3.2 
Demographics 
and 
other 
baseline 
characteristics 
30-
August 
- 2024 
Prior to 
DB lock 
To 
clear 
the 
definition of the 
visit date 
The dose level for each visit is 
defined as the dose level of 
dosing interval with its start date 
prior to or equal to the 
scheduled visit date and its end 
date later than or equal to the 
scheduled visit date. For EOS 
visit, actual visit date is used to 
identify the dose level. 
2.4.1 
Study 
treatment/ 
compliance 
30-
August 
- 2024 
Prior to 
DB lock 
To correct the 
summarization 
category 
summarized 
by 
medication 
category and preferred term 
2.4.2 Prior, 
concomitant 
and 
post 
therapies 
30-
August 
- 2024 
Prior to 
DB lock 
To remove RMP 
text 
from 
description 
of 
The 
following 
treatment 
emergent 
adverse 
event 
of 
special 
interest 
will 
be 
summarized. 
2.7.1.1
 
Advers
e 
events 
of 
special interest 


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Page 3 of 24 
SAP v2 
 
Study No. CLCZ696B2319E2 
 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
adverse event of 
special interest 
/ grouping of 
AEs 
30-
August 
- 2024 
Prior to 
DB lock 
Updated eCRS 
to remove some 
risk definitions 
from the eCRS 
and 
change 
some 
risk 
names. 
- Anaphylaxis, Hypersensitivity, 
and Malignancy were removed 
from event list. 
- Changed 'Change in bone 
growth and density' to 'Long 
term effects on growth bone 
growth and mineralisation in the 
pediatric population' 
-  Removed "(Narrow SMQ)" 
following risk name 
2.7.1.1
 
Advers
e 
events 
of 
special interest 
/ grouping of 
AEs 
30-
August 
- 2024 
Prior to 
DB lock 
To add rules for 
handling 
overlap between 
EOS and Visit 
M6 
If the timing of EOS and Visit 
M6 overlaps and two visits are 
made simultaneously, the data 
will be used for both EOS and 
Visit M6. The window of Visit 
M6 is defined as ±1 month of the 
scheduled 
visit 
date 
(day183±30). 
2.7.4.2 
Vital 
signs 
30-
August 
- 2024 
Prior to 
DB lock 
To add rules for 
handling 
overlap weight 
data 
between 
EOS and Visit 
M6 
For weight, if the timing of EOS 
and Visit M6 overlaps and two 
visits are made simultaneously, 
the data will be used for both 
EOS and Visit M6. The window 
of Visit M6 is defined as ±1 
month of the scheduled visit date 
(day183±30). 
2.7.4.3 
Hight 
and Wight 
 
 
 
 
 


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SAP v2 
 
Study No. CLCZ696B2319E2 
 
 
 
Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.2 
Study objectives, endpoints and estimands ............................................................. 8 
1.2.1 
Primary estimand(s) ................................................................................ 9 
1.2.2 
Secondary estimand(s) ............................................................................ 9 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets .......................................................................................................... 10 
2.2.1 
Subgroup of interest .............................................................................. 10 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 10 
2.3.1 
Patient disposition ................................................................................. 10 
2.3.2 
Demographics and other baseline characteristics ................................. 10 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 11 
2.4.1 
Study treatment / compliance ................................................................ 11 
2.4.2 
Prior, concomitant and post therapies ................................................... 12 
2.5 
Analysis supporting primary objective(s) .............................................................. 14 
2.5.1 
Primary endpoint(s) ............................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.5.3 
Handling of intercurrent events ............................................................. 14 
2.5.4 
Handling of missing values not related to intercurrent event ............... 14 
2.5.5 
Sensitivity analyses ............................................................................... 14 
2.5.6 
Supplementary analyses ........................................................................ 14 
2.6 
Analysis supporting secondary objectives ............................................................. 14 
2.7 
Safety analyses....................................................................................................... 14 
2.7.1 
Adverse events (AEs) ............................................................................ 14 
2.7.2 
Deaths .................................................................................................... 17 
2.7.3 
Laboratory data ..................................................................................... 17 
2.7.4 
Other safety data ................................................................................... 17 
2.8 
Pharmacokinetic endpoints .................................................................................... 19 
2.9 
PD and PK/PD analyses ........................................................................................ 19 
2.10 
Patient-reported outcomes ..................................................................................... 19 


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2.11 
Biomarkers ............................................................................................................. 19 
2.12 
Other Exploratory analyses.................................................................................... 19 
2.13 
Interim analysis ...................................................................................................... 19 
3 
Sample size calculation ..................................................................................................... 19 
4 
Change to protocol specified analyses .............................................................................. 19 
5 
Appendix ........................................................................................................................... 20 
5.1 
Imputation rules ..................................................................................................... 20 
5.1.1 
Study drug ............................................................................................. 20 
5.1.2 
AE date imputation ............................................................................... 20 
5.1.3 
Concomitant medication date imputation ............................................. 21 
5.2 
AEs coding/grading ............................................................................................... 23 
5.3 
Laboratory parameters derivations ........................................................................ 23 
5.4 
Statistical models ................................................................................................... 23 
5.4.1 
Analysis supporting primary objective(s) ............................................. 23 
5.4.2 
Analysis supporting secondary objective(s).......................................... 23 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 23 
6 
Reference ........................................................................................................................... 24 
 


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List of abbreviations 
ACEI 
Angiotensin Converting Enzyme Inhibitor 
AE 
Adverse Event 
AGB 
ADaM Governance Board 
ARB 
Angiotensin Receptor Blocker 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
eCRS 
electronic Case Retrieval Strategy 
EOS 
End of Study 
ENR 
Enrolled Set 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MRAs 
Mineralcorticoid Receptor Antagonists 
PDs 
Protocol deviations 
PK 
Pharmacokinetics 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SGLT2i 
Sodium-GLucose co-Transporter2 inhibitor 
WHO 
World Health Organization 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes details of the analyses as outlined in section 9 of 
the study protocol. Results will be summarized in the clinical study report (CSR).  
1.1 
Study design 
This study (CLCZ696B2319E2) is a multicenter, open-label extension study for Japanese 
patients who have successfully completed the CLCZ696B2319E1 (PANORAMA-HF OLE) 
study (Figure 1-1). PANORAMA-HF OLE study is an on-going Phase 3b study in pediatric 
patients with systemic left ventricular systolic dysfunction to evaluate long- term safety and 
tolerability of sacubitril/valsartan in eligible CLCZ696B2319 (PANORAMA-HF) 
participants. 
Only Japanese patients who successfully completed PANORAMA-HF OLE study and fulfill 
protocol requirements are eligible to participate in this study, and will be offered the option to 
initiate treatment with sacubitril/valsartan by enrolling into this study at the discretion of the 
Investigator. Participants who permanently discontinued study drug treatment during 
PANORAMA-HF OLE study are not eligible for this study. 
For all consenting patient’s eligibility for this study will be assessed at the first visit (Visit 
Day1) and the study medication will be initiated. The first visit (Visit Day1) is the same day 
as the End of Study visit (Visit 599) of PANORAMA-HF OLE study.  
The starting dose of study drug will be determined by the Investigator considering the 
participant’s condition. The dose level of open-label sacubitril/valsartan at the end of study 
visit of PANORAMA-HF OLE study may remain the same, or the dose level may be changed 
at the discretion of the Investigator.  
 
Study Duration: 
Actual duration depends on the timing of sacubitril/valsartan formulation for pediatrics 
available on the market in Japan. 
Treatment Duration: 
Until marketed product of pediatric formulation is available in Japan 
Visit Frequency: 
Every 3 months (including telephone visits) 
Treatment of interest 
The investigational treatment sacubitril/valsartan 
Number of Participants: 
A maximum of 8 Japanese patients will be enrolled into the study. 


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Key Inclusion criteria 
1. Signed informed consent as well as assent at an appropriate age must be obtained prior to 
participation in the study. 
2. Male or female, inpatient or outpatient, and < 18 years of age (at the time of signing 
informed consent). 
3. Patients who have completed PANORAMA-HF OLE study and are able to be safely 
enrolled into this study as judged by the Investigator. 
Key Exclusion criteria 
1. Patients who permanently discontinued the study drug treatment during PANORAMA-
HF OLE study. 
2. Renal vascular hypertension (including renal artery stenosis). 
3. Patients with a history of angioedema. 
4. 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. 
5. 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. 
Figure 1-1 
Study design 
 
1.2 
Study objectives, endpoints and estimands  
The primary objective is to collect additional safety information of sacubitril/valsartan in the 
eligible Japanese patients who completed CLCZ696B2319E1 study. 
There are no secondary or exploratory objectives for this study. 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
• Adverse events (AEs) 


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Objective(s) 
Endpoint(s) 
• 
To collect additional safety information of 
sacubitril/valsartan in Japanese patients after 
long-term treatment of sacubitril/valsartan in 
CLCZ696B2319E1 study 
 
1.2.1 
Primary estimand(s) 
Not applicable  
1.2.2 
Secondary estimand(s) 
Not applicable 
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 current version R® at time of analysis, by Novartis personnel.  
In general, continuous variables will be summarized using number of observations, mean, 
standard deviation, median, minimum and maximum. Categorical variables will be summarized 
using frequencies and percentages. 
Study completion is defined as having reached the end of study visit (Figure 1-1). 
Data from all study centers will be combined. 
2.1.1 
General definitions  
• The study treatment is sacubitril/valsartan. 
• The date of first administration of study treatment during this study is the day of the first 
non-zero dose of sacubitril/valsartan after patient is enrolled in CLCZ696B2319E2 study. 
• The date of last administration of study treatment is the day of the last non-zero dose of 
sacubitril/valsartan. 
• The study period starts with the date of the signature on informed consent (Visit Day 1, 
the same day as Visit 599 (EOS visit) of PANORAMA-HF OLE study) and ends with the 
date of end-of-study or premature study discontinuation visit (Visit EOS).  
• The treatment period starts with the date of first administration of study treatment in 
CLCZ696B2319E2 study and ends with the date of treatment disposition. In the case that 
no EOS visit is undertaken (e.g., because the participant died or withdrew from the study 
without such a visit), the treatment period ends with the death/withdrawal date, or the last 
dose taken. 
• Baseline is defined as the variable on the date of Visit Day 1 regardless of whether the 
study treatment is administered on Visit Day 1. 
• Study day is defined as actual date – date of Visit Day1 + 1 


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• Treatment day is defined as actual date – the date of first administration of study treatment 
+ 1 
• Each scheduled visit date is defined using the study day as follows: 
• Visit M3 = day 91 
• Visit M6 = day 183 
2.2 
Analysis sets  
The following analysis sets will be used for the statistical analyses: 
• Enrolled set (ENR): All patients who signed the informed consent for the extension open-
label study. 
• Safety Set (SAF): All ENR patients who received at least one dose of open-label study 
treatment during this extension open-label study. 
The number of patients and percentage for all patients who enrolled in this study will be 
provided for each analysis set. 
2.2.1 
Subgroup of interest 
No subgroup analysis will be provided in this study considering the small number of patients. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number and percentage of patients who don’t meet a screen failure will be provided. For 
screen failures, the inclusion/ exclusion criteria they did not meet will be summarized using the 
numbers and percentages of patients.  
These summaries will be performed for the ENR. 
The number and percentage of patients who complete the study, who discontinue from the study 
and the primary reasons for discontinuation will be summarized. In addition, the number and 
percentage of patients with protocol deviations (PDs) will be provided. 
These summaries will be performed based on the SAF. 
2.3.2 
Demographics and other baseline characteristics 
Demographic and other characteristics at Visit Day1, including age, age group (6 years and 
older, < 6 years), sex, weight, height, body mass index (BMI), vital signs, and age adjusted 
percentile for weight and height, and z-score for height will be summarized descriptively. 
BMI will be calculated as weight (kg) / height2 (m2) using the collected height and weight at 
Visit Day1. 
For the calculation of z-score and age adjusted percentile, the child growth database presented 
by World Health Organization (WHO) (WHO global database) will be used. Z-score will be 
calculated using the Box-Cox power, median and coefficient of variation in the database 


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following the procedure recommended in database instructions (WHO computation 
instructions). 
The individual z-score (zind) for a measurement at age t is defined as: 
𝑧𝑧𝑖𝑖𝑖𝑖𝑖𝑖= 
൤𝑥𝑥
𝑀𝑀(𝑡𝑡)൨
𝐿𝐿(𝑡𝑡)
−1
𝑆𝑆(𝑡𝑡)𝐿𝐿(𝑡𝑡)
 
where, the Box-Cox power, median and coefficient of variation corresponding to age t are 
denoted by L(t), M(t) and S(t), respectively. 
Final z-score is calculated as: 
 
• |𝑧𝑧𝑖𝑖𝑖𝑖𝑖𝑖| ≤3              𝑧𝑧-𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠= 𝑧𝑧𝑖𝑖𝑖𝑖𝑖𝑖             
• 𝑧𝑧𝑖𝑖𝑖𝑖𝑖𝑖 > 3                 𝑧𝑧-𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠=  3 +
𝑥𝑥−𝑀𝑀(𝑡𝑡)[1+3𝐿𝐿(𝑡𝑡)𝑆𝑆(𝑡𝑡)]
1
𝐿𝐿(𝑡𝑡)
𝑀𝑀(𝑡𝑡)[1+3𝐿𝐿(𝑡𝑡)𝑆𝑆(𝑡𝑡)]
1
𝐿𝐿(𝑡𝑡)−𝑀𝑀(𝑡𝑡)[1+2𝐿𝐿(𝑡𝑡)𝑆𝑆(𝑡𝑡)]
1
𝐿𝐿(𝑡𝑡)
          
• 𝑧𝑧𝑖𝑖𝑖𝑖𝑖𝑖 < −3              𝑧𝑧-𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠= −3 +
𝑥𝑥−𝑀𝑀(𝑡𝑡)[1+(−3)𝐿𝐿(𝑡𝑡)𝑆𝑆(𝑡𝑡)]
1
𝐿𝐿(𝑡𝑡)
𝑀𝑀(𝑡𝑡)[1+(−2)𝐿𝐿(𝑡𝑡)𝑆𝑆(𝑡𝑡)]
1
𝐿𝐿(𝑡𝑡)−𝑀𝑀(𝑡𝑡)[1+(−3)𝐿𝐿(𝑡𝑡)𝑆𝑆(𝑡𝑡)]
1
𝐿𝐿(𝑡𝑡)
       
Age adjusted percentile will be calculated from z-score as the probability that an observation 
from the standard normal distribution is less than or equal to z-score. 
Relevant medical histories at Visit Day1 will be summarized, by system organ class and 
preferred term. 
The SAF will be used for the above analyses. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The study treatment administration is recorded on the Case Report Form (CRF) page: 
“Dosage Administration Record” using start date, end date, dispensing name of the study 
treatment and the type of change. Each pair of start date and end date will be considered as a 
dosing interval, if type of change is recorded as ‘Dose interrupted’ then this dosing interval 
will be considered as temporary interruptions. 
Duration of exposure to the study treatment will be defined as both the treatment period 
including temporary interruptions and the treatment period excluding temporary interruptions 
and summarized for continuous variable.  
Dose levels will be summarized for continuous variable by visit, regardless of the pediatric or 
adult dose level. In addition, the number and percentage of patients for each dose level (Dose 
level 1 to 4, and No treatment) will be provided by visit. 


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The dose level for each visit is defined as the dose level of dosing interval with its start date 
prior to or equal to the scheduled visit date and its end date later than or equal to the 
scheduled visit date. For EOS visit, actual visit date is used to identify the dose level. 
In addition, the following information will be listed. 
• Subject ID 
• Date of Visit Day1 
• Start date (Study day) 
Displays the start date entered on CRF or imputed and corresponding Study day (number 
of days from Visit Day1).  
• End date (Study day) 
Displays the end date entered on CRF or imputed and corresponding Study day (number 
of days from Visit Day1). 
• Dose Form (Granule/ Liquid/ Tablet) 
• Dispensing Name (Dose Level) 
• Dose administered 
• Unit 
• Type of Change (Dose changed/ Dose interrupted/ Dose permanently discontinued) 
• Reason for Change (Adverse event/ Disease improvement under study/ Dosing error/ 
Dispensing error/ Technical problems/ Subject decision/ Guardian decision/ Physician 
decision/ As per protocol) 
 
The SAF will be used for the above analyses. 
2.4.2 
Prior, concomitant and post therapies 
Prior medications and significant non-drug therapies are defined as any medication or 
significant non-drug therapy within 30 days prior to Visit Day1 with its start date prior to the 
date of Visit Day1. Concomitant medications and significant non-drug therapies are defined as 
any medication or significant non-drug therapy with its end date later than or equal to the date 
of the Visit Day1 and start date prior to or equal to the end date of the treatment period.  
Prior and concomitant medications and significant non-drug therapies will be summarized by 
anatomical therapeutic classification (ATC), preferred term. 
Concomitant heart failure medications (Angiotensin converting enzyme inhibitor (ACEI), 
Angiotensin receptor blocker (ARB), Beta-blockers, mineralcorticoid receptor antagonists 
(MRAs), diuretics (excluding MRAs), Cardiac glycocytes (Digoxin/digitalis glycoside), and 
sodium-glucose co-transporter2 inhibitors (SGLT2i) ) will be summarized by  medication 
category and preferred term. 


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In addition, the prior or concomitant medications and other non-drug therapies will be listed as 
follows: 
 Medications 
• Subject ID 
• Date of Study Treatment start 
• Start date (Treatment day) 
Displays the start date entered on CRF or imputed and corresponding Treatment day 
(the number of days from the date of treatment start). 
• End date (Treatment day) 
Displays the end date entered on CRF or imputed and corresponding Treatment day (the 
number of days from the date of treatment start).  
• On going 
If the check box of ‘On going’ on CRF (the medication is ongoing at the end of the 
study), provide ‘Yes’. 
• Primary indication 
• ATC 
• Preferred term 
• Reported medication name 
• Dose 
• Dose unit 
• Frequency 
• Route 
 
 Non-drug therapies 
• Subject ID 
• Date of Study Treatment start 
• Start date (Treatment day) 
Displays the start date entered on CRF or imputed and corresponding Treatment day 
(the number of days from the date of treatment start). 
• End date (Treatment day) 
Displays the end date entered on CRF or imputed and corresponding Treatment day (the 
number of days from the date of treatment start). 
• Primary Indication 


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• Procedure name 
 
The SAF will be used for the above analyses. 
2.5 
Analysis supporting primary objective(s) 
2.5.1 
Primary endpoint(s) 
Any adverse events (treatment emergent or not) are considered primary endpoints. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
There are no statistical hypotheses to be tested in this study and no model analyses will be 
performed. 
Adverse events will be summarized by primary system organ class and preferred term, using 
numbers and percentages of patients with at least one adverse event in the corresponding class. 
The SAF will be used for analyses for primary endpoints. 
2.5.3 
Handling of intercurrent events  
Not applicable. 
2.5.4 
Handling of missing values not related to intercurrent event 
The missing value for laboratory assessments, vital signs, height, weight, and other 
assessments will be not imputed. 
The missing or partially missing start/end date for AEs, prior/concomitant therapies, and study 
drug will be imputed using the Novartis ADaM Governance Board (AGB) global standard 
approach.  Details are provided in Section 5.1. 
2.5.5 
Sensitivity analyses  
Not applicable 
2.5.6 
Supplementary analyses 
Not applicable 
2.6 
Analysis supporting secondary objectives  
Not applicable. There are no secondary endpoints. 
2.7 
Safety analyses 
2.7.1 
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. 


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The following adverse events will be summarized by primary system organ class, and preferred 
term as appropriate using numbers and percentages of patients with at least one adverse event 
in the corresponding class.  Similarly, Summarization by maximum severity will be conducted. 
• Any serious adverse event (treatment emergent or not) 
• Treatment emergent adverse event (TEAE) 
• Treatment emergent serious adverse event 
TEAEs are defined as any recorded AE with its start date (recorded or imputed) on or after Visit 
Day 1 (the date of first administration of study treatment if treatment did not start at Visit Day1) 
and end date as the end date of the treatment period or the date of last dose taken as reported in 
the DAR page. Any AE happening after treatment discontinuation 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. 
All outputs will be created for AEs regardless of study-drug relationship, and for study-drug 
related AEs. Study drug related AEs are defined as any recorded AE with “Relationship to study 
treatment” answered as “Related”. Serious adverse events (SAEs) are defined as any recorded 
AE with “Was the adverse evevnt serious?” answered as “Yes”. 
The following rules are applicable to the summaries: 
• If a patient reported more than one AE with the same PT, the patient will be counted 
only once with the greatest severity at the PT level  
• If a patient reported more than one AE within the same SOC, the patient will be counted 
only once with the greatest severity at the SOC level, where applicable. 
In addition, the following information will be listed for all AEs. 
• Subject ID 
• Date of Study Treatment start  
• Start date (Treatment day) 
Displays the start date entered on CRF or imputed and corresponding Treatment day 
(the number of days from the date of treatment start). 
• End date (Treatment day) 
Displays the end date entered on CRF or imputed and corresponding Treatment day (the 
number of days from the date of treatment start). 
• Duration 
End date – Start Date + 1 will be calculated. For on-going AE, leave blank.  
• Reported Name of AE 
• SOC 
• PT 


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• Relationship to study treatment (Related/ Not related) 
• SAEs (Yes/No) 
• Severity (Mild/ Moderate/ Severe) 
• Action Taken with Study Treatment (Dose increased/ Dose not changed/ Dose reduced/ 
Drug interrupted/ Drug withdrawn/ Not applicable/ Unknown) 
• Concomitant or additional treatment (Yes/ No) 
• Outcome 
• TEAE (Yes/No) 
The SAF will be used for the above analyses. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
The following treatment emergent adverse event of special interest will be summarized. 
• Angioedema 
• Long term effects on growth bone growth and mineralisation in the pediatric population 
• Cognitive impairment 
• Embryo-fetal toxicity or lethality  
• Hepatotoxicity 
• Hyperkalaemia  
• Hypotension  
• Neonatal or infantile toxicity through exposure from breast milk  
• Renal impairment  
• Statin drug-drug interaction 
The definitions of these events will be defined in the electronic Case Retrieval Strategy (eCRS, 
ID: 6511 LCZ696 Hf (adult and pediatric)). 
For each risk, the following analyses will be conducted. 
• Numbers and percentages of patients with any TEAE within the risk category (or 
SOC/PT within risk category) by risk category, SOC, PT and maximum severity. 
• Listing of Subject ID per risk. 
In addition, the MedDRA coding definitions for each risk on the eCRS used to analysis will be 
listed regardless of the presence or absence of applicable patients. 
The SAF will be used for the above analyses. 


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2.7.2 
Deaths 
Death during the treatment period and the primary cause of death will be summarized using 
frequencies and percentages. 
A listing of all deaths and heart transplant will also be provided. 
The SAF will be used for the above analyses. 
2.7.3 
Laboratory data 
A listing of laboratory data collected in eCRF (i.e. Serum sodium, potassium, creatinine, and 
estimated Glomerular Filtration Rate (eGFR)) will be provided for the following information 
by each test item. 
• Subject ID 
• Date of Study Treatment start 
• Collection date (Treatment day) 
Displays the collection date entered on CRF or imputed and corresponding Treatment 
day (the number of days from the date of treatment start) . 
• Test name 
• Test value 
Displays the value converted to SI units. 
• SI Unit 
• Normal range 
Displays the normal range converted to SI units. 
• Abnormality (H/L) 
Displays ‘H’ if the test value is above the upper limit of the normal range, ‘L’ if the test 
value is below the lower limit, otherwise leave blank. 
The SAF will be used for the above analyses. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
Not applicable 
2.7.4.2 
Vital signs 
Descriptive statistics of vital signs (pulse rate (PR), systolic blood pressure (SBP), diastolic 
blood pressure (DBP)) for test values and the number of patients and percentages with clinically 
notable vital signs during the treatment period will be provided by visit (Day1, M6, EOS). These 
by-visit summaries will only include scheduled assessments. If the timing of EOS and Visit M6 


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overlaps and two visits are made simultaneously, the data will be used for both EOS and Visit 
M6. The window of Visit M6 is defined as ±1 month of the scheduled visit date (day183±30). 
Criteria of clinically notable vital signs are shown in the Table 2-1. 
Table 2-1 
Criteria for clinically notable vital signs 
Age 
PR [min-1] 
SBP [mmHg] 
DBP [mmHg] 
1- <3 years 
<60, >120 
<76, >115 
<45, >75 
3- <6 years 
<55, >120 
<82, >120 
<50, >80 
6- <12 years 
<50, >105 
<90, >130 
<50, >80 
≥12 years 
<45, >95 
<90, >145 
<55, >90 
 
In addition, all vital signs data collected in eCRF (including unscheduled assessments) will be 
listed for the following information. 
• Subject ID 
• Date of Study Treatment start 
• Collection date (Treatment day, Visit name) 
Displays the collection date entered on CRF or imputed, corresponding Treatment day 
(the number of days from the date of treatment start) and Visit name. 
• Test name 
• Test value 
• Unit 
• Clinically notable vital signs 
Displays ‘Yes’ if the criteria of clinically notable vital signs is met. 
The SAF will be used for the above analyses. 
2.7.4.3 
Height and Weight 
Descriptive statistics will be provided for test values of weight, height, BMI, age adjusted 
percentile for weight and height, and z-score for height by visit. For weight, if the timing of 
EOS and Visit M6 overlaps and two visits are made simultaneously, the data will be used for 
both EOS and Visit M6. The window of Visit M6 is defined as ±1 month of the scheduled visit 
date (day183±30). 
A listing for these items (i.e. weight, height, BMI, age adjusted percentile for weight and height, 
and z-score for height) will be provided for all visits including unscheduled assessments. 
• Subject ID 
• Date of Study Treatment start 
• Assessment date (Treatment day, Visit name (Weight only)) 


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Displays the assessment date entered on CRF or imputed, corresponding Treatment day 
(the number of days from the date of treatment start) and Visit name (Weight only) 
• Test name 
• Value 
• Unit 
• Adjusted percentile (Weight, height) 
• Z-score (Height only) 
BMI will be calculated as weight (kg) / height2 (m2) using the collected height and weight at 
each visit. 
Refer to Section 2.3.2 for Z-score and age adjusted percentile. 
The SAF will be used for the above analyses. 
2.8 
Pharmacokinetic endpoints   
Not applicable 
2.9 
PD and PK/PD analyses 
Not applicable 
2.10 
Patient-reported outcomes 
Not applicable 
2.11 
Biomarkers 
Not applicable. 
2.12 
Other Exploratory analyses 
Not applicable. There are no exploratory endpoints. 
2.13 
Interim analysis 
Not applicable 
3 
Sample size calculation 
All patients who have completed PANORAMA-HF OLE study and who meet all Inclusion 
and Exclusion criteria (Section 1.1), are eligible for this extension study.  
There is no specific sample size required for the study. A maximum of 8 Japanese patients will 
be enrolled into the study. 
4 
Change to protocol specified analyses 
None 


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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.  
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 treatment start date is missing, then the planned start date (the date of Visit Day1) 
will be used. If only the start day is missing (but the month is known), then the start day will be 
the 1st day of that month, unless the planned date of the Visit Day1 is in the same month, then 
it will be the planned date of the Visit Day1. 
5.1.2 
AE date imputation 
5.1.2.1 
Adverse Event End Date Imputation 
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow up period date, last day of the month, date of death). 
3.  If AE year is missing or AE is ongoing, the end date will not be imputed. 
5.1.2.2 
Adverse Event Start Date Imputation 
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed. 
 
The following matrix explains the logic behind the imputation. 
 
Before imputing AE start date, find the AE start reference date. 


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1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min(informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
 
Impute AE start date; 
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the AE year value is missing, the imputed AE start date is set to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment. Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-
month point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later 
of (month start point (01MONYYYY), AE start reference date + 1 day). 
4.  If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.3 
Concomitant medication date imputation 
 Concomitant medication end date imputation 
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY). 
3. If CM day/month/year is missing then use the treatment end date + 1 day as the imputed 
CM end date.  


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4. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date. 
 
 Concomitant medication start date imputation 
The following table explains the notation used in the logic matrix. Please note that missing start 
dates will not be imputed. 
 
The following matrix explains the logic behind the imputation. 
 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM started 
before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date.  
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY). 


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c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
5.1.3.1 
Prior therapies date imputation 
See Section 5.1.3. 
5.1.3.2 
Post therapies date imputation 
See Section 5.1.3. 
5.1.3.3 
Other imputations 
None 
5.2 
AEs coding/grading 
Not applicable 
5.3 
Laboratory parameters derivations 
Not applicable 
5.4 
Statistical models 
Not applicable 
5.4.1 
Analysis supporting primary objective(s)  
Not applicable 
5.4.2 
Analysis supporting secondary objective(s) 
Not applicable 
5.5 
Rule of exclusion criteria of analysis sets  
PDs excluded from the ENR or SAF are shown in Table 5-1. Patients with only PDs that are 
not included in the list will not be excluded from any analysis sets. 
Table 5-1 
Protocol deviation criteria leading to exclusion from the analysis sets 
PD ID  
Description 
ENR 
SAF 
INCL01A 
 
No informed consent. 
X 
X 
INCL01C 
ICF was not signed by subject/ parent/legal 
guardian; however, other family member 
signed on behalf the subject. 
 
 
X 
 
X 


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PD ID  
Description 
ENR 
SAF 
INCL02 
Patients aged >= 18 was enrolled in the 
study. 
 
 
X 
EXCL04A 
Patient who has parents or legal guardians 
who do not give consent or allow the child to 
give assent. 
 
X 
 
X 
 
 
 
 
 
 
 
 
6 
Reference 
1. WHO Global Database on Child Growth and Malnutrition (Internet) Available from: 
[https://iris.who.int/bitstream/handle/10665/63750/WHO_NUT_97.4.pdf] (Accessed 11 
September 2023). 
2. COMPUTATION OF CENTILES AND Z-SCORES FOR HEIGHT-FOR-AGE, 
WEIGHT-FOR-AGE AND BMI-FOR-AGE (Internet) Available from: 
[https://cdn.who.int/media/docs/default-source/child-growth/growth-reference-5-19-
years/computation.pdf] (Accessed 16 Oct 2023).