Clinical trial NCT02678312
Conditions: Pediatric Heart Failure
Keywords: Pediatric Heart failure, systemic left ventricle, reduced ejection fraction
Sponsor: Novartis Pharmaceuticals
Start date: 2016-11-03; Completion date: 2022-01-03
Enrollment: 393 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of two parts (Part 1 and Part 2). The purpose of Part 1 is to evaluate the way the body absorbs, distributes, metabolizes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study.

The purpose for Part 2 is to compare the effectiveness and safety of LCZ696 with enalapril in a double-blind manner, in pediatric heart failure patients over 52 weeks of treatment.

Detailed description:
This study consists of two parts (Part 1 and Part 2). The purpose of Part 1 is to evaluate the way the body absorbs, distributes, metabolizes and removes the drug LCZ696. This will help determine the proper dose of LCZ696 for Part 2 of the study.

The purpose for Part 2 is to compare the effectiveness and safety of LCZ696 with enalapril in a double-blind manner, in pediatric heart failure patients over 52 weeks of treatment.

Arms: arm 1: LCZ696 open label: For Age Groups 1 and 2, either 1) 0.8 mg/kg or 2) 3.1 mg/kg or both. For Age Group 3, either 1) 0.4 mg/kg or 2) 1.6 mg/kg or both. After LCZ696 PK assessment, patients will be maintained on open-label Enalapril provided locally by the study site, or standard of care also provided locally by the study site, for heart failure treatment, if patient intended to participate in Part 2. arm 2: The target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose) with a maximum dose of 10 mg bid (20 mg total daily dose). Administered in a double-blind fashion. arm 3: LCZ696 3.125 mg granules and adult formulation (50, 100, 200 mg) can be given based on patient weight. Administered in a double-blind fashion.
Interventions: intervention 1: LCZ696 intervention 2: Enalapril intervention 3: Placebo of LCZ696 intervention 4: Placebo of Enalapril intervention 5: LCZ696
Intervention descriptions: intervention 1: LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules) intervention 2: Enalapril tablets: 2.5 mg, 5 mg, 10 mg dosage strengths intervention 3: None intervention 4: None intervention 5: LCZ696: 3.125 mg granules (packaged in capsules containing 4 or 10 granules), tablets: 50 mg, 100 mg, 200 mg dosage strengths

Protocol documents:
SAP_002.pdf: 
Clinical Development 
LCZ696 
CLCZ696B2319 / NCT02678312
Multicenter, open-label, study to evaluate safety, 
tolerability, pharmacokinetics and, pharmacodynamics of 
LCZ696 followed by a 52-week randomized, double-blind, 
parallel group, active-controlled study to evaluate the 
efficacy and safety of LCZ696 compared with enalapril in 
pediatric patients from 1 month to < 18 years of age with 
heart failure due to systemic left ventricle systolic 
dysfunction 
Statistical Analysis Plan (SAP) for China Sub-CSR 
Author: 
Statistician, 
; 
Document type: 
SAP Documentation 
Document status: 
Final version 
Release date: 
25-October-2021
Number of pages: 
21 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section and 
title impacted 
(Current) 
25-Oct-
2021 
Prior to DB 
lock 
Creation of final 
version 
N/A - First version 
NA 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 4 
1 
Introduction ......................................................................................................................... 5 
1.1 
Study design ............................................................................................................ 5 
1.2 
Study objectives and endpoints ............................................................................... 6 
1.2.1 
Primary objective .................................................................................... 6 
1.2.2 
Secondary objectives ............................................................................... 6 
2 
Statistical methods ............................................................................................................... 6 
2.1 
Data analysis general information ........................................................................... 6 
2.1.1 
General definitions .................................................................................. 6 
2.2 
Analysis sets ............................................................................................................ 7 
3 
List of tables/figures ............................................................................................................ 7 
4 
Site specific report ............................................................................................................. 22 
 


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List of abbreviations 
ACE 
Angiotensin-Converting Enzyme 
AE 
Adverse Event 
AMI 
Acute Myocardial Infarction 
ARB 
Angiotensin Receptor Blockers 
ATC 
Anatomical Therapeutic Classification 
CEC 
Clinical Event Committee 
CRF 
Case Report Form 
CV 
Cardiovascular 
CSR 
Clinical Study report 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
HF 
Heart failure 
PCI 
Percutaneous Coronary Intervention 
PRO 
Patient-reported Outcomes 
RAAS 
Renin-Angiotensin-Aldosterone System 
SAP 
Statistical Analysis Plan 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
Data will be analyzed according to the planned statistical analyses outlined in the 
CLCZ696B2319 study protocol  (version 06) Section 9 and the CLCZ696B2319 SAP document. 
This document is created to identify the required tables and figures for the submission in China. 
1.1 
Study design 
This study uses a seamless design which consists of two parts. 
Part 1 is a multi-center, open-label, study to evaluate safety, tolerability, pharmacokinetics (PK) 
and pharmacodynamics (PD) of LCZ696 in pediatric patients (1 month to <18 years) with heart 
failure due to systemic left ventricle systolic dysfunction (left ventricular ejection fraction 
[LVEF] ≤ 40% or fractional shortening ≤ 20%). Eligible patients will be placed into three age 
groups (Age Group 1: 6 years to < 18 years, Age Group 2: 1 year to < 6 years, and Age Group 
3: 1 month to < 1 year). Patient enrollment will start sequentially from the eldest age group to 
the youngest age group. 
For each age group, available PK/PD and safety data will be reviewed to confirm or modify the 
doses. After completion of the PK/PD assessment visit, patients can either be maintained on 
open-label enalapril or their standard of care HF medical regimen until Part 2. Patients in each 
age group can enroll in Part 2 after the target dose for that age group is determined based on 
Part 1 data for the corresponding age cohort. Patients that discontinue from Part 1 (PK/PD) will 
be allowed to screen and enroll for participation in Part 2. 
Part 2: This is a randomized, double-blind, parallel-group, active controlled, 52-week study to 
evaluate the efficacy, safety, and tolerability of LCZ696 compared to enalapril in pediatric HF 
patients (1 month to < 18 years). A screening epoch of up to 3 weeks will be used to assess 
eligibility. Three hundred and sixty eligible patients will be randomized to one of the two 
treatment arms (LCZ696 vs. enalapril) and continue treatment for 52 weeks duration. Both 
hospitalized patients and outpatients are eligible. Chronic HF patients that are either previously 
treated for HF or newly diagnosed are eligible.  
An interim efficacy analysis is planned to be performed when at least 180 patients (at least 36 
patients from each age group) have completed the study (i.e., reached a positively adjudicated 
event in Category 1 or completed the 1 year study visit), and at least 40 patients have had an 
event in Category 1 or 2. Further details about interim analysis are provided in Section 2.15 in 
the CLCZ696B2319 SAP document. 
If not stopped early for efficacy or futility based on the interim analysis, Part 2 will continue 
until at least 360 patients have completed the study and at least 80 patients have an event in 
Category 1 or 2. If necessary, study enrollment will continue beyond 360 patients in order to 
obtain at least 80 patients with an event in Category 1 or 2, based on event prediction. 
A penalty-free blinded sample size adjustment may be made in the latter part of the study to 
ensure a power of 80% for the study. 
For the submission in China, only outcomes assessed in Part 2 will be analysed because there 
is no patients from mainland China included in Part 1.  


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1.2 
Study objectives and endpoints – Part 2 
1.2.1 
Primary objective 
The primary objective of Part 2 is to determine whether LCZ696 is superior to enalapril for the 
treatment of HF as assessed using a global rank endpoint in pediatric HF patients.  
 
1.2.2 
Secondary objectives 
• To determine whether LCZ696 is superior to enalapril in delaying time to first 
occurrence of the composite of either Category 1 or 2 events (e.g. death, worsening HF) 
• To determine whether LCZ696 is superior to enalapril for improving NYHA/ROSS 
functional class 
• To determine whether LCZ696 is superior to enalapril for improving the PGIS score 
• To assess the safety and tolerability of LCZ696 compared to enalapril in pediatric 
patients with HF 
• To characterize the population PK of LCZ696 exposure in pediatric patients with HF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The final CSR analysis will be performed by Novartis. The same analysis method used in the 
global SAP will be used for the each of the specified endpoints in this SAP. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings. 
Since the study was designed for the global population and all below indicated subpopulations 
are subsets of the Asia/Pacific subset of the global population and are not pre-specified for the 
design, the analysis results from them must be cautiously interpreted and no results can be 
confirmatory. 
The PK results in Chinese may be summarized and analyzed in a separate report. 
2.1.1 
General definitions  
The general definitions are the same as the main SAP for CLCZ696B2319. 


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2.2 
Analysis sets 
The analysis sets are the same as the main SAP for CLCZ696B2319. Each sub-population is 
defined as below: 
China mainland Population 
The China Mainland Population (CHN) refers to patients from Mainland China. 
Chinese Population 
The Chinese Population (CHINESE) refers to all Chinese patients regardless of residential 
country (this includes Chinese patients from Mainland China, Taiwan, Singapore and USA). 
East Asia Population 
The East Asia Population (EASTASIA) refers to patients from East Asia, including: China 
mainland, Taiwan , Japan , Korea, Singapore and Thailand. 
 
3 
List of tables/figure 
Below is the list of tables and figures specified for each of the regional subpopulation. The 
China Mainland population (CHN) will be used as an example and the same list of tables and 
figures will be generated for each of the regional subpopulation, i.e. Chinese population 
(CHINESE), East Asia population (EASTASIA).  
 
 


 
 
 
 
 
Table 10-1_CHN 
Part 2 patient disposition - double-blind epoch (Randomized Set: China Mainland Population) 
Programming note: Refer to Table 10-1 in CLCZ696B2319 RAP Section 14 
 
Table 10-2_CHN 
Part 2 study treatment disposition - double-blind epoch (Randomized Set: China Mainland Population) 
Programming note: Refer to Table 10-2 in CLCZ696B2319 RAP Section 14 
 
Table 11-1_CHN 
Part 2 demographic and baseline characteristics (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 11-1 in CLCZ696B2319 RAP Section 14 
 
Table 11-2_CHN 
Part 2 pediatric heart failure history (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 11-2 in CLCZ696B2319 RAP Section 14 
 
Table 11-3_CHN 
Part 2 global rank endpoint - patient allocation (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 11-3 in CLCZ696B2319 RAP Section 14 
 
Table 11-4_CHN 
Part 2 time to first positively adjudicated Category 1 or Category 2 event during the double-blind 
epoch - Kaplan-Meier estimates - cumulative event rate (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 11-4 in CLCZ696B2319 RAP Section 14 
 
Table 12-1_CHN  
Part 2 treatment emergent (newly occurring or worsening) adverse events of special interest (TEAESIs) 
during the double-blind epoch, regardless of study treatment relationship - exposure adjusted incidence rate (EAIR) (Part 
2 Safety Set) 
 
Programming note: Refer to Table 12-1 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.1.3_CHN 
Part 2 patient disposition - double-blind epoch (Randomized Set: China Mainland Population)  
Programming note: Refer to Table 14.1-1.1.3 in CLCZ696B2319 RAP Section 14 
 


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Table 14.1-1.1.4_CHN 
Part 2 patient disposition - double-blind epoch by COVID-19 period (Randomized Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.1-1.1.4 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.3_CHN     Part 2 study treatment disposition - double-blind epoch (Randomized Set: China Mainland Population) 
Programming note: Refer to Table 14.1-1.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.3.1_CHN 
Part 2 study treatment disposition - double-blind epoch COVID-19 period (Randomized Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.1-1.3.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.4.2_CHN 
Part 2 analysis sets (Randomized set: China Mainland Population)  
Programming note: Refer to Table 14.1-1.4.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.5.2_CHN 
Part 2 criteria leading to exclusion from analysis sets (Randomized Set: China Mainland 
Population)  
Programming note: Refer to Table 14.1-1.5.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.6.2_CHN 
Protocol deviations of Part 2 patients (Randomized Set: China Mainland Population) 
 
Programming note: Refer to Table 14.1-1.6.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.6.3_CHN     Protocol deviations of Part 2 patients by COVID-19 period (Randomized Set: China Mainland 
Population)  
Programming note: Refer to Table 14.1-1.6.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-1.6.4_CHN    COVID-19 related protocol deviations for part2 patients  (Randomized Set: China Mainland 
Population)  
Programming note: Refer to Table 14.1-1.6.4 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-3.1.2_CHN 
Part 2 demographic and baseline characteristics (Full Analysis Set: China Mainland Population) 


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Programming note: Refer to Table 14.1-3.1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-3.2.2_CHN 
Part 2 medical history - by primary system organ class and preferred term (Full Analysis Set: 
China Mainland Population) 
Programming note: Refer to Table 14.1-3.2.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-3.3.2_CHN 
Part 2 pediatric heart failure history (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.1-3.3.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.1-3.4.2_CHN 
Part 2 medical history possibly contributing to liver dysfunction (Full Analysis Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.1-3.4.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-2.1_CHN       Part 2 global rank endpoint - patient allocation (Full Analysis Set: China Mainland Population) 
Programming note: Refer to Table 14.2-2.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-2.3_CHN       Part 2 Clinical events for Category 1 and 2 summary (Full Analysis Set: China Mainland 
Population)  
Programming note: Refer to Table 14.2-2.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-2.2.1_CHN     Part 2 global rank endpoint - primary rank score (PACE) - Mann–Whitney analysis - LOCF (Full 
Analysis Set: China Mainland Population) 
Programming note: Refer to Table 14.2-2.2.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-2.4.1_CHN 
Part 2 global rank endpoint - response category (PACE) - Mann–Whitney analysis - LOCF (Full 
Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-2.4.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-3.1.1_CHN 
Part 2 time to first positively adjudicated Category 1 or Category 2 event during the double-
blind epoch - Kaplan-Meier estimates - cumulative event rate (Full Analysis Set: China Mainland Population) 
 


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Programming note: Refer to Table 14.2-3.1.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-3.1.2_CHN 
Part 2 time to first positively adjudicated Category 1 or Category 2 event during the double-
blind epoch - Cox proportional hazard model (Full Analysis Set: China Mainland Population)  
Programming note: Refer to Table 14.2-3.1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-3.2.1_CHN 
Part 2 time to first investigator reported Category 1 or Category 2 event during the double-
blind epoch - Kaplan-Meier estimates - cumulative event rate (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-3.2.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-3.2.2_CHN 
Part 2 time to first investigator reported Category 1 or Category 2 event during the double-
blind epoch - Cox proportional hazard model (Full Analysis Set: China Mainland Population)  
Programming note: Refer to Table 14.2-3.2.2 in CLCZ696B2319 RAP Section 14 
 
Figure 14.2-3.1.1_CHN 
Part 2 time to first positively adjudicated Category 1 or Category 2 event during the double-
blind epoch - Kaplan-Meier estimates - cumulative event rate (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Figure 14.2-3.1.1 in CLCZ696B2319 RAP Section 14 
 
Figure 14.2-3.2.1_CHN 
Part 2 time to first investigator reported Category 1 or Category 2 event during the double-
blind epoch - Kaplan-Meier estimates - cumulative event rate (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Figure 14.2-3.2.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-4.1_CHN    Part 2 NYHA/ROSS classification - proportional cumulative odds model – post Category 1 event set to 
worsened (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-4.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-4.3_CHN    Part 2 NYHA/ROSS classification - shift from baseline - by visit and treatment group (Full Analysis 
Set: China Mainland Population)  
Programming note: Refer to Table 14.2-4.3 in CLCZ696B2319 RAP Section 14 
 


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Table 14.2-4.5_CHN   Part 2 NYHA/ROSS classification - proportional cumulative odds model – post Category 1 event set to 
worsened (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-4.5 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-5.1_CHN   Part 2 patient global impression of severity (PGIS) - proportional cumulative odds model – post 
Category 1 event set to worsened (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-5.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-5.3_CHN   Part 2 patient global impression of severity (PGIS) - shift from baseline - by visit (Full Analysis 
Set: China Mainland Population)  
Programming note: Refer to Table 14.2-5.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-5.5_CHN   Part 2 patient global impression of severity (PGIS) - proportional cumulative odds model - post 
Category 1 event set to worsened - without cutoff (Full Analysis Set: China Mainland Population)  
Programming note: Refer to Table 14.2-5.5 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-8.2_CHN   Part 2 biomarkers – summary (Full Analysis Set: China Mainland Population)  
Programming note: Refer to Table 14.2-8.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-8.3_CHN   Part 2 NT-proBNP – change from baseline – Mixed Model for Repeated Measures (MMRM) (Full Analysis 
Set: China Mainland Population) 
Programming note: Refer to Table 14.2-8.3 in CLCZ696B2319 RAP Section 14 
 
Figure 14.2-8.3_CHN   Part 2 biomarkers - geometric mean line plot (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Figure 14.2-8.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-9.1_CHN   Part 2 total (first and recurrent) positively adjudicated Category 1 and Category 2 events - LWYY 
analysis (Full analysis set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-9.1 in CLCZ696B2319 RAP Section 14 
 


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Table 14.2-9.2_CHN   Part 2 total (first and recurrent) investigator reported Category 1 and 2 events - LWYY analysis 
(Full analysis set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-9.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.2-9.3_CHN   Part 2 Number (%) of total (first and recurrent) positively adjudicated Category 1 and Category 2 
events - (Full Analysis Set: China Mainland Population) 
 
Programming note: Refer to Table 14.2-9.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.2_CHN   Part 2 study treatment - treatment exposure during the double-blind epoch (Part 2 Safety Set: China 
Mainland Population) 
Programming note: Refer to Table 14.3-1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.3_CHN   Part 2 study treatment – Weight based daily dose and dose level - by visit (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3-1.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.4_CHN   Part 2 study treatment - mean weight based daily dose and mean dose level during the double-blind 
epoch (Part 2 Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3-1.4 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.5_CHN   Part 2 study treatment - dispensing level and dose level - by visit (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3-1.5 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.6_CHN   Part 2 study treatment - last recorded dose during the double-blind epoch (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3-1.6 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.7_CHN   Part 2 study treatment - dose down titration and dose interruption during the double-blind epoch 
(Part 2 Safety Set: China Mainland Population) 
 


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Programming note: Refer to Table 14.3-1.7 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.8_CHN   Part 2 study treatment - time to first dose of each dose level during the double-blind epoch - 
Kaplan-Meier estimates - cumulative event rate (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-1.8 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.9_CHN   Part 2 study treatment - time to permanent discontinuation of the study drug (excluding 
discontinuation due to death) during the double-blind epoch - Kaplan-Meier estimates - cumulative event rate (Part 2 
Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3-1.9 in CLCZ696B2319 RAP Section 14 
 
Figure 14.3-1.1_CHN    Part 2 study treatment - time to first dose of each dose level during the double-blind epoch - 
Kaplan-Meier estimates - cumulative event rate (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Figure 14.3-1.1 in CLCZ696B2319 RAP Section 14 
 
Figure 14.3-1.2_CHN      Part 2 study treatment - time to permanent discontinuation of the study drug (excluding 
discontinuation due to death) during the double-blind epoch - Kaplan-Meier estimates - cumulative event rate (Part 2 
Safety Set: China Mainland Population)  
Programming note: Refer to Figure 14.3-1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.2.3_CHN     Part 2 prior medications - by anatomical therapeutic classification (ATC) and preferred term 
(Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-1.2.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.2.4_CHN     Part 2 concomitant medications by anatomical therapeutic classification (ATC) and preferred term 
(Part 2 Safety Set)  
Programming note: Refer to Table 14.3-1.2.4 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.3.3_CHN     Part 2 prior heart failure and cardiovascular medications - by anatomical therapeutic 
classification (ATC) and preferred term (Part 2 Safety Set: China Mainland Population) 
 


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Programming note: Refer to Table 14.3-1.3.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.3.4_CHN     Part 2 concomitant heart failure and cardiovascular medications - by anatomical therapeutic 
classification (ATC) and preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-1.3.4 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.4.3_CHN   Part 2 prior non-drug therapies - by primary system organ class, preferred term (Part 2 Safety Set: 
China Mainland Population) 
Programming note: Refer to Table 14.3-1.4.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-1.4.4_CHN    Part 2 concomitant non-drug therapies - by primary system organ class, preferred term (Part 2 
Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3-1.4.4 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.1.2_CHN     Part 2 laboratory parameters - test values and change from baselines - by visit - hematology 
(local laboratory) (Part 2 Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3-2.1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.1.3_CHN     Part 2 laboratory parameters - test values and change from baselines - by visit - hematology 
(central laboratory) (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-2.1.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.2.2_CHN     Part 2 laboratory parameters - test values and change from baselines - by visit - biochemistry 
(local laboratory) (Part 2 Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3-2.2.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.2.3_CHN     Part 2 laboratory parameters - test values and change from baselines - by visit - biochemistry 
(central laboratory) (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-2.2.3 in CLCZ696B2319 RAP Section 14 
 


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Table 14.3-2.7.2_CHN     Part 2 laboratory parameters - clinically notable events during the double-blind epoch - 
hematology (local laboratory and central laboratory) (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-2.7.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.8.2_CHN     Part 2 laboratory parameters – clinically notable events during the double-blind epoch – 
biochemistry (local laboratory and central laboratory) (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-2.8.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.9.2_CHN 
Part 2 post-baseline abnormal liver enzymes during the double-blind epoch (local laboratory and 
central laboratory) (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-2.9.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.10.2_CHN 
Part 2 newly occurring abnormal liver enzymes during the double-blind epoch (local laboratory 
and central laboratory) (Part 2 Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3-2.10.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-2.11.2_CHN 
Part 2 renal event during the double-blind epoch (Part 2 Safety Set: China Mainland Population) 
Programming note: Refer to Table 14.3-2.11.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-3.1.2_CHN 
Part 2 vital signs - test values and change from baselines - by visit (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3-3.1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-3.2.2_CHN 
Part 2 vital signs - clinically notable events during the double-blind epoch (Part 2 Safety Set: 
China Mainland Population) 
Programming note: Refer to Table 14.3-3.2.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-3.3.2_CHN 
Part 2 vital signs - newly occurring clinically notable events during the double-blind epoch 
(Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-3.3.2 in CLCZ696B2319 RAP Section 14 


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Figure 14.3-3.1.3_CHN 
Part 2 vital signs – heart rate - mean line plot (Part 2 Safety Set: China Mainland Population) 
Programming note: Refer to Figure 14.3-3.1.3 in CLCZ696B2319 RAP Section 14 
 
Figure 14.3-3.2.3_CHN 
Part 2 vital signs – - systolic blood pressure - mean line plot (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Figure 14.3-3.2.3 in CLCZ696B2319 RAP Section 14 
 
Figure 14.3-3.3.3_CHN 
Part 2 vital signs - diastolic blood pressure - mean line plot (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Figure 14.3-3.3.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-4.1.2_CHN 
Part 2 electrocardiogram (ECG) - test values and change from baselines - by parameter and visit 
(Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3-4.1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3-4.2.2_CHN    Part 2 electrocardiogram (ECG) - new onset clinically significant abnormality (Part 2 Safety Set: 
China Mainland Population) 
Programming note: Refer to Table 14.3-4.1.2 in CLCZ696B2319 RAP Section 14 
 
Section 14.3.1_CHN    Displays of adverse eventsTable (China Mainland Population) 
Programming note: Refer to Section 14.3.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-1.2_CHN 
Part 2 treatment emergent adverse events - overall summary (Part 2 Safety Set: China Mainland 
Population) 
Programming note: Refer to Table 14.3.1-1.1.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-2.2_CHN 
Part 2 treatment emergent adverse events (TEAEs) during the double-blind epoch (regardless of 
study treatment relationship) - by primary system organ class, preferred term (Part 2 Safety Set: China Mainland 
Population)  
Programming note: Refer to Table 14.3.1-2.2 in CLCZ696B2319 RAP Section 14 


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Table 14.3.1-3.2_CHN 
Part 2 treatment emergent adverse events (TEAEs) during the double-blind epoch (regardless of 
study treatment relationship) - by primary system organ class, preferred term, maximum severity (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3.1-3.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-4.2_CHN 
Part 2 treatment emergent serious adverse events (TESAEs) during the double-blind epoch 
(regardless of study treatment relationship) - by primary system organ class, preferred term (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3.1-4.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-4.3_CHN 
Part 2 treatment emergent serious adverse events of special interest (TESAESIs) during the 
double-blind epoch - by risk category, preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-4.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-7.2_CHN 
Part 2 study drug related treatment emergent adverse events (TEAEs) during the double-blind 
epoch - by primary system organ class, preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-7.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-8.2_CHN 
Part 2 study drug related treatment emergent serious adverse events (TESAEs) during the double-
blind epoch - by primary system organ class, preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-8.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-9_CHN Part 2 study drug related treatment emergent adverse events of special interest TEAESIs)  during the 
double-blind epoch - by risk category, preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-9 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-10.1_CHN 
Part 2 treatment emergent adverse events (TEAEs) during the double-blind epoch, leading to 
permanent discontinuation of study treatment (regardless of study treatment relationship) - by primary system organ class, 
preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-10.1 in CLCZ696B2319 RAP Section 14 


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Table 14.3.1-10.2_CHN 
Part 2 treatment emergent serious adverse events (TESAEs) during the double-blind epoch, leading 
to permanent discontinuation of study treatment (regardless of study treatment relationship) - by primary system organ 
class, preferred term (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-10.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-10.3_CHN 
Part 2 treatment emergent adverse events of special interest (TEAESIs) during the double-blind 
epoch, leading to permanent discontinuation of study treatment (regardless of study treatment relationship) - by risk 
category, preferred term (Part 2 Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3.1-10.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-12.1_CHN 
Part 2 most common (>=1%) treatment emergent adverse events (TEAEs) during the double-blind 
epoch(regardless of study treatment relationship) - by primary system organ class, preferred term (Part 2 Safety Set: 
China Mainland Population) 
Programming note: Refer to Table 14.3.1-12.1 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-12.2_CHN    Part 2 most common (>=1%) treatment emergent serious adverse events (TESAEs) during the double-
blind epoch(regardless of study treatment relationship) - by primary system organ class, preferred term (Part 2 Safety 
Set: China Mainland Population) 
Programming note: Refer to Table 14.3.1-12.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-13.2_CHN 
Part 2 serum potassium related events - shift from baseline during the double-blind epoch (Part 
2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-13.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-14.2_CHN 
Part 2 hypotension related events during the double-blind epoch (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3.1-14.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-15.2_CHN 
Part 2 renal impairment related events during the double-blind epoch (baseline eGFR<=170) (Part 
2 Safety Set: China Mainland Population) 
 


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Programming note: Refer to Table 14.3.1-15.2 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-15.3_CHN     Part 2 renal impairment related events during the double-blind epoch(baseline eGFR>170) (Part 2 
Safety Set: China Mainland Population)  
Programming note: Refer to Table 14.3.1-15.3 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-16.2_CHN 
Part 2 treatment emergent (newly occurring or worsening) adverse events (TEAEs) of positively 
adjudicated angioedema and angioedema-like event during the double-blind epoch by severity (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3.1-16.2 in CLCZ696B2319 RAP Section 14, without categorizing results by 
race 
 
Table 14.3.1-19_CHN      Part 2 treatment emergent (newly occurring or worsening) adverse events of special interest 
(TEAESIs)  during the double-blind epoch, regardless of study treatment relationship - exposure adjusted incidence rate 
(EAIR) (Part 2 Safety Set: China Mainland Population) 
 
Programming note: Refer to Table 14.3.1-19 in CLCZ696B2319 RAP Section 14 
 
Table 14.3.1-20_CHN      Part 2 death during the double-blind epoch and primary cause of death (Part 2 Safety Set: China 
Mainland Population) 
 
Programming note: Refer to Table 14.3.1-20 in CLCZ696B2319 RAP Section 14 
 
 
 
 
 
 
 
 
 


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4 
Site specific report 
For the site-specific reports, the list of significant adverse events for patients in China mainland will be needed for each site, which includes 
all of the following adverse events: 
• 
Severe adverse events 
• 
Adverse events leading to any change of study treatment or concomitant medications or non-drug therapy 
• 
Adverse events linked to laboratory abnormalities 
However, it is difficult to identify adverse events linked to laboratory abnormalities. Hence, the list of severe adverse events and adverse 
events leading to any change of study treatment or concomitant medications or non-drug therapy for patients in China mainland will be 
exported to a spreadsheet, and the rest adverse events for patients in China mainland will be exported to another spreadsheet. The adverse 
events linked to laboratory abnormalities need to be manually picked up. 

Prot_000.pdf: 
Global Clinical Development - General Medicine 
LCZ696/Entresto®
Clinical Trial Protocol CLCZ696B2319 / NCT02678312
Multicenter, open-label, study to evaluate safety, 
tolerability, pharmacokinetics and, pharmacodynamics of 
LCZ696 followed by a 52-week randomized, double-blind, 
parallel group, active-controlled study to evaluate the 
efficacy and safety of LCZ696 compared with enalapril in 
pediatric patients from 1 month to < 18 years of age with 
heart failure due to systemic left ventricle systolic 
dysfunction
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2015-004207-22, PIP02-11-M05
Version number:
07 (Clean)
Clinical trial phase:
II/III
Release date:
15-Nov-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)


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Protocol No CLCZ696B2319
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 7 ...........................................................................................................................12
Amendment 6 ...........................................................................................................................14
Amendment 5 ....................................................................................................................16
Amendment 4 ....................................................................................................................20
Amendment 3 ....................................................................................................................22
Amendment 2 ....................................................................................................................24
Amendment 1 ....................................................................................................................24
Protocol summary..............................................................................................................27
1
Introduction .......................................................................................................................32
1.1
Background............................................................................................................32
1.2
Purpose ..................................................................................................................34
2
Study objectives and endpoints .........................................................................................34
2.1
Primary objectives .................................................................................................34
2.2
Secondary objectives .............................................................................................34
35
2.4
Objectives and related endpoints...........................................................................35
3
Investigational plan ...........................................................................................................39
3.1
Study design...........................................................................................................39
3.2
Rationale for study design .....................................................................................50
3.3
Rationale for Global Rank primary endpoint ........................................................50
3.4
Rationale for patient population ............................................................................54
3.5
Rationale for dose/regimen, route of administration and duration of treatment....55
3.6
Rationale for choice of comparator .......................................................................57
3.7
Purpose and timing of interim analyses/design adaptations..................................58
3.8
Risks and benefits..................................................................................................58
4
Population..........................................................................................................................60
4.1
Inclusion criteria ....................................................................................................61
4.2
Exclusion criteria...................................................................................................61
5
Treatment...........................................................................................................................63
5.1
Study treatment......................................................................................................63


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5.1.1
Investigational and control drugs..........................................................63
5.1.2
Additional treatment..............................................................................66
5.2
Treatment arms......................................................................................................66
5.3
Treatment assignment and randomization.............................................................67
5.4
Treatment blinding.................................................................................................67
5.5
Treating the patient................................................................................................68
5.5.1
Patient numbering .................................................................................68
5.5.2
Dispensing the study drug.....................................................................68
5.5.3
Handling of study and additional treatment..........................................69
5.5.4
Instructions for prescribing and taking study treatment........................69
5.5.5
Permitted dose adjustments and interruptions of study treatment ........70
5.5.6
Rescue medication ................................................................................72
5.5.7
Concomitant medication .......................................................................72
5.5.8
Prohibited medication ...........................................................................73
5.5.9
Emergency breaking of assigned treatment code..................................73
5.6
Study completion and discontinuation...................................................................74
5.6.1
Study completion and post-study treatment..........................................74
5.6.2
Discontinuation of study treatment .......................................................74
5.6.3
Withdrawal of informed consent...........................................................75
5.6.4
Loss to follow-up ..................................................................................75
5.6.5
Early study termination by the sponsor.................................................76
6
Visit schedule and assessments .........................................................................................76
6.1
Information to be collected on screening failures..................................................86
6.2
Patient demographics/other baseline characteristics .............................................86
6.3
Treatment exposure and compliance .....................................................................86
6.4
Efficacy..................................................................................................................87
6.4.1
Efficacy assessment ..............................................................................87
6.4.2
Secondary efficacy endpoints ...............................................................90
90
6.5
Safety.....................................................................................................................90
6.5.1
Physical examination ............................................................................91
6.5.2
Vital signs..............................................................................................91
6.5.3
Height/length, head circumference and weight.....................................92
6.5.4
Laboratory evaluations..........................................................................92
6.5.5
Electrocardiogram (ECG) .....................................................................96


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6.5.6
Left ventricular ejection fraction (LVEF) or fractional shortening 
assessments ...........................................................................................96
6.5.7
Pregnancy and assessments of fertility .................................................97
6.5.8
Angioedema ..........................................................................................97
6.5.9
Appropriateness of safety measurements..............................................98
6.6
Other assessments..................................................................................................98
6.6.1
Clinical outcome assessments (COAs) .................................................98
6.6.2
Pharmacokinetics ................................................................................101
7
Safety monitoring............................................................................................................103
7.1
Adverse events.....................................................................................................103
7.2
Serious adverse events.........................................................................................105
7.2.1
Definition of SAE ...............................................................................105
7.2.2
SAE reporting......................................................................................106
7.3
Protocol specific unblinding rules .......................................................................107
7.3.1
Adverse events that are commonly seen in the study population .......107
7.4
Liver safety monitoring .......................................................................................108
7.5
Renal safety monitoring.......................................................................................109
7.6
Reporting of study treatment errors including misuse/abuse ..............................109
7.7
Pregnancy reporting.............................................................................................109
8
Data review and database management...........................................................................110
8.1
Data collection.....................................................................................................111
8.2
Database management and quality control..........................................................111
8.3
Data monitoring committee (DMC) ....................................................................111
8.4
Adjudication committee.......................................................................................112
8.5
Part 1 PK/PD data review....................................................................................112
9
Data analysis....................................................................................................................113
9.1
Analysis sets ........................................................................................................113
9.2
Patient demographics and other baseline characteristics.....................................114
9.3
Treatments ...........................................................................................................114
9.4
Analysis of the primary variable(s) .....................................................................115
9.4.1
Variable(s)...........................................................................................115
9.4.2
Statistical model, hypothesis, and method of analysis........................116
9.4.3
Handling of missing values/censoring/discontinuations.....................116
9.4.4
Sensitivity analyses .............................................................................117
9.4.5
Supportive analyses.............................................................................117
9.5
Analysis of secondary variables ..........................................................................117


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9.5.1
Efficacy variables................................................................................117
9.5.2
Safety variables ...................................................................................118
119
9.5.4
PK/PD .................................................................................................119
119
9.6
Interim analyses...................................................................................................120
9.7
Sample size calculation........................................................................................121
10 Ethical considerations......................................................................................................123
10.1
Regulatory and ethical compliance......................................................................123
10.2
Informed consent procedures...............................................................................124
10.3
Responsibilities of the Investigator and IRB/IEC ...............................................124
10.4
Publication of study protocol and results.............................................................124
11 Protocol adherence ..........................................................................................................125
11.1
Protocol amendments...........................................................................................125
12 References .......................................................................................................................125
13 Appendix 1: Clinically notable laboratory values and vital signs...................................129
14 Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ....................................................................................................................131
15 Appendix 3: Specific renal alert criteria and actions.......................................................133
15.1
Guidelines for the management of renal dysfunction..........................................134
16 Appendix 4: American heart association (AHA) pediatric advanced life support
(PALS) guidelines ...........................................................................................................135
16.1
Guidelines for the management of blood pressure ..............................................136
17 Appendix 5: Treatment guidelines for elevated potassium and hyperkalemia (serum 
potassium greater than or equal to 5.3 mmol/L)..............................................................137
18 Appendix 6: Reference table - blood volume by weight.................................................139
19 Appendix 7: NYHA/Ross classification..........................................................................141
20 Appendix 8: Patient global impression of severity (PGIS) .............................................142
143
21.1
Teen report (ages 13-18)......................................................................................143
145
21.3
Child report (ages 8-12).......................................................................................147
149
21.5
Young child report (ages 5-7)..............................................................................151
153
155
157


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21.9
160
22 Appendix 10: GFR by age...............................................................................................163
164
 
166
166
167
168
.168
.168
25 Appendix 13: Safety Monitoring for Age Group 3 patients............................................170
25.1
Safety Monitoring for Age Group 3 patients:......................................................170
26 Appendix 14: Up-titration dosing instructions for patients in Age Group 3 (1 month 
to <1 year at randomization) who turn 1 year old during Part 2 .....................................171
26.1
Up-titration instructions for Age Group 3 patients who turn one year old 
during Part 2 ........................................................................................................171
27 Appendix 15: Urgent safety measure (USM)..................................................................172
27.1
Instructions for patients impacted by the USM ...................................................172
27.2
USM implications regarding data collection and study results ...........................173
List of tables
Table 2-1
Objectives and related endpoints ..........................................................35
Table 3-1
Part 1: PK/PD - Minimum required pre-study body-weight 
normalized daily doses of commonly prescribed ACEIs or ARBs 
that should be tolerated prior to the LCZ696 1.6 mg/kg and 3.1 
mg/kg single dose PK/PD assessment...................................................42
Table 3-2
Part 1 (PK/PD) - Visit 101, 201, and UNS PK/PD blood and urine 
sample collection...................................................................................44
Table 3-3
Safety monitoring criteria for initiation/up-titration of study drug.......46
Table 3-4
Part 2 (Efficacy): Total daily dose levels of commonly prescribed 
ACEI/ARBs to guide selection of the study medication starting 
dose .......................................................................................................47


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Table 3-5
Part 2 (Efficacy): Study drug dose levels for double-blind enalapril 
and LCZ696 for age groups 1 and 2......................................................49
Table 3-6
Part 2(Efficacy): Study drug dose levels for double-blind enalapril 
and LCZ696 for age group 3.................................................................49
Table 5-1
LCZ696 drug supply for Part 1 (PK/PD) and Part 2 (Efficacy)............65
Table 5-2
Enalapril drug supply for Part 2 (Efficacy)...........................................66
Table 5-3
Prohibited treatment by medication class .............................................73
Table 6-1
Part 1 Assessment Schedule..................................................................78
Table 6-2
Part 2 Assessment Schedule..................................................................81
Table 6-3
Primary endpoint algorithm using ranked analysis...............................87
Table 6-4
Laboratory examinations.......................................................................93
Table 6-5
Sparse PK Assessment Schedule Part 2 Group 2 Subset....................102
Table 7-1
Adverse events (AEs) commonly seen in study population................107
Table 7-2
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................109
Table 9-1
Assumed percentage of patients in each category of the primary 
efficacy endpoint in Part 2 by treatment group at Month 8 (Week 
32) .......................................................................................................122
Table 9-2
Assumed percentage of patients in each category of the primary 
efficacy endpoint in Part 2 by treatment group at Month 12 (Week 
52) .......................................................................................................123
Table 13-1
Clinically notable laboratory values....................................................129
Table 13-2
Criteria for clinically notable vital signs.............................................130
Table 14-1
Liver event and laboratory trigger definitions ....................................131
Table 14-2
Follow up requirements for liver events and laboratory triggers........131
Table 15-1
Specific renal alert criteria and actions...............................................133
Table 16-1
5th percentile systolic blood pressure table .........................................135
Table 18-1
Reference table – blood collection volumes by body weight (kg)......139
Table 22-1
GFR by age for initiation/up-titration and exclusion criteria..............163
Table 26-1
Part 2 (Efficacy): Study drug dose level for double-blind enalapril 
and LCZ696 for Age Group 3 patients who turn 1 year old during 
the study ..............................................................................................171
List of figures
Figure 3-1
Study design..........................................................................................41
Figure 3-2
Global rank endpoint categories 3, 4, 5.................................................53


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List of abbreviations
γGT
Gamma-glutamyl transferase
ACEI
Angiotensin converting enzyme inhibitor
AE
Adverse Events
AHA
American heart association
Alb
Albumin
ALT
Alanine aminotransferase 
ARB
Angiotensin receptor blockers 
AST
Aspartate aminotransferase
AT1
Angiotensin type 1
AUC
Area under the curve
bid
Twice a day
BMI
Body mass index
BNP
B-type natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen
CCB
Calcium channel blocker
CEC
Clinical Endpoint Committee 
CFR
Code of Federal Regulations
cGMP
Cyclic guanosine monophosphate
CHBP
Child-bearing potential (female)
CHF
Chronic heart failure
CI
Confidence interval
CL or CL/F
Clearance
ClinRO
Clinician reported outcome
Cmax
Maximum drug concentration
COA
Clinical outcome assessments
CPO
Country pharma organization
CRF
Case report form
CV
Cardiovascular 
CV%
Coefficient of variation%
DAR
Dose administration record
DMC
Data monitoring committee
EC
Ethics committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECMO
Extracorporeal membrane oxygenation
EDC
Electronic data capture
EF
Ejection fraction
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ENA
Enalapril


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EU
European Union
FAS
Full analysis set
FS
Fractional shortening
FDA
Food and Drug Administration
GMR
Geometric mean ratio
HF
Heart failure
HFH
Heart failure hospitalization
HFrEF
Heart failure reduced ejection fraction
IB
Investigator brochure
ICH
International Conference on Harmonisation
ICU
Intensive care unit
IEC
IMP
Independent ethics committee
Investigational medicinal product
IN
Investigator notification
INR
International normalised ratio
IRB
Institutional review board
IRT 
Interactive response technology
ISHLT
International society for heart and lung transplantation
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
LBQ657
Active metabolite of AHU377(sacubitril)
LFT
Liver function test
LOCF
Last observation carried forward
LLOQ
Lowest limit of quantification
LVEF
Left ventricular ejection fraction
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MMRM
Mixed model for repeated measures
MRI
Magnetic resonance imaging
MUGA
Multi gated acquisition scan
NEP
Neprilysin
NP
Natriuretic peptide
NTproBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
PBPK
Physiologically based pharmacokinetic
PCR
Protein-creatinine ratio
PD
Pharmacodynamics
PDCO
Paediatric Committee
PedsQL
Pediatric Quality of Life Inventory
PGIS
Patient Global Impression of Severity
PIP
Paediatric investigation plan


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PK
Pharmacokinetics
PP
Per protocol
PRO
Patient reported outcome
PSD
Premature subject/patient discontinuation
PT
Preferred term
PVR
Peripheral vascular resistance
RAAS
Renin angiotensin aldosterone system
RAS
Renin-angiotensin system
RDW
Red blood cell distribution width
SAE
Serious adverse events
SAF
Safety population
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Time required for drug concentration to decrease by half
TBL
Total bilirubin
ULN
Upper limits of normal
UNOS
United Network for Organ Sharing
ULOQ
Upper limit of quantification
UNS
Unscheduled
UNS TD
Unscheduled study treatment discontinuation
US
United States
USM
Urgent Safety Measure
VAD
Ventricular assist device
WHF
Worsening heart failure
WHO
World Health Organization


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Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in 
patients/subjects with established disease and in those with newly-
diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug(s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of study consent: Withdrawal of consent from the study 
occurs only when a subject does not want to participate in the study 
any longer, and does not allow any further collection of personal data.


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Amendment 7
Amendment rationale
An urgent safety measure (USM) has been implemented, effective 26 October 2021, in 
consideration of a quality event affecting the active comparator (Enalapril) used in this study in
order to maintain the safety of the patients and the integrity of this ongoing study.
Recruitment closed in January 2021 and 339 of 375 randomized patients who received study 
drug, have completed or were discontinued from the study at the time the USM was issued. The 
study is expected to be completed by early January 2022. Thirty-six (36) patients were ongoing 
as of 26 October 2021, of whom 5 had discontinued study medication. Thirty-one (31) patients 
were taking study medication at the start of the USM. As of 31 October 2021, all patients had 
to discontinue study drug treatment and be changed to local standard of care, respecting required 
washout periods. The changes included in this amendment in the context of the USM are 
intended to maintain the scientific integrity of the study.
This amendment is to reflect the action taken under the USM and revise the primary analysis to 
account for the USM. 
Changes to the protocol
The following changes have been made:
Section 27 Appendix 15 Urgent safety measure (USM): Details regarding the USM, instructions 
for patients impacted by the USM and USM implications regarding data collection and study 
results, are included in this Appendix.
Section 6, Table 6-2 Part 2 Assessment Schedule: Changes made to assessments done at visits 
UNS/TD (Unscheduled/Treatment discontinuation), UNS and 416/499 for patients impacted by 
the USM, are included. Two additional footnotes, 18 and 19, have been added to clarify what 
assessments need to be done at these visits for these patients.
References to Section 27 Appendix 15 Urgent safety measure (USM) and/or Section 6, Table 
6-2 Part 2 Assessment Schedule have been made in multiple sections of the protocol, including 
the following: 
-
Section 3.1 Study design 
-
Section 3.3 Rationale for Global Rank primary endpoint
-
Section 6.4.1 Efficacy Assessment 
-
Section 6.6.1.2 Patient reported outcomes (PRO)
-
Section 6.6.2 Pharmacokinetics, Part 2 (Efficacy)
Section 7.2.2 SAE reporting: Revised text regarding SAE reporting as required by BfArM HA 
for all protocols and amendments submitted for sites in Germany
Section 9.4.2 Statistical model, hypothesis, and method of analysis: Added text related to USM
Section 9.4.3 Handling of missing values/censoring/discontinuations Part 2 (Efficacy): Added 
text related to USM


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Section 9.4.4 Sensitivity analyses: Added text related to USM
Section 9.5.1 Efficacy variables Part 2 (Efficacy): Added text related to USM
Section 9.5.3 Biomarkers: Added text related to USM 
Updates have been made to the List of abbreviations. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRB/EC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
This amendment is required for patient safety (i.e., necessary to eliminate immediate hazards 
to the trial subjects ICH GCP 3.3.8). Therefore, it will be implemented prior to IRB/IEC
approval, but will be sent for approval as well.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Summary of previous amendments 
Amendment 6 (08-Oct-2020)
Amendment 5 (18-Sep-2020
Amendment 4 (04-Feb-2019)
Amendment 3 (01-Oct-2018)
Amendment 2-JP (05-Sep-2017)
Amendment 2 (10-Jul-2017)
Amendment 1 (08-Aug-2016)
Original protocol (19-Nov-2015)


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Amendment 6
Amendment rationale
The reason for this amendment is 
1) to correct a typographical error in the dosing regimen for enalapril for Age Group 3.
2) to align study medication starting dose selection for Age Group 3 with Age Groups 1 
and 2, based on prior ACEI/ARB use.
3) to align contraception language with the current LCZ696 Investigator’s Brochure
4) to qualify the follow up duration for the babies of study participants who become 
pregnant during study participation
This study is ongoing. Age Groups 1, 2 and 3 in Part 1 have been completed. In Part 2, 
recruitment is ongoing for Age Groups 1 and 2, and approximately 335 patients have been 
enrolled in the study, thus far. These changes are not expected to influence the patient 
population or the study results.
Changes to the protocol
The following changes have been made:

In the “Changes to the protocol” Section of Amendmdnt 5, a further description of the 
changes that were made to the protocol with Amendment 5, is provided.

Section 3.1 Study Design, Part 2 (Efficacy) - Randomized treatment epoch (Visit 401 to 
Visit 416/499) Table 3-4 Total daily dose levels of commonly prescribed ACEI/ARBs 
to guide selection of the study medication starting dose: Clarified “low” and “higher”
ACEI/ARB doses in the text. Removed dose levels 1x through 4x of commonly 
prescribed ACEI/ARBs from Table 3-4.

Section 3.1 Study Design, Table 3-6 Part 2 (Efficacy) Study drug dose levels for double-
blind enalapril and LCZ696 for age group 3: The enalapril dose for Dose Level 2x has 
been corrected to 0.075 mg/kg bid.

Section 4.2 Exclusion Criteria, Exclusion Criterion 19: Expanded contraception 
requirements per the current LCZ696 Investigator’s Brochure (i.e. contraception to 
continue for 7 days after discontinuation of study drug).

Section 7.7 Pregnancy Reporting: Added revised follow up requirement (i.e. 12 months) 
after birth of the baby for participants who become pregnant during the study.

Section 10.2 Informed consent procedures: Expanded contraception requirements per 
the current LCZ696 Investigator’s Brochure (i.e. contraception to continue for 7 days 
after discontinuation of study drug)
Updates have been made to the List of abbreviations. Typographical and grammatical errors 
have also been corrected in various sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.


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IRB/EC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments 
Amendment 5 (18-Sep-2020
Amendment 4 (04-Feb-2019)
Amendment 3 (01-Oct-2018)
Amendment 2-JP (05-Sep-2017)
Amendment 2 (10-Jul-2017)
Amendment 1 (08-Aug-2016)
Original protocol (19-Nov-2015)


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Amendment 5 
Amendment rationale
The main reasons for this amendment are as follows:

Based on review of Part 1 Age Group 3 PK/PD/Safety data, this amendment defines the 
target dose and dose regimen for Part 2 Age Group 3 to enable enrollment into Part 2 
for Age Group 3. The planned target dose of LCZ696 2.3 mg/kg bid for Part 2 Age 
Group 3 together with the implementation of additional hypotension safety monitoring 
for Part 2 Age Group 3 during the initial up-titration phase is supported by the DMC 
and has been added to the protocol with this amendment. The DMC also supports the 
protocol changes with this amendment that enables Age Group 3 patients who turn 1 
year old during Part 2 of the study and who are safely tolerating the LCZ696/placebo 
2.3 mg/kg bid dose, to be able to up-titrate to LCZ696/placebo 3.1 mg/kg bid dose (the 
target dose for Age Group 2), if it is in the patient’s best interest as assessed by the 
Investigator. 

Based upon agreement with the EMA/PDCO (PIP M04) to align the age groups with 
the ICH E11 guidelines on pediatric subsets, modified age groups that will be included 
in the analysis.

The enrollment target of 25% ACEI/ARB naïve patients has been removed, as it is 
considered not attainable given that patients in this study population are often initially 
treated with some form of RAS inhibition when first diagnosed. Ninety percent (90%) 
of the patients have been randomized thus far and only a small percentage 
(approximately 5%) of these patients are ACEI/ARB naïve.

The requirement to include 20% randomized patients per age group in the analysis of 
Part 2 has been removed. Given the challenges of recruiting patients 1 month to  <1 year 
old (Age Group 3), it is considered not feasible to enroll 72 patients (20% of 360 patients) 
in this age group. The requirement for 80 patients with an event in Category 1 or 2 has 
also been removed. The study is sufficiently powered based on the Global Rank 
Endpoint and the number of patients expected to have a Category 1 or 2 event.
 
 

Patients in Age Group 2 will be required to be Ross class II or higher at randomization. 
This is based on the lower event rate observed in Age Group 2 patients vs. Age Group 
1 patients.

Measurement of height has been clarified with a statement recommending use of a 
stadiometer for standing height measurements.

Text has been added to the protocol in order to be able to address health authority 
requests for data if required for an ongoing marketing authorization application 
regulatory review.


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
Based upon Health Authority agreement, the rationale for collecting race and ethnicity 
data has been added to the protocol.
This study is ongoing. Age Groups 1, 2 and 3 in Part 1 have been completed. In Part 2, 
recruitment is ongoing for Age Groups 1 and 2, and approximately 325 patients have been 
enrolled in the study, thus far.
Changes to the protocol
The following changes have been made:

Protocol Summary: Treatment Section: Added target dose level (Dose Level 4x) for Age 
Group 3. Added statement enabling Age Group 3 patients that turn 1 year old during the 
study, to be up-titrated to Group 3 Dose Level 5x (LCZ696 3.1 mg/kg bid/ enalapril 0.2 
mg/kg bid). Data Analysis Section: Clarified age groups for Part 1 analysis. Added 
modified age groups for Part 2 analysis.
 

Section 3.1 Study design: Removed enrollment target of 25% ACEI/ARB naïve patients. 
Removed requirement for 20% of the total n of 360 (72 patients) to be randomized and 
included for analysis in each age group. Removed required number of patients (80) with 
an event in Category 1 or 2 (in two places in this section). Clarified Part 1 age groups. 
Clarified target dose for Age Groups 1 and 2 (Dose Level 4) and added target dose level
(Dose Level 4x) for Age Group 3. Modified Tables 3-4, 3-5 and 3-6. Added safety 
monitoring requirements for Part 2 Age Group 3 patients. Added details enabling Age 
Group 3 patients that turn 1 year old during the study, to be up-titrated to Group 3 Dose 
Level 5x (LCZ696 3.1 mg/kg bid/ enalapril 0.2 mg/kg bid). Also added a statement 
indicating that a scheduled or unscheduled visit may be used for these up-titrations and 
added detailed criteria for up-titration. Note: References to dose levels 1 through 4
throughout the protocol have been changed to dose levels 1x to 4x for Age Group 3 
patients.

Section 3.1 Part 2 (Efficacy) Table 3-4: Total daily dose levels of commonly prescribed 
ACEI/ARBs for purpose of comparing to dose levels of study drug: Added Part 2 Age 
Group 3 dose levels 1x through 4x comparative ACEI/ARB doses.

Section 3.8 Risks and Benefits: Added text describing data from Part 1 Age Group 3 
and additional safety monitoring requirements for Age Group 3 patients in Part 2.

Section 4 Population: Clarified age groups and NYHA/Ross class group for Part 2 
stratification. Removed requirement for 20% of the total n of 360 (72 patients) to be 
randomized and included for analysis in each age group.

Section 4.1 Inclusion criteria: Removed the enrollment target of 25% ACEI/ARB naïve 
patients. Removed the option for Age Group 2 patients (with a prior history of Ross 
class II or higher) to be Ross class I at randomization. Age Group 2 patients must be 
Ross class II or higher at randomization.


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
Section 5.1.1 Study treatment – Investigational and control drugs, Table 5-2: Added 
blister as packaging option for enalapril tablets (2.5 mg).

Section 5.3 Treatment assignment and randomization: Clarified age groups and 
NYHA/Ross class group for Part 2 stratification.

Section 5.5.4 Instructions for prescribing and taking study treatment, Part 2: Clarified 
Part 2 study drug supplies.

Section 5.5.5 Permitted dose adjustments and interruptions of study treatment: Clarified 
target dose for Age Groups 1 and 2 (Dose Level 4) and added target dose for Age Group 
3 (Dose Level 4x). Added safety monitoring requirements for Age Group 3 patients in 
Part 2. 

Section 6, Table 6-2 Part 2 Assessment Schedule: Footnote 6, clarified requirements 
regarding use of a Central Laboratory for laboratory analyses. Footnote 7, added text 
clarifying abbreviated labs for visits 402 and 404; added text with regard to abbreviated 
labs for Part 2 Group 3 patients who turn 1 year old during the study, who are up-titrated; 
Footnote 17, added text with regard to additional vital signs monitoring for Part 2 Group 
3 patients at the initial dose for each dose level up-titration.

Section 6.2 Patient demographics /other baseline characteristics: Added note regarding 
rationale for collecting race and ethnicity data.

Section 6.5.2 Vital Signs: Added instructions regarding additional vital sign 
measurement requirements for Part 2 Group 3 patients

Section 6.5.3 Height/length head circumference and weight: Clarification added 
regarding measurement of height.

Section 6.5.4 Laboratory Evaluations: added text clarifying abbreviated labs for visits 
402 and 404 

Section 6.5.4.3 Estimated GFR: Corrected text stating that change in estimated GFR 
will be calculated from screening for local labs and from randomization for central labs.

Section 6.5.9 Appropriateness of safety measurements: Correction: ICH E12 should 
have been ICH E11 (correct in the Reference section).

Section 8.3 Data Monitoring Committee: Noted that data may be provided to Health 
Authorities, if required for an ongoing marketing authorization application regulatory 
review and Novartis will inform the DMC should this occur.

Section 9.2 Patient demographics and other baseline characteristics: Added modified 
age groups for analysis.

Section 9.3 Treatments Part 1 (PK/PD) and Treatments Part 2 (Efficacy): Minor 
clarifications to analysis text.

Section 9.4.1 Analysis of the primary variable(s), Variables, Part 1 (PK/PD): Clarified 
PK/PD model analysis description text.


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
Section 9.4.2 Statistical model, hypothesis and method of analysis: Added modified age 
groups and NYHA/Ross class groups and noted that the number and percentage of 
patients in each category will be provided by treatment group for each age group, each 
modified age group, and for overall.

Section 9.5 Analysis of secondary variables: Added modified age groups for analysis to 
multiple subsections in this section and clarified the efficacy analysis text.

Section 12: References have been updated.

Section 13 Appendix 1 Table 13-2 Criteria for clinically notable vital signs: Clarified 
criteria for clinically notable vital signs with the addition of missing < and ≥ signs.

Section 25 Appendix 13 Safety Monitoring for Part 2 Age Group 3 patients: New 
Appendix added (Appendix 13)

Section 26 Appendix 14 Up-titration dosing instructions for patients in Age Group 3 (1 
month to <1 year at randomization) who turn 1 year old during Part 2: New Appendix 
added (Appendix 14).

Updates have been made to the List of abbreviations. Typographical errors have also 
been corrected in various sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments 
Amendment 4 (04-Feb-2019)
Amendment 3 (01-Oct-2018)
Amendment 2-JP (05-Sep-2017)
Amendment 2 (10-Jul-2017)
Amendment 1 (08-Aug-2016)
Original protocol (19-Nov-2015)


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Amendment 4
Amendment rationale
 
 
 
 
 
In addition, clarification is provided in this amendment regarding location alternatives if local 
requirements do not allow home urine pregnancy testing
This study is ongoing. In Part 1 of the study, Age Groups 1 and 2 have been completed and Age 
Group 3 is ongoing. In Part 2 of the study, approximately 144 patients have been randomized, 
thus far.
These changes will not influence the study population or results of the study and will not impact 
patient safety.
Changes to the protocol
The following changes have been made:


 

 


Section 6 Visit schedule and assessments: removed the words “at home” as it relates to urine 
pregnancy testing given the clarification added to Table 6-2 Part 2

Table 6-2 Part 2 Assessment Schedule: Clarified footnote 5 providing location alternatives 
if local requirements do not allow home urine pregnancy testing 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require IRB/IEC
approval prior to implementation.


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The changes herein related to the clarification regarding location alternatives for urine 
pregnancy testing, affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Summary of previous amendments 
Amendment 3 (01 October 2018)
Amendment 2-JP (05 September 2017)
Amendment 2 (10 July 2017)
Amendment 1 (08 August 2016)
Original protocol (19 November 2015)


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Amendment 3
Purpose of the amendment
The main purposes of this amendment are to:

expand the examination of the exposure-response relationship for Group 3 (i.e. 1 month to 
< 1 year) in the Part 1 pharmacokinetic (PK)/pharmacodynamic (PD) assessment. (This 
will be done by evaluating two dose levels of LCZ696, specifically LCZ696 0.4 mg/kg 
and LCZ696 1.6 mg/kg in Part 1 Group 3.)

add the target dose level for Group 3 in Part 2 

add sparse PK assessment at steady state in a subset of patients in Part 2 Age Group 2 to 
further confirm the target dose for this age group

modify the left ventricular ejection fraction (LVEF) and the fractional shortening (FS) 
inclusion threshold to expand the eligibility range for patients

 
This study is ongoing. Age Group 1 and Group 2 in Part 1 have been completed. In Part 2 
approximately 86 patients have been enrolled in the study, thus far.
These changes are not expected to influence the results of the study or to impact patient safety.
Changes to the protocol
The following changes have been made:

For Part 1 Group 3 patients, removed the single dose level of LCZ696 0.8 mg/kg and 
replaced it with two dose levels: LCZ696 0.4 mg/kg and LCZ696 1.6 mg/kg. Inclusion 
criterion 7 has been modified accordingly. Total of approximately 4 observations per dose 
(approximately 8 in total) and a minimum of 4 patients is planned for Group 3 in Part 1.

Added the target dose level for Group 3 in Part 2 (Table 3-6).

Updated “Exclusion 4” and “Exclusion 7” to clarify the applicability only to Part 2. 

Modified “Inclusion 5" regarding left ventricular ejection fraction and the fractional 
shortening as described in Section 4.1.

Added “Exclusion 26” to exclude a patient that is breast fed by a mother that is using an 
ACEI. 

Updated “Exclusion 19” to clarify the methods of contraception.

Additional pregnancy testing (monthly) that must be done for women of child-bearing 
potential for studies that include study medication where highly effective contraception is 
required, has been added.

Changed the Abbreviated laboratory evaluations at weeks 2 and 6 from required to optional 
(see Table 6-2).


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
Added to Part 2 of the study, a steady-state Sparse PK blood collection visit, applicable to 
a subset of patients in Group 2 (approximately 24 patients of whom approximately 12 
patients are expected to be randomized to LCZ696) who agree to participate.
 
 
 
 
 
 

Applies to sites in Japan only: Added an extra clinic visit to Part 2 of the protocol at week 
1 (Visit 401JPN) in Table 6-2. 

Clarified and updated language around ACEI/ARB dosing prior to the dosing with LCZ696 
for Part 1.

Clarified and updated language around the weight measurement and visit schedule in Part 
1.

Added clarification to Section 3.1 regarding additional patients in Part 1 Group 3 to be 
evaluated if needed for dose determination for Part 2.

Added instructions regarding “plasma potassium” in Section 6.5.4.

Removed Endpoint collection from the Assessment Table for Part 1 (Table 6-1). Endpoints
from Part 1 (open-label, single dose PK/PD) are not part of the efficacy analysis and will 
not be adjudicated.

Added instructions regarding countries where blood samples cannot be shipped out of the 
country due to local regulations (Table 6-2).

Made changes to “Glossary of Terms” and Section 5.6.3 to align with the new “Withdrawal 
of Consent” language. Corrected typographical errors in various sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through font for deletions and underlined for insertions.
A copy of this protocol amendment will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) for all sites and Health Authorities.
The changes described in this protocol amendment require IRB/IEC approval prior to 
implementation. In addition, as the changes herein affect the Informed Consent, sites are 
required to submit for approval an Informed Consent that takes into account the changes 
described in this amended protocol.


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Amendment 2
Purpose of the amendment
The main purpose of this amendment is to remove technical details pertaining to the preparation 
of liquid formulation of the study drugs, LCZ696 and enalapril.
These changes will not influence the study population or results of the study and will not impact 
patient safety.
Changes to the protocol

Deleted information related to liquid formulation of LCZ696 and enalapril in Part 1 and 
Part 2.

Clarified that instructions for the preparation of the liquid study drugs are provided in the 
Pharmacy Manual which is provided to the site/pharmacy as a separate document.

Other clarification: Clarified the early study termination procedure (Section 5.6.5) 
according to the “Detailed Guidance from the European Commission, CT-1, 4.2.2-163”.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol are non-substantial and do not require IRB/IEC 
approval prior to implementation.
In addition, details regarding compounding the liquid formulation will be removed from the 
Informed Consent. Sites should update and submit for approval a revised Informed Consent that 
takes into account the changes described in this amended protocol.
Amendment 1
Purpose of the amendment
All of the amendment changes are made prior to enrolling patients into the study. 
The main purpose of this amendment is to examine the exposure-response relationship for 
Groups 1 (6 to < 18 years) and 2 (1 to < 6 years) by the addition of a second (and lower) dose 
of LCZ696 (0.8 mg/kg) to the LCZ696 (3.1 mg/kg) Part 1 pharmacokinetic 
(PK)/pharmacodynamic (PD) assessment. 
In addition, to ensure an adequate number of clinical endpoints are included in the Global Rank 
primary endpoint in Part 2, the study will stop when at least 80 patients have an event in 
Category 1 or 2.  
For the Global Rank primary endpoint determination, the Pediatric Quality of Life inventory 
(PedsQL) Physical Functioning domain will be used only for Group 1 (ages 6 to < 18 years), 


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since Group 1 is the only age group where all the patients will be doing a patient self-report 
PedsQL.
This amendment also adds a number of other clarification changes to the PK, PD biomarkers, 
and blood collection information; updated information about study drugs LCZ696 and enalapril; 
updates to endpoint and adjudication information. There are other changes included to add 
clarity, enhance readability, correct typographical errors and provide further details.
Changes to the protocol
The following changes have been made:

Added second dose to Part 1 study design and other relevant sections. Assessment 
schedule, Safety, PK, and PD data review have been revised accordingly. 

Total of six patients per dose for each age group is planned.  Two doses are being assessed 
in Groups 1 and 2, and one dose is being assessed in Group 3.

Added plasma B-type natriuretic peptide (BNP) to Part 1.  Relevant changes have been 
made to biomarker data and blood collection details.  

Detailed information about PK blood sample handling was moved to the laboratory 
manual.

Added urine cGMP (cyclic guanosine monophosphate) collection at baseline pre-dose for 
PD assessment in Part 1.

Updated and corrected blood volumes for PK and PD sampling in Part 1.

Added information about at least 80 patients with events in Category 1 or 2.

Added safety and tolerability Secondary objective in Part 1.

For the PedsQL scale, the chronic version (one month recall period) was replaced with the 
acute version (7 days recall period). The reason for this change is that the patient reported 
assessment of 7 days is considered more appropriate compared to 1 month for pediatric 
heart failure patients. Added text indicating that the PedsQL Physical Functioning module 
will be used for the primary Global Rank endpoint only for Group 1 (6 to <18 years old) 
(Section 3.3 and Section 6.4.1).

Updated Patient Global Impression of Severity (PGIS) age range to consistently state 5 to 
< 7 years and 7 to < 18 years old, and changed ‘Very Mild’ to ‘None’ for the PGIS scale.
 

Secondary objective was clarified for “delaying” for time to first occurrence of event.

Inclusion and exclusion criteria updated to provide further information and clarity.

Added that a confirmatory serum pregnancy test should be performed when urine 
pregnancy test is positive, and added serum pregnancy test at Visit 416/499. 

Deleted biomarkers from the list of the safety parameters in Section 6.5 as biomarkers are 
not a safety parameter in this study.

Reference table for blood volume by weight was updated (Appendix 6, Table 18-1).

Clinical events and adjudication information updated in Sections 6.4.1 and Section 9.7.


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
Added systolic BP 5th percentile information for patients with age of 1 month to < 1 year 
(Appendix 4, Table 16-1) and ≥30% mean GFR (glomerular filtration rate) by age table 
(Appendix 10, Table 22-1).

Updated renal safety monitoring Section 7.5.

Added reference for FDA guidance in Section 7.3.1 for safety reporting.

Clarified and updated language around management of study drug.

Typographical errors were corrected in various sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.


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Protocol summary
Protocol number
CLCZ696B2319
Title
Multicenter, open-label, study to evaluate safety, tolerability, 
pharmacokinetics and, pharmacodynamics of LCZ696 followed by a 52-
week randomized, double-blind, parallel group, active-controlled study to 
evaluate the efficacy and safety of LCZ696 compared with enalapril in 
pediatric patients from 1 month to < 18 years of age with heart failure due 
to systemic left ventricle systolic dysfunction
Brief title
Pharmacokinetics (PK), pharmacodynamics (PD), safety and efficacy 
study of LCZ696 in children (1 month to < 18 years) with heart failure due 
to systemic left ventricle systolic dysfunction
Sponsor and clinical 
phase
Novartis; Phase 2/3 
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this study is to determine whether pediatric heart failure 
(HF) patients (1 month to < 18 years old) will derive greater clinical 
treatment benefit with LCZ696 compared to enalapril over 52 weeks 
treatment duration. This study includes two parts. Part 1 will determine 
the dose for Part 2. Part 2 will assess the efficacy and safety of LCZ696 
compared to enalapril.
Primary objective(s)

Part 1: The primary objective is to determine the 
pharmacokinetics (PK) and pharmacodynamics (PD) of LCZ696 
in pediatric HF patients

Part 2: The primary objective is to determine whether LCZ696 is 
superior to enalapril for treatment of heart failure as assessed 
using a global rank endpoint in pediatric HF patients
Secondary objectives

Part 1: To assess the safety and tolerability of LCZ696 in 
pediatric patients with HF

Part 2: To determine whether LCZ696 is superior to enalapril in 
delaying time to first occurrence of the composite of either
Category 1 or 2 events (e.g. death, worsening HF)

Part 2: To determine whether LCZ696 is superior to enalapril for 
improving NYHA (New York Heart Association)/Ross functional 
class

Part 2: To determine whether LCZ696 is superior to enalapril for 
improving the Patient Global Impression of Severity (PGIS) 
score

Part 2: To characterize the population PK of LCZ696 exposure 
in pediatric patients with HF, including an assessment of steady-
state sparse PK data in a subset of Group 2 patients

Part 2: To assess the safety and tolerability of LCZ696 
compared to enalapril in pediatric patients with HF
Study design
This is a multi-center study in pediatric patients (1 month to <18 years) 
with HF (i.e. LVEF/fractional shortening criteria as described in Inclusion 
Criterion Number 5). This study uses a seamless design which consists 
of two parts: 


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
Part 1: This is a multi-center, open-label study to characterize 
the PK and PD of LCZ696. This information will enable the 
prediction of multiple dose PK exposure and support dosage 
determination for Part 2 of this study

Part 2: This is a 52-week randomized, double blind, parallel-
group, active controlled, study to evaluate the efficacy, safety, 
and tolerability of LCZ696 compared to enalapril in addition to 
conventional HF treatment in pediatric patients with HF
Population
The study population consists of pediatric HF patients 1 month to <18 
years, inpatient or outpatient, with systemic left ventricle systolic 
dysfunction; and includes at least 18 patients in Part 1; and randomizes 
360 patients in Part 2 at centers worldwide. For Part 1 and Part 2, the
patients will be divided across three groups based on age: Group 1: 6 to 
<18 years; Group 2: 1 to <6 years; Group 3: 1 month to < 1 year. 
Key inclusion criteria
1.
Written informed consent by parent(s)/legal guardian(s) for the 
pediatric patient must be obtained before any study-specific 
assessment is performed. A consent or assent may also be required 
for some patients depending upon their age and local requirements
2.
Male or female, inpatient or outpatient, 1 month to < 18 years of age
3.
Chronic heart failure resulting from left ventricular systolic 
dysfunction, and receiving chronic HF therapy (if not newly 
diagnosed)
4.
NYHA classification II-IV (older children: 6 to <18 years old) or Ross 
CHF classification II-IV (younger children: < 6 years old) any time 
prior to screening
5.
Systemic left ventricular ejection fraction (EF) ≤ 45% or fractional 
shortening ≤22.5% (assessed by most recent echocardiography, 
MRI, MUGA or left ventricular angiogram). For Part 2, this 
assessment must be within 1 month from screening.[Note: The study 
will target enrollment of approximately 80% patients with a systemic 
left ventricular ejection fraction (EF) ≤ 40% or fractional shortening 
≤20% for Part 2 only].
6.
Biventricular physiology with systemic left ventricle
7.
For Part 1 PK/PD, patients must be treated with an ACEI
(Angiotensin converting enzyme inhibitor) or ARB (Angiotensin 
receptor blockers) prior to screening. For Part 1 PK/PD, patients in 
Group 1 and 2 must be currently treated with a daily dose equivalent 
of at least enalapril 0.2 mg/kg (Table 3-1) prior to the LCZ696 3.1 
mg/kg single dose assessment. For Part 1 PK/PD, patients in Group
3 must be currently treated with a daily dose equivalent of at least 
enalapril 0.1 mg/kg (Table 3-1) prior to the LCZ696 1.6 mg/kg single 
dose assessment
For additional information, refer to Section 4.1
Key exclusion criteria
1.
Patients with single ventricle or systemic right ventricle
2.
Patients listed for heart transplantation as United Network for Organ 
Sharing (UNOS) status 1A or hospitalized waiting for transplant while 
on inotropes or with ventricular assist device at time of entry into the 
study
3.
Sustained or symptomatic dysrhythmias uncontrolled with drug or 
device therapy
4.
For Part 2 only, patients that have had cardiovascular surgery or 
percutaneous intervention to palliate or correct congenital 


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cardiovascular malformations within 3 months of the screening visit. 
Patients anticipated to undergo corrective heart surgery during the 12 
months after entry into Part 2.
5.
Patients with unoperated obstructive or severe regurgitant valvular 
(aortic, pulmonary, or tricuspid) disease, or significant systemic 
ventricular outflow obstruction or aortic arch obstruction
6.
Patients with restrictive or hypertrophic cardiomyopathy
7.
For Part 2 only, active myocarditis (diagnosed with presumed or 
acute myocarditis within 3 months of enrollment)
8.
Symptomatic hypotension or blood pressures (BPs) below the 
calculated 5th percentile systolic BP (SBP) for age at screening visit 
and as described in Appendix 4
9.
Renal vascular hypertension (including renal artery stenosis)
10. Severe pulmonary hypertension (defined by pulmonary vascular 
resistance (PVR) index >6 Wood units-m2) unresponsive to 
vasodilator agents (such as oxygen, nitroprusside or nitric oxide). 
Note measurement of PVR is not a requirement for study eligibility.
11. History or current clinical evidence of moderate-to severe obstructive 
pulmonary disease or reactive airway diseases (e.g. asthma)
12. Serum potassium >5.3 mmol/L at Visit 1 or at Visit 301
13. Patients with significant renal (eGFR calculated using the modified 
Schwartz formula < 30% mean GFR for age, Appendix 10, Table 22-
1); hepatic (serum aspartate aminotransferase or alanine 
aminotransferase > 3 times upper limit of normal); gastrointestinal or 
biliary disorders (that could impair absorption, metabolism, or 
excretion of orally administered medications)
14. Concurrent terminal illness or other severe disease (e.g. acute 
lymphocytic leukemia) or other significant laboratory values that, in 
the opinion of the Investigator, precludes study participation or 
survival
15. Patients with history of angioedema
16. Patients with allergy or hypersensitivity to ACEI/ARB
For additional information, refer to Section 4.2
Study treatment
LCZ696
Part 1: single dose 0.8 mg/kg, 3.1 mg/kg (age Groups 1 and 2) and 0.4 
mg/kg, 1.6 mg/kg (age Group 3), (using 3.125 mg granules or liquid 
formulation)
Part 2: projected target dose 3.1 mg/kg bid for age Groups 1 and 2 (Dose 
Level 4 for Groups 1 and 2) (actual dose dependent on Part 1; using 3.125 
mg granules, 50 mg tablets, 100 mg tablets, 200 mg tablets or liquid
formulation). For age Group 3, the target dose will be 2.3 mg/kg bid (Dose 
Level 4x for Group 3 patients). In addition, Group 3 patients who turn 1 
year old during the study, may be further up-titrated to a dose of 3.1 mg/kg 
bid (Dose Level 5x for Age Group 3 patients). See Appendix 14 for details.
Enalapril
Part 1: open-label enalapril (tablet or liquid) and 
Part 2: target dose 0.2 mg/kg bid for Groups 1 and 2, (Dose Level 4 for 
Groups 1 and 2); using liquid formulation, 2.5 mg tablets, 5 mg tablets, 10
mg tablets. For Group 3, the target dose will be 0.15 mg/kg bid (Dose Level 


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4x for Group 3 patients). In addition, Group 3 patients who turn 1 year old 
during the study, may be further up-titrated to a dose of 0.2 mg/kg bid 
(Dose Level 5x for Group 3 patients). See Appendix 14 for details
All study treatment in Part 2 will be bid dosing.
Efficacy assessments
The primary global rank endpoint will be derived based on 5 categories 
ranking worst outcome to best outcome:
1.
Category 1: Death; UNOS status 1A listing for heart transplant or 
equivalent; VAD/ECMO/mechanical ventilation/intra-aortic balloon 
pump requirement for life support at end of study
2.
Category 2: Worsening HF (WHF); defined by signs and symptoms of 
WHF that requires an intensification of HF therapy
3.
Category 3: Worsened; worse NYHA/Ross or worse Patient Global 
Impression of Severity (PGIS); and further ranking by PedsQL
physical functioning domain
4.
Category 4: Unchanged; unchanged NYHA/Ross and unchanged 
PGIS; and further ranking by PedsQL physical functioning domain
5.
Category 5: Improved; improved NYHA/Ross or improved PGIS 
(neither can be worse); and further ranking by PedsQL physical 
functioning domain)
Key safety 
assessments

Adverse events (AEs) and serious adverse events (SAEs)

Blood pressure, heart rate

Height, weight and head circumference (≤ 3 years)

Laboratory values (including potassium & serum creatinine)

Angioedema surveillance

Electrocardiogram (ECG) changes
Other assessments

NYHA/Ross class

Patient Global Impression of Severity (PGIS)

PK of LCZ696 analytes

Plasma NTproBNP, BNP

Urine and plasma cGMP
Data analysis
Part 1 PK and PD variables

The PK and PD parameters of LCZ696 will be summarized 
descriptively by age group (Group 1: 6 to < 18 years; Group 2: 1 
to < 6 years; Group 3: 1 month to < 1 year), and dose.
Part 2 efficacy variables

To characterize the effects of LCZ696 and enalapril on whether 
the patients were improved or not improved using the global rank 
endpoint. The endpoint will be assessed using a stratified 
Wilcoxon rank-sum analysis (Kawaguchi 2011), stratifying by 
modified age group (Group 1: 6 to < 18 years; Group 2a: 2 to < 6 
years; Group 3a: 1 month to < 2 years) and NYHA/Ross class
group (Class I/II, Class III/IV)


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Key words
Pediatric, heart failure, pharmacokinetics, pharmacodynamics, safety, 
efficacy, multicenter, systemic left ventricle systolic dysfunction, global 
rank endpoint


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1
Introduction
1.1
Background 
Pediatric heart failure (HF) is characterized by significant morbidity and mortality, frequent 
hospitalization and medical care, and poor quality of life. It is estimated that between 12,000 to 
35,000 children below age 19 are diagnosed with HF in the United States (US) each year (Hsu 
and Pearson 2009a). HF can develop or exacerbate in childhood, during adolescence and also 
later in adulthood as made evident by the growing number of adults with congenital heart 
disease. Congenital heart disease and cardiomyopathy are the two most common causes of 
pediatric HF (Sharma 2003, Andrews 2008). 
The largest HF burden comes from children born with congenital malformations. Congenital 
heart disease occurs in approximately 8 per 1,000 live births of which 1-2 per 1,000 develop 
HF (Kay 2001). A wide variety of congenital abnormalities may be present including ventricular 
or atrial septal defect, patent ductus arteriosus, aorto-pulmonary window, hypoplastic left heart, 
aortic or pulmonary vein stenosis, anomalous origin of the left coronary artery, and coarctation 
of the aorta. Most of these children are diagnosed before ages 1 and many have early surgical 
intervention, usually before age 2. 
The other main cause of pediatric HF is cardiomyopathy, with an estimated annual incidence 
of 1 per 100,000 children in the US, Australia, United Kingdom and Ireland (Lipshultz 2003, 
Nugent 2003, Andrews 2008). Dilated cardiomyopathy (usually diagnosed as idiopathic, 
familial, or myocarditis) is the most common type. Hypertrophic cardiomyopathy due to 
familial isolated cardiomyopathy, an inborn error of metabolism, or a malformation syndrome 
is the next most common type. Cardiomyopathy can also be associated with muscular 
dystrophies such as Duchenne’s muscular dystrophy and myotonic dystrophy. In developing 
countries, rheumatic heart disease, nutritional deficiencies, and other tropical diseases such as 
Chagas disease can also be a substantial cause of pediatric HF. 
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 
2009). Furthermore, nearly 40% of children in the US with symptomatic cardiomyopathy either 
undergo heart transplantation or die within 2 years (Lipshultz 2003). 
In contrast to HF in adults, there is very limited research in pediatric HF. Consequently, 
treatment of HF in children is based on information and results provided by adult studies 
(Kantor 2010). Pediatric HF treatment is outlined in the recent guidelines published by the 
International Society of Heart and Lung Transplantation (ISHLT) (Kirk 2014). Respondents to 
the Diovan Pediatric Heart Failure Survey confirmed that ‘efficacy shown in adult HF trials’ 
and ‘Consensus Statements and Guidelines’ were the two most important factors they 
considered when making treatment decisions for pediatric patients with HF (CVAL489K2304 


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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 this point, no trial has demonstrated an outcome benefit of any pharmacotherapy in children 
with HF. The largest pediatric HF trial done thus far is the randomized, double-blind, placebo-
controlled, parallel-group trial of carvedilol in patients 8 months to 14 years with HF due to 
congenital heart disease or cardiomyopathy (Shaddy 2007). The primary endpoint for the 
pediatric carvedilol study was a composite measure of HF outcomes, assessing the response to 
treatment as worsening, improved or unchanged. While adult HF populations have shown 
benefit with β-blockade, this study did not meet its composite primary endpoint. This may have 
been attributable to the known issues related to pediatric HF trials in general including: varying 
causes of HF, uncertain natural history of HF in children, and trial design challenges unique to 
the pediatric population. 
LCZ696 is sacubitril/valsartan and has the trade name ENTRESTO. In some countries where 
ENTRESTO is approved, it is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg 
sacubitril/valsartan, but will be subsequently referred to as LCZ696 50 mg, 100 mg, 200 mg in 
this study protocol. LCZ696 is a first-in-class, angiotensin receptor neprilysin inhibitor 
treatment for chronic HF (CHF). Neprilysin (NEP) inhibition with chronic oral administration 
of LCZ696 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. LCZ696, unlike any other 
therapy for HF, provides concomitant inhibition of NEP and the angiotensin type 1 (AT1) 
receptor. The resulting increase in natriuretic peptide (NP) activity due to NEP inhibition and 
AT1 receptor blockade through renin-angiotensin-aldosterone system (RAAS) inhibition have 
complementary effects on the cardiovascular (CV) system that benefit HF patients. 
In PARADIGM-HF (CLCZ696B2314; N=8442), the pivotal Phase 3 study in adult patients 
with HF with reduced ejection fraction (HFrEF), LCZ696 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, LCZ696 
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 21% RRR (p=0.00004). PARADIGM-HF also 
showed that LCZ696 is generally safe and well tolerated in adult patients with HF (McMurray 
2014).
In both pediatric and adult HF due to systolic dysfunction, there is a decrease in systemic cardiac 
output. The pathophysiologic adaptation to decreased cardiac output for both adult and pediatric 
HF involves increased sympathetic tone and activation of the renin-angiotensin system (RAS) 
(Momma 2006). In addition, also similar to adult HF, pediatric HF results in increased 
activation of the natriuretic peptide system (Favilli 2009). This pathophysiologic neurohumoral 
activation plays a key role in the progression of HF due to systolic dysfunction in adults and 
children, and this is why heart failure management in this pediatric HF subset with systemic left 
ventricular systolic dysfunction is similar to adult HFrEF.


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This protocol focuses on studying a subset of pediatric HF with systemic left ventricular systolic
dysfunction. The rationale for studying this patient population is that it allows for examination 
of a more homogeneous pediatric HF population that also has pathophysiology similar to adult 
HFrEF where LCZ696 has demonstrated a significant mortality and morbidity benefit 
(McMurray 2014) compared to current standard of care (ACEI). In addition, for the Carvedilol 
Pediatric HF study using a related clinical endpoint as planned in this study, there was a 
potential treatment benefit in the subgroup of patients with systemic left ventricle morphology 
(Shaddy 2007).
The efficacy of LCZ696 over the standard of care enalapril for reducing mortality and morbidity 
in adult HFrEF patients provides strong rationale that LCZ696 may have clinically meaningful 
benefits for pediatric HF patients with reduced left ventricular ejection fraction (LVEF). Despite 
differences with regards to the etiology of pediatric and adult HF with systolic dysfunction (or 
reduced LVEF), there is overlap in the pathophysiology and clinical management between both 
populations. Thus, we are seeking to prospectively evaluate the effects of LCZ696 in pediatric 
patients with symptomatic systemic left ventricular systolic dysfunction.
1.2
Purpose 
The purpose of this study is to determine whether pediatric HF patients will derive greater 
clinical treatment benefit assessed by a global rank endpoint with LCZ696 compared to 
enalapril over 52-week treatment duration. This study includes two parts. Part 1 will confirm
the dose for Part 2. Part 2 will be used to assess the efficacy and safety of LCZ696 compared 
to enalapril. 
2
Study objectives and endpoints
2.1
Primary objectives
Part 1:

The primary objective is to determine the pharmacokinetics (PK) and pharmacodynamics 
(PD) of LCZ696 in pediatric HF patients
Part 2:

The primary objective is to determine whether LCZ696 is superior to enalapril for the 
treatment of HF as assessed using a global rank endpoint (described in Section 6.4) in 
pediatric HF patients
2.2
Secondary objectives
Part 1:

To assess the safety and tolerability of LCZ696 in pediatric patients with HF
Part 2:

To determine whether LCZ696 is superior to enalapril in delaying time to first occurrence 
of the composite of either Category 1 or 2 events (e.g. death, worsening HF)


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
To determine whether LCZ696 is superior to enalapril for improving NYHA/Ross 
functional class

To determine whether LCZ696 is superior to enalapril for improving the Patient Global 
Impression of Severity (PGIS) score

To characterize the population PK of LCZ696 exposure in pediatric patients with HF, 
including an assessment of steady-state sparse PK data in a subset of Group 2 patients.

To assess the safety and tolerability of LCZ696 compared to enalapril in pediatric patients 
with HF
 
 
 
2.4
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of 
Measure
Stat Analysis Section
Primary
Part 
1: 
The 
primary 
objective is to determine 
the pharmacokinetics (PK) 
and 
pharmacodynamics 
(PD) 
of 
LCZ696 
in 
pediatric HF patients
Title: PK and PD of LCZ696 after single dose
treatment
Unit of measure: PK: Cmax (ng/mL); Tmax (h); 
AUClast, AUCinf (h▪ng/mL); Cl/F (L/h); T1/2 (h); 
PD: plasma BNP, plasma NTproBNP, plasma 
cGMP, urine cGMP change from baseline 
geometric mean ratio (GMR) after single dose 
treatment
Description: Part 1 PK
assessment: The 
samples will be collected at the following 
intervals for the various age groups:

Patients ≥6 years of age: Blood 
samples  are collected at pre-dose 
(pre-dose sample for all patients), 
0.5, 1, 2, 4, 8, 10, and optional 24 
hours post dosing

Patients <6 years of age: Blood 
samples  are collected at pre-dose 
(pre-dose sample only from those 
patients who are on valsartan), 1, 2, 
Section 9.4.1, Section 
9.5.3 and, Section 9.5.4


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of 
Measure
Stat Analysis Section
4, 10, and optional 24 hours post 
dosing
Part 1 PD assessments: The blood samples 
will be collected at pre-dose, 4, 8 and optional 
24 hours post dosing. The urine samples will 
be collected at pre-dose and once between 4 
to 8 hours post dosing.
Time Frame: Single dose PK/PD visit
Part 
2: 
The 
primary 
objective is to determine 
whether 
LCZ696 
is 
superior to enalapril for 
the treatment of HF as 
assessed using a global 
rank endpoint in pediatric 
HF patients
Title: Global Rank endpoint through 52 weeks 
of treatment
Unit of Measure: The mean global rank 
endpoint does not have a unit. Patients are 
ranked from worst to best. The ranking is 
based on clinical events such as death, listing 
for urgent heart transplant, mechanical life 
support requirement at end of study, worsening 
HF, NYHA/Ross, PGIS, PedsQL physical 
functioning domain. 
Description: The effects of LCZ696 and 
enalapril will be assessed using the Global 
Rank endpoint as outlined below through 52 
weeks of double-blind treatment. The primary 
endpoint will be derived based on 5 categories 
ranking worst to best outcome:

Category 1: Death; UNOS status 1A 
listing for heart transplant or 
equivalent; VAD/ECMO/mechanical 
ventilation/intra-aortic balloon pump
requirement for life support at end of 
study

Category 2: Worsening HF (WHF); 
defined by signs and symptoms of 
WHF that requires an intensification 
of HF therapy

Category 3: Worsened; worse 
NYHA/Ross or worse Patient Global 
Impression of Severity (PGIS); and 
further ranking by PedsQL physical 
functioning domain

Category 4: Unchanged; unchanged 
NYHA/Ross and unchanged PGIS; 
and further ranking by PedsQL 
physical functioning domain 

Category 5: Improved; improved 
NYHA/Ross or improved PGIS 
(neither can be worse); and further 
ranking by PedsQL physical 
functioning domain
Section 9.4.1


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of 
Measure
Stat Analysis Section
Within each category, patients are ranked from 
worst to best based on pre-defined criteria.
Time Frame: 52 Weeks 
Secondary
To 
determine 
whether 
LCZ696 is superior to 
enalapril in delaying time 
to first occurrence of the 
composite 
of 
either 
Category 1 or 2 events 
(e.g.
death, 
worsening 
HF)
Title: Time to first occurrence of Category 1 or 
Category 2 event through 52 weeks of 
treatment
Unit of Measure: Days
Description: Time to first occurrence of 
Category 1 or Category 2 event will be 
compared for LCZ696 and enalapril through 
52 weeks of double-blind treatment
Time Frame: 52 Weeks
Section 9.5.1
To 
determine 
whether 
LCZ696 is superior to 
enalapril 
for 
improving 
NYHA/Ross 
functional 
class
Title: NYHA/Ross functional class change 
from baseline through 52 weeks of treatment
Unit of Measure: NYHA/Ross classification
Description: NYHA/Ross functional class will 
be compared through 52 weeks of double-
blind treatment
Time Frame: 52 Weeks
Section 9.5.1
To 
determine 
whether 
LCZ696 is superior to 
enalapril for improving the 
Patient Global Impression 
of Severity (PGIS) score
Title: PGIS score change from baseline 
through 52 weeks of treatment
Unit of Measure: PGIS scale
Description: PGIS scale will be compared for 
LCZ696 and enalapril through 52 weeks of 
double-blind treatment
Time Frame: 52 weeks
Section 9.5.1
To 
characterize 
the 
population PK of LCZ696 
exposure 
in 
pediatric 
patients with HF, including
an assessment of steady-
state sparse PK data in a 
subset 
of 
Group 
2 
patients. 
Title: Population PK LCZ696
Unit of Measure: ng/mL/kg, ng*h/mL/kg, 
L/h/kg, L/kg, and 1 /h
Description: During Part 2 Efficacy, population 
PK will be assessed with chronic dosing.
Population PK allows us to estimate clearance 
and total exposure.
Time frame: weeks 4, 12, 52
Title: Steady-state Sparse PK data
Unit of measure: ng/mL, ng*h/mL, and L/h/kg 
Description: During Part 2 Efficacy, a sparse 
PK assessment at steady state will be done in 
a subset of Group 2 patients which allows for 
Section 9.4.1 and Section 
9.5.1


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of 
Measure
Stat Analysis Section
an estimate clearance and total exposure to 
further confirm the target dose for this age 
group. Available BioMarker data will also be 
assessed.
Time frame: week 8 or a subsequent visit
To assess the safety and 
tolerability of LCZ696 in 
pediatric patients with HF
Title: Safety and tolerability of LCZ696 in Part 
1
Unit of Measure: Multiple
Description: Safety and tolerability including 
AEs, laboratory, vital signs 
Time Frame: Single dose PK/PD visit
Section 9.5.2
To assess the safety and 
tolerability 
of 
LCZ696 
compared to enalapril in 
pediatric patients with HF
Title: Safety and tolerability through 52 weeks 
of treatment
Unit of Measure: Multiple
Description: Safety and tolerability including 
AEs, laboratory, ECG, vital signs data through 
52 weeks of double-blind treatment
Time Frame: 52 weeks
Section 9.5.2


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3
Investigational plan
3.1
Study design
This study uses a seamless design which consists of two parts (Figure 3-1): 
Part 1: This is a multi-center, open-label, study in pediatric patients (1 month to <18 years) 
with HF (LVEF ≤ 45% or LV fractional shortening ≤22.5%). 
A screening epoch of up to 3 weeks will be used to assess eligibility. Eligible patients who 
participate in this open-label PK/PD assessment will be placed into three Groups based on age 
(Group 1: 6 to < 18 years, Group 2: 1 to < 6 years, and Group 3: 1 month to < 1 year). To ensure 
that patients are enrolled in both high and low end of the 6 to < 18 years of age group, 
approximately 50% patients will be enrolled who are 6 to 11 years of age in Group 1.
The following stepwise recruitment will be utilized: 

Group 1 (6 to < 18 years): A sample size of at least 6 patients will be prospectively 
planned to be recruited to evaluate PK and PD of LCZ696 analytes following the single 
dose administration of LCZ696 0.8 mg/kg (N=6 observations) and then the single dose 
administration of LCZ696 3.1 mg/kg (N=6 observations). The patients who receive the 
LCZ696 single dose of 0.8 mg/kg treatment will also have an option to subsequently 
receive the LCZ696 3.1 mg/kg dose. If a patient who received the LCZ696 0.8 mg/kg does 
not qualify or declines to receive the LCZ696 3.1 mg/kg dose, an additional patient will be 
recruited to receive the LCZ696 3.1 mg/kg dose.

Group 2 (1 to < 6 years): A sample size of at least 6 patients will be prospectively planned 
to be recruited to evaluate PK and PD of LCZ696 analytes following the single dose 
administration of LCZ696 0.8 mg/kg (N=6 observations) and then the single dose 
administration of LCZ696 3.1 mg/kg (N=6 observations). The patients who receive 
LCZ696 single dose of 0.8 mg/kg treatment will have an option to receive LCZ696 3.1 
mg/kg dose subsequently. If a patient who received the LCZ696 0.8 mg/kg dose does not 
qualify or declines to receive the LCZ696 3.1 mg/kg dose, an additional patient will be 
recruited to receive the LCZ696 3.1 mg/kg dose.


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
Group 3 (1 month to < 1 year): A sample size of at least 4 patients will be prospectively 
planned to be recruited to evaluate PK and PD of LCZ696 analytes following the single 
dose administration of LCZ696 0.4 mg/kg (N= approximately 4 observations) and then the 
single dose administration of LCZ696 1.6 mg/kg (N= approximately 4 observations). The 
patients who receive LCZ696 single dose of 0.4 mg/kg treatment will have an option to 
receive LCZ696 1.6 mg/kg dose subsequently. If a patient who received the LCZ696 0.4 
mg/kg dose does not qualify or declines to receive the LCZ696 1.6 mg/kg dose, an 
additional patient will be recruited to receive the LCZ696 1.6 mg/kg dose. 
Available PK/PD and safety data will be reviewed to confirm or modify the doses tested for 
each age group (Section 3.5 and Section 9.4.1).
If deemed necessary for dose determination for Part 2, additional age group 3 patients may be 
enrolled in Part 1.
Eligible patients will first receive the LCZ696 0.4 mg/kg single dose (Group 3) or 0.8 mg/kg 
single dose (Group 1 or 2). Patients must be currently treated with an ACEI or ARB (at any 
dose) at screening to be eligible for the LCZ696 0.4 mg/kg (Group 3) or 0.8 mg/kg (Group 1 
and 2) single dose.
To be eligible for the subsequent LCZ696 3.1 mg/kg dose, patients in Group 1 or 2 must be 
currently treated with a daily dose equivalent of at least enalapril 0.2 mg/kg (Table 3-1) prior 
to the LCZ696 3.1 mg/kg (Group 1 and 2) single dose assessment.
To be eligible for the subsequent LCZ696 1.6 mg/kg dose, patients in Group 3 must be currently 
treated with a daily dose equivalent of at least enalapril 0.1 mg/kg (Table 3-1) prior to the 
LCZ696 1.6 mg/kg single dose assessment.
If a patient who has completed the LCZ696 0.4 mg/kg or 0.8 mg/kg single dose does not 
participate in the LCZ696 1.6 mg/kg or 3.1 mg/kg dose, the next eligible replacement patient 
may be enrolled to directly receive the LCZ696 1.6 mg/kg or 3.1 mg/kg dose, respectively. 
The LCZ696 1.6 mg/kg or 3.1 mg/kg dose can be administered after a minimum of 5 days 
following the LCZ696 0.4 mg/kg or 0.8 mg/kg dose, respectively (to allow for washout of the 
LCZ696 analytes from the first dose).
Patients previously taking an ACEI are required to discontinue their ACEI at least 36 hours 
before the LCZ696 dose to minimize the potential risk of angioedema due to overlapping ACEI-
NEP inhibition.  Similarly, all patients who have taken LCZ696 should discontinue their 
LCZ696 at least 36 hours before taking an ACEI. Patients taking an ARB or renin inhibitor are 
required to discontinue the ARB or renin inhibitor the morning of the LCZ696 single dose visit.
After completion of the PK/PD assessment visit, patients can either be maintained on open-
label enalapril or their standard of care HF medical regimen until Part 2 (Efficacy). Patients in 
each age group can enroll in Part 2 after the target dose for that age group is determined based 
on Part 1 data for the corresponding age cohort. Patients that discontinue from Part 1 (PK/PD) 
will be allowed to screen and enroll for participation in Part 2 (Efficacy).
Part 2: This is a randomized, double blind, parallel-group, active controlled, 52-week study to 
evaluate the efficacy, safety, and tolerability of LCZ696 compared to enalapril in pediatric HF 
patients (1 month to < 18 years). A screening epoch of up to 3 weeks will be used to assess 


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eligibility. 360 eligible patients will be randomized to one of the two treatment arms (LCZ696 
vs. enalapril) and continue treatment for 52 weeks duration (see Appendix 15 for USM 
exception). Both hospitalized patients and outpatients are eligible. Chronic HF patients that are 
either previously treated for HF or newly diagnosed are eligible.
An interim efficacy analysis is planned to be performed when at least 180 patients (at least 36 
patients from each age group) have completed the study (i.e., reached a terminal endpoint or 
completed the 1 year study visit), and at least 40 patients have had an event in Category 1 or 2.
Further details about interim analyses are provided in Section 9.6.
Part 2 will stop when at least 360 patients have completed the study.
Figure 3-1
Study design
Part 1 (PK/PD) - Screening epoch
Part 1 will be conducted in selected countries and centers due to the limited number of patients 
required. At least 18 patients combining the three age groups will be enrolled. All eligible 
patients will be consented (parent/legal guardian ICF and if applicable, patient assent) at Visit 
1. A screening period of approximately up to three weeks will be used to determine if patients 


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qualify to enter the Part 1 (PK/PD) epoch. No study medication will be administered during this 
time. Both hospitalized patients and outpatients are eligible for participation.
Qualifying LVEF or LV fractional shortening assessment will be based on a locally obtained 
echocardiogram (ECHO), MRI, MUGA, or left ventricular angiogram. If a qualifying LVEF or 
fractional shortening measurement is not available, a qualifying echocardiogram measurement 
must be obtained during screening before the patient receives study treatment. The preferred 
LV function assessment is by ECHO. A MUGA, MRI or ventriculogram that is done as part of 
standard of care can be used instead of ECHO.
Screening laboratory values will be assessed by sending blood and urine samples to the local 
laboratory. Only patients with the required values per the entry criteria will be eligible to 
continue in the study. It is recommended that at Visit 1 (Part 1 PK/PD – Screening), the site 
schedule the patient’s next visit approximately one week after Visit 1.
In order to be eligible for Part 1, patients in Groups 1, 2 and 3 must be taking an ACEI/ARB (at 
any dose) prior to the single dose LCZ696 0.4 mg/kg (Group 3) or 0.8 mg/kg PK/PD assessment
(Group 1 and 2) and meet all the inclusion/exclusion criteria at Visit 1.
Patients in Group 1 and 2 must be currently treated with the equivalent of at least enalapril 0.2 
mg/kg daily dose (Table 3-1) prior to the single dose LCZ696 3.1 mg/kg and Group 3 patients 
must be treated with the equivalent of at least enalapril 0.1 mg/kg daily dose (Table 3-1) prior 
to the single dose LCZ696 1.6 mg/kg PK/PD assessment and meet all the inclusion/exclusion 
criteria at Visit 1.
Dosing will be performed with patient supine or sitting and under close observation. Enalapril 
0.1 mg/kg and 0.2 mg/kg provides similar renin angiotensin system inhibition compared to the 
LCZ696 1.6 mg/kg and 3.1 mg/kg dose being examined, respectively. If a patient is not taking 
one of the commonly prescribed ACEI/ARBs shown in Table 3-1, the Investigator may use 
his/her judgment regarding the equivalent ACEI/ARB dose based on product information, 
medical literature, medical expertise, and/or consultation with Novartis. 
Table 3-1
Part 1: PK/PD - Minimum required pre-study body-weight normalized 
daily doses of commonly prescribed ACEIs or ARBs that should be 
tolerated prior to the LCZ696 1.6 mg/kg and 3.1 mg/kg single dose 
PK/PD assessment
ACEI/ARB
Body weight 
normalized daily 
dose
Body weight normalized 
daily dose
Adult daily dose
Prior to the LCZ696 1.6 mg/kg (Group 3)
Prior to the LCZ696 3.1 mg/kg (Group 1 and 2)
Captopril
0.3 mg/kg
0.6 mg/kg
37.5 mg
Enalapril
0.1 mg/kg
0.2 mg/kg
10 mg
Enalaprilat
0.01 mg/kg
0.02 mg/kg
-
Lisinopril
0.1 mg/kg
0.2 mg/kg
10 mg
Valsartan
1.25 mg/kg
2.5 mg/kg
160 mg
Losartan
0.75 mg/kg
1.5 mg/kg
100 mg
Candesartan
0.25 mg/kg
0.5 mg/kg
32 mg


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A patient who enters screening, but is determined not to be eligible to enter Part 1 will be 
considered a screen failure. The Investigator may consider re-screening the patient for Part 1 at 
a later time if the patient’s condition has changed and they may potentially be eligible. A patient 
may be re-screened for Part 1 up to two times. A minimum of 2 weeks must elapse between re-
screenings. A patient not eligible for Part 1 (PK/PD) may also be re-screened for Part 2
(Efficacy) when Part 2 begins.
Part 1 (PK/PD) - Visits 101, 201, UNS PK/PD (if performed) – Period 1 and 2 
epoch
Visit 101 will occur approximately up to three weeks after Visit 1. Visit 201 may occur 
approximately up to three weeks after Visit 1 if patient is directly going to second dose PK 
assessment from Visit 1. 
Part 1 PK/PD assessment is conducted using three age groups (Groups 1, 2 and 3) enrolled into 
the study in a sequential and descending age group order. A single dose of LCZ696 0.4 mg/kg 
(Group 3) or 0.8 mg/kg (Groups 1 and 2) followed by a single dose of 1.6 mg/kg (Group 3) or 
3.1 mg/kg (Groups 1 and 2) will be administered for PK and PD evaluations in participating 
patients.
All patients in Part 1 will be administered the single dose of LCZ696 using the 3.125 mg 
granules. Safety, tolerability, PK and PD data will be evaluated by Sponsor and an independent 
Data Monitoring Committee (DMC). This data will be used to guide and/or confirm the dose 
level for the other age groups in Part 1 (Groups 1, 2 and 3) and the same age group in Part 2. 
Patients are required to discontinue their enalapril or other ACEI at least 36 hours before taking 
the single dose LCZ696 to minimize the potential risk of angioedema due to overlapping ACEI-
NEP inhibition. Patients taking an ARB or renin inhibitor are required to discontinue their ARB 
or renin inhibitor the morning of their single dose LCZ696 PK/PD visit.
Patients should, if possible, fast for 2 hours prior to the PK/PD assessment at Visits 101, 201,
and UNS PK/PD (if performed). Patients may eat starting at two hours after the patient is 
administered LCZ696. If the patient is not able to fast, this will be recorded and the PK/PD 
assessment will still be performed. The reason for collecting this information is to consider any 
food effect on the PK/PD assessments. All eligible patients will provide a blood sample for PK 
(Section 6.6.2) and biomarkers (Section 6.5.4.5) prior to taking any study medication. 
Additional blood and urine samples will be collected at pre-specified time points during Visit 
101, 201, and UNS PK/PD (Table 3-2). Biomarker blood samples for plasma cGMP, plasma B-
type natriuretic peptide (BNP) and plasma NTproBNP are scheduled to be collected based on
Table 3-2. Details about blood volume drawing restrictions, blood biomarker prioritization 
(given blood volume restrictions), blood volume laboratory requirements for PK/PD samples, 
sample collection, processing and storage instructions are provided in the laboratory manual.
Abbreviated chemistry laboratory samples will be obtained at the end of Visit 101, 201 and 
Unscheduled PK/PD (if performed). The number of PK/PD samples collected is dependent on 
the age group and blood volume drawing restrictions (Table 18-1). Efforts to minimize patient 
discomfort should be used when possible. To minimize discomfort and multiple needle sticks, 
pre-existing venous access may be used. Where feasible, a temporary indwelling venous 
catheter will be inserted if not already present. Local anesthetic cream may also be considered 


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for use to reduce pain and discomfort from venipuncture, if possible. The collection of the 24 
hour post-dose blood sample for PK and biomarkers is optional. 
Table 3-2
Part 1 (PK/PD) - Visit 101, 201, and UNS PK/PD blood and urine sample 
collection
Time point
Blood (PK)
Plasma 
cGMP
Plasma 
BNP
Plasma 
NTproBNP
Urine
cGMP
Group 1
≥6 yr
Groups 2 
and 3
<6 yr
Pre-dose
x
x1
x
x
x
x3
0.5 hours post-dose
x
1 hour post-dose
x
x
2 hours post-dose
x
x
4 hours post-dose
x
x
x
x
x (4-8 h)3
8 hours post-dose
x
x2
x2
10-hours post-dose
x
x
24 hours post-dose 
(optional)
x2
x2
x2
1Due to blood volume restrictions (dependent on patient weight), this sample will only be collected for 
patients taking valsartan. The sample will be used to measure the plasma concentration of the pre-
dose valsartan, if valsartan is being used by the patient prior to the single dose PK. 
2Patients with blood volume restrictions (dependent on patient weight) will not have this sample 
collected. See Laboratory manual for details about biomarker prioritization when blood volume that can 
be drawn is limited.
3 A spot urine sample will be collected at pre-dose and at any time between 4 to 8 hours post-dose.
Additional information about LCZ696 liquid formulation preparation is available in the 
(Pharmacy Manual).
AEs and vital signs will be monitored throughout the PK/PD assessment visits. Other safety 
evaluations will include abbreviated physical exam and abbreviated laboratory tests (refer to 
Table 6-1). 
For all age groups, additional single dose PK/PD assessments may be performed if deemed 
necessary for dose determination for Part 2. This will be a decision made by the Sponsor and 
the DMC (Section 9.6). Unscheduled PK/PD visits may be used for additional PK/PD 
assessments. Additional PK/PD assessments may involve new Part 1 patients, or patients who 
have completed a PK/PD assessment and agree to another PK/PD assessment.


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Part 1 (PK/PD) - Open-label enalapril or standard of care HF medical regimen 
(Visits 102 to 199 and 202 to 299) – Period 1 and 2 epoch
Visits 101 through 199 and 201 through 299 are for first PK dose and second PK dose,
respectively. 
A telephone call (Visit 102 and/or Visit 202) will occur 2 weeks after Visit 101 (first PK dose 
visit) and/or Visit 201 (second PK dose visit) for safety evaluation (refer to Table 6-1). 
Patients who have successfully completed Visit 101 and/or Visit 201 and will consent to 
participate in Part 2 (Efficacy) will take open-label enalapril or be maintained on their standard 
of care HF medical regimen (which may include captopril or other ACEI/ARB). Open-label 
enalapril visits will begin after Visit 101 and/or Visit 201 and continue until Part 2 (Efficacy) 
begins. 
All patients will be seen at the site every 12 weeks (3 months) after Visit 101 and/or Visit 201 
until Part 2 begins with monthly telephone visits in between the three month visits.
Patients taking the open-label enalapril adult formulation will come to the site for their 
scheduled visits and to receive open-label enalapril medication every 12 weeks (e.g. Visit 
105/205, 108/208, etc.). Telephone visits will occur monthly for these patients between the 
every 3 month visits (e.g. 103/203, 104/204, 106/206, etc.). Refer to Table 6-1 and Table 6-2
for assessments performed by telephone.
If needed, based on the patient’s age and/or inability to swallow tablets, liquid enalapril may be 
used. The liquid enalapril can be prepared at the site’s pharmacy and can be commercially 
sourced such as Epaned (if available).
Patients receiving liquid enalapril must return to the site for resupply at intervals dependent on 
the storage life of liquid enalapril (every 1 month; or every 2 months if Epaned (enalapril) is 
available and used, which has a 2 month shelf life). Given the burden of traveling to the site for 
the study visit for patients and families, the parent/caregiver can come to the site without the 
patient for dispensation of study drug. Delivery of study drug to the patient can also be used 
where possible and allowed per local regulations. If the parent/caregiver comes to the visit 
without the patient, a telephone call to the patient (≥6 years old) can be used in conjunction 
with the parent/caregiver visit for the visit assessments that can be performed verbally. 
Patients that discontinue from Part 1 (PK/PD) will be allowed to screen and enroll for 
participation in Part 2 (Efficacy).
Novartis or its representatives will notify Investigators once Part 1 is complete for each age 
group. At that time, patients in the completed age group will be scheduled for their final visit in 
Part 1 (PK/PD, for first dose Visit 199, for second dose Visit 299). For the patient who 
completed second dose PK/PD assessment, Visit 299 may occur on the same day as Visit 301
(Part 2 Pre-Randomization/Screening) if the patient will participate in Part 2. For the patient 
that only participated in first dose PK/PD assessment (and not second dose PK/PD assessment), 
the Visit 199 may occur on the same day as Visit 301, if the patient will participate in Part 2.
Part 2 (Efficacy) - Overview
All participating countries and centers will be eligible for Part 2 (Efficacy).


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Part 2 is a double-blind, randomized treatment epoch. Patients will receive either LCZ696 or 
enalapril, and matching placebo for enalapril or LCZ696, respectively. The target dose of 
LCZ696 for Groups 1 and 2 is dose level 4 and for Group 3 is dose level 4x, and was selected 
based on the Part 1 PK/PD results. Blinded study drug will be titrated to the target dose as 
tolerated per the safety monitoring criteria (Table 3-3) (e.g. if the patient does not experience 
adverse events that include symptomatic hypotension, worsening renal function, or 
hyperkalemia). AEs or conditions that preclude initiation or up-titration of study drug can 
include abnormalities in laboratory chemistry values based on local laboratory normal reference 
ranges and the Investigator’s judgment. Additional safety monitoring will be required for Group 
3 patients. Starting with the first dose of study medication, vital signs must be checked for up 
to 4 hours after the initial dose at each dose level (i.e. dose levels 1x through 4x, as applicable). 
Note: this does not apply for up-titrations following study drug interruptions or down-titrations 
up to the prior achieved maximal dose level). See Appendix 13 for details.
Table 3-3
Safety monitoring criteria for initiation/up-titration of study drug
Parameter
Description
Potassium level
K ≤ 5.4 mmol/L (mEq/L)
Kidney function
eGFR (calculated using the modified Schwartz 
formula) ≥ 30% mean GFR for age (Appendix 10,
Table 22-1)
Kidney function
eGFR reduction < 35% compared to 
randomization Visit 401 (Part 2). 
Blood pressure
SBP > than the calculated 5th percentile SBP for 
age as described in Appendix 4
AEs or conditions
No conditions that preclude continuation 
according to Investigator’s judgment, including 
hypotension.
Part 2 (Efficacy) - Pre-randomization/screening epoch, Visit 301
All patients will be consented for Part 2 efficacy (parent/legal guardian ICF and if applicable, 
patient assent) before any study-specific procedures are performed. All patients entering Part 2 
must fulfill all inclusion criteria and none of the exclusion criteria at Visit 301 (Part 2 Efficacy-
Pre-Randomization/Screening). Local laboratory evaluations are required to assess the patient’s 
eligibility at Visit 301 (refer to Table 6-1, Table 6-2 and Section 6.5.4). 
Patients may enter Part 2 (Efficacy) via two pathways:

Patients participating in Part 1 will be re-evaluated to assess all inclusion and exclusion 
criteria. A repeat assessment of LVEF or fractional shortening is only required if the last 
assessment of LVEF or fractional shortening was > 1 month prior to Visit 301 

Patients that did not participate in Part 1 (PK/PD) will be evaluated to assess all inclusion 
and exclusion criteria for participation in Part 2 (Efficacy). 
The screening period will be up to three weeks. No study medication will be administered 
during this time.


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Qualifying LVEF or fractional shortening measurements will be based on a locally obtained 
echocardiogram, MRI, MUGA, or left ventriculogram. If these qualifying measurements are 
not available within 1 month of Visit 301 (Part 2 Efficacy- Pre-Randomization/Screening), then 
an echocardiogram should be obtained during the screening period. 
Part 2 screening laboratory assessments should be performed locally. Only patients with the 
required values per the entry criteria will be eligible to continue in the study. 
Both hospitalized patients and outpatients are eligible for participation in Part 2 (Efficacy). A 
hospitalized patient is defined as a patient who is being treated in the hospital at the time of 
Visit 401 (Part 2 Efficacy - Randomization). An outpatient is a patient who is screened in stable 
health status and can initiate study medication intake in an ambulatory setting.
Part 2 (Efficacy) - Randomized treatment epoch (Visit 401 to Visit 416/499)
The Part 2 randomized treatment epoch begins at Visit 401. Part 2 will enroll 360 patients. 
Patients are required to discontinue their enalapril or other ACEI at least 36 hours before taking 
blinded study drug at randomization to minimize the potential risk of angioedema due to 
overlapping ACEI-NEP inhibition. Patients taking an ARB or renin inhibitor are required to 
discontinue their ARB or renin inhibitor on the day of randomization (i.e. patient should not 
have taken ARBs, or renin inhibitor on the day of randomization).
At randomization (Visit 401), patients who meet eligibility and safety criteria will be 
randomized to 1 of 2 treatment arms: double-blind enalapril bid or LCZ696 bid. The initial 
study drug dose started at randomization for Group 1 and 2 is dose level 1 or 2 (Table 3-5), and 
for Group 3 is dose level 1x or 2x (Table 3-6). Patients who are ACEI/ARB naïve or on low 
dose ACEI/ARB (dose levels 1 or 2; Table 3-4) prior to randomization should start at dose level 
1 or 1x at randomization, depending upon the age group (Table 3-5, Table 3-6). Patients who 
are on higher doses of ACEI/ARB (dose levels 3 or 4; Table 3-4) prior to randomization may
start at dose level 2 or 2x, based on age group (Table 3-5, Table 3-6). Given the patient’s 
condition is often dynamic, patients may start, depending upon the age group, on dose levels 1
or 1x or 2 or 2x at randomization based on Investigator judgement.
Patients will continue taking their background HF therapy except for ACEIs and/or ARBs, 
which are replaced by the study medication. The concomitant use of ACEIs, ARBs, or renin 
inhibitors with study medication is strictly prohibited. 
Table 3-4
Part 2 (Efficacy): Total daily dose levels of commonly prescribed 
ACEI/ARBs to guide selection of the study medication starting dose
Dose levels for 
pediatric formulation
Enalapril/Lisinopril 
total daily dose
Captopril total daily 
dose
Dose level 1
0.1 mg/kg
0.3 mg/kg
Dose level 2
0.2 mg/kg
0.6 mg/kg
Dose level 3
0.3 mg/kg
1.2 mg/kg
Dose level 4
0.4 mg/kg
1.5 mg/kg
Dose levels for adult 
formulation
Enalapril/Lisinopril 
total daily dose
Captopril total daily 
dose
Cilazapril total daily 
dose
Dose level 1
5 mg
18.75 mg
0.5 mg


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Dose level 2
10 mg
37.5 mg
1.0 mg
Dose level 3
15 mg
75 mg
2.5 mg
Dose level 4
20 mg
150 mg
5.0 mg
Dose levels for 
pediatric formulation
Valsartan total daily 
dose
Losartan total daily 
dose
Candesartan total 
daily dose
Dose level 1
0.7 mg/kg
0.4 mg/kg
0.2 mg/kg
Dose level 2
1.4 mg/kg
0.7 mg/kg
0.25 mg/kg
Dose level 3
2.0 mg/kg
1.0 mg/kg
0.32 mg/kg
Dose level 4
2.7 mg/kg
1.4 mg/kg
0.64 mg/kg
Dose levels for adult 
formulation
Valsartan total daily 
dose
Losartan total daily 
dose
Candesartan total 
daily dose
Dose level 1
40 mg
25 mg
4 mg
Dose level 2
80 mg
50 mg
8 mg
Dose level 3
160 mg
75 mg
16 mg
Dose level 4
320 mg
100 mg
32 mg
For age groups 1 and 2, the target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose) 
with a maximum dose of 10 mg bid (20 mg total daily dose). For age groups 1 and 2, the target 
dose for LCZ696 is projected to be 3.1 mg/kg bid. Based on the PK/PD results from Part 1 for 
Group 3 patients, the target dose for LCZ696 (dose level 4x) will be 2.3 mg/kg bid. In addition, 
for Group 3 patients who turn 1 year old during the study, consideration should be given to up-
titrate to a dose of 3.1 mg/kg bid (dose level 5x). See Appendix 14 for details. The LCZ696
dose is not to exceed 200 mg bid irrespective of the body weight (Table 3-5, Table 3-6). The 
actual target dose (dose level 4 or 4x, depending upon age group) and lower dose levels (1, 2, 
3 or 1x, 2x, 3x, depending upon age group) of LCZ696 for Part 2 were determined based on PK 
and PD results from Part 1 of the study. 
Study drug is titrated to target dose level 4 for Group 1 and 2, or to target dose level 4x for 
Group 3, as tolerated based on the safety monitoring criteria approximately every 2 weeks 
beginning at Visit 401 (Part 2 Efficacy – Randomization) and continuing at Visits 402 and 403
(Table 3-3). Investigators have the option to schedule a patient for an additional visit (Visit 404; 
6 weeks post-randomization) in order to complete the titration to the target dose. Additional 
safety monitoring will be required for Group 3 patients. Starting with the first dose of study 
medication, vital signs must be checked for up to 4 hours after the initial dose at each dose level 
(i.e. dose levels 1x through 4x, as applicable). Note: this does not apply for up-titrations 
following study drug interruptions or down-titrations up to the prior achieved maximal dose 
level) See Appendix 13 for details. Unscheduled visits may be necessary to assess the patient 
and/or adjust study medication as needed. Group 3 patients who turn 1 year old during the study 
and for whom study drug is to be up-titrated based on the safety monitoring criteria, a scheduled 
or unscheduled visit may be used for these up-titration visits. See Appendix 14 for details.
Single PK samples will be collected during Part 2 (Efficacy) at the following visits: Visit 403, 
Visit 406, and Visit 416/499 (Week 52/End of Study) (see Appendix 15 for USM exception).
Additional samples for PK may be considered if patient has an unscheduled visit. 
In approximately 24 Group 2 patients, sparse PK blood samples will be collected at steady-state 
at 3 time-points on the same day, at Visit 405 or at a subsequent scheduled or unscheduled visit


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(except visits 406 and 416/499), when the patient is on Dose-Level 4 or at his/her highest 
tolerated dose for at least 1 week. Refer to Section 6.6.2 for additional PK information.
To assess the patient’s eligibility to titrate to the next dose level, local laboratories should be 
used. 
Table 3-5
Part 2 (Efficacy): Study drug dose levels for double-blind enalapril and 
LCZ696 for age groups 1 and 2
Dose levels for pediatric 
formulation
Enalapril dose
LCZ696 dose †
Dose level 1
0.05 mg/kg bid.
0.8 mg/kg bid.
Dose level 2
0.1 mg/kg bid.
1.6 mg/kg bid.
Dose level 3
0.15 mg/kg bid.
2.3 mg/kg bid.
Dose level 4
0.2 mg/kg bid.
3.1 mg/kg bid.
Dose levels for adult 
formulation
Enalapril dose
LCZ696 dose †
Dose level 1
2.5 mg bid.
50 mg bid.
Dose level 2
5 mg bid.
100 mg bid.
Dose level 3
7.5 mg bid.
150 mg bid.
Dose level 4
10 mg bid.
200 mg bid.
†Note: LCZ696 target dose (dose level 4) and other dose levels shown in table are based on target 
dose of LCZ696 3.1 mg/kg bid. LCZ696 target dose has been verified by Part 1 PK/PD.
Table 3-6
Part 2(Efficacy): Study drug dose levels for double-blind enalapril and 
LCZ696 for age group 3
Dose levels for pediatric 
formulation
Enalapril dose
LCZ696 dose †
Dose level 1x
0.05 mg/kg bid.
0.8 mg/kg bid.
Dose level 2x
0.075 mg/kg bid.
1.2 mg/kg bid.
Dose level 3x
0.1 mg/kg bid.
1.6 mg/kg bid.
Dose level 4x
0.15 mg/kg bid.
2.3 mg/kg bid.
†Note: LCZ696 target dose 2.3 mg/kg (dose level 4x) is based on Part 1 PK/PD Safety data. The other 
dose levels for LCZ696 shown in table are based on target dose of LCZ696 2.3 mg/kg bid and Part 1 
PK/PD Safety data. For Group 3 patients who turn 1 year old during the study, consideration should be 
given to up-titrate to a dose of 3.1 mg/kg bid (Dose Level 5x). See Appendix 14 for details.
Randomized, ongoing, Part 2 Age Group 3 patients (i.e. patients who are 1 month to <1 year 
old at randomization) who are safely tolerating Dose Level 4x (i.e. LCZ696/Placebo, 2.3 mg/kg 
bid / Enalapril/Placebo 0.15 mg/kg bid) for at least 2 weeks, and who turn 1 year old during the 
study, may be up-titrated to Dose Level 5x (LCZ696/Placebo, 3.1 mg/kg bid / Enalapril/Placebo 
0.2 mg/kg bid), if it is the patient’s best interest to be up-titrated based on the medical judgement 
of the investigator. See Appendix 14, Table 26-1 for Dose Level 5x up-titration information for
Age Group 3 patients.
Study drug dose level adjustments should be based on overall safety and tolerability. Patients 
should be titrated to the next dose level if there is no symptomatic hypotension, hyperkalemia, 
worsening renal function, or other AEs per the Investigator’s judgment as shown in Table 3-3.


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Additional safety monitoring will be required for Group 3 patients with each initial dose level 
up-titration. See Appendix 13 for details.
Every attempt should be made to achieve and maintain patients on the target study drug dose 
level throughout Part 2 (Efficacy). If, in the opinion of the Investigator, the patient does not 
tolerate the assigned study medication, the Investigator should consider whether non-disease-
modifying medication (e.g. calcium channel blockers, diuretics, α-blockers) can be reduced to 
rectify the situation. The Investigator may adjust doses of disease-modifying medications (e.g.
beta-blockers, aldosterone antagonists) if it is believed that they are the most likely cause of the 
adverse effect. If adjustment/elimination of concomitant medications is not possible or does not 
alleviate the side effects of concern, the Investigator may down-titrate or interrupt the study 
drug. Refer to Section 5.5.5 for guidance on permitted study drug dose adjustments and 
interruptions. If the reason for a dose adjustment is due to an adverse event, an adverse event 
should be reported.
At each visit after randomization (Part 2 Efficacy - Visit 401), the patient’s medication 
compliance, safety, and tolerability of the study medication are assessed. This will include, but 
not be limited to signs and symptoms of hypotension, serum potassium level, and renal function. 
Patients who experience angioedema as determined by the Investigator at any time during the 
double-blind epoch must be discontinued from the study.
Both scheduled and unscheduled visits can be utilized for up-titration/down-titration throughout 
the study based on Investigator judgment (Section 5.5.5) for re-evaluation of safety criteria 
parameters and study drug management.
3.2
Rationale for study design
The patient population will be described in more detail in Section 4 below.
The study is comprised of two parts combined into a seamless design: 

Part 1: PK and PD assessments to determine the LCZ696 dose for Part 2

Part 2: 52-week efficacy and safety assessments
The purpose of this design is to improve study efficiency compared to a sequential approach 
involving two separate studies. 
3.3
Rationale for Global Rank primary endpoint
There is no agreed upon, validated clinical efficacy endpoint for this patient population. In 
addition, the low prevalence of HF in children limits the possibility to conduct large outcome 
trials. The Global Rank primary endpoint is developed based on Packer’s composite score to 
assess the totality of the interventions. Packer’s composite score has been widely used in 
cardiovascular clinical trials (Packer 2001) including ularitide TRUE-AHF (Anker 2015, Chang 
2015). Packer’s composite score classifies patients into three categories: worsened, unchanged, 
and improved. Similarly, a clinical composite endpoint with three categories (worsened, neither 
worsened nor improved, and improved) was also used in the Carvedilol Pediatric HF study
(Shaddy 2007). 
The primary endpoint for this LCZ696 pediatric HF study uses a Global Rank endpoint that 
builds on Packer’s composite score with a methodology that further differentiates patients 


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between treatment groups (Felker 2010, Sun 2012). The Global Rank endpoint rank orders 
patients from worst to best using: (a) objective outcome events of death, listing for urgent heart 
transplant or mechanical support; (b) events of worsening HF; and (c) measures of functional 
assessment (NYHA/Ross) and patient reported outcomes: Patient Global Impression of Severity 
(PGIS) and the PedsQL (physical functioning subgroup of questions). Thus, the global ranked 
endpoint encompasses important clinical events grouped into broadly agreed categories of 
severity from mortality to disease progression (worsening HF) to measures of symptoms and 
physical functioning. This global rank endpoint for this study has been developed with input 
and endorsement by world leading pediatric heart failure experts.
The effects of LCZ696 and enalapril will be assessed after 52 weeks of double-blind treatment
using the Global Rank endpoint algorithm (as outlined in Table 6-3) (see Appendix 15 for USM 
exception). Clinical events that are potential endpoints for Categories 1 and 2 (described below) 
will be adjudicated by a blinded, external adjudication committee.
Classification of patients in the global rank endpoint according to severity

Category 1: Death; UNOS status 1A listing for heart transplant or equivalent; 
VAD/ECMO/mechanical ventilation/intra-aortic balloon pump requirement for life 
support at end of study
Reducing Category 1 endpoints such as death is a major goal for treating pediatric HF. HF 
transplant is a major therapy and treatment of last resort for pediatric HF. Listing for urgent HF 
transplant instead of the heart transplant itself is used for the time to event analysis given the 
assumptions that these patients would die without an imminent heart transplant and that the 
duration waiting for a heart transplant is dependent on the availability of the donor heart. Urgent 
HF transplant is defined as UNOS status 1A or equivalent where the patient must be in the 
intensive care unit on intravenous inotropic medications and/or mechanical life support. The 
requirement for mechanical life support (VAD, ECMO, mechanical ventilation, intra-aortic 
balloon pump) at the end of the study is also Category 1. In this case, the patient would die or 
need a heart transplant if removed from this mechanical support to qualify for Category 1. Death 
and other Category 1 events should be modifiable by treatments that improve HF. Within 
Category 1, the patients will be ranked by time to first event.

Category 2: Worsening HF (WHF); defined by signs and symptoms of WHF that requires 
an intensification of HF therapy
There is general agreement that reducing WHF is a major goal for treating pediatric HF. 
Inpatient and outpatient WHF events reflect disease-specific endpoints related to progressive 
worsening of the HF syndrome. These WHF events should be modifiable by treatments that 
improve this condition. 
WHF is defined as new or worsening symptoms and signs of heart failure that requires 
intensification of HF therapy (Section 6.4.1). Within Category 2, the events will be classified 
into 3 subcategories from worst to best:

Worsening HF hospitalization with intensive care unit (ICU) stay

Worsening HF hospitalization without ICU stay


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
Worsening HF without hospitalization
Within Category 2, the patients will be ranked first by event subcategory, and then by number 
of events within each subcategory. Further ranking will be performed by time to first event in 
the worst subcategory.
Patients who do not have a clinical event that qualifies for Categories 1 or 2 will be placed into 
Categories 3, 4, and 5 (refer to Table 6-3).

Category 3: Worsened; worse NYHA/Ross or worse Patient Global Impression of 
Severity (PGIS); and further ranking by PedsQL physical functioning domain

Category 4: Unchanged; unchanged NYHA/Ross and unchanged PGIS; and further 
ranking by PedsQL physical functioning domain

Category 5: Improved; improved NYHA/Ross or improved PGIS (neither can be worse); 
and further ranking by PedsQL physical functioning domain
The hypothesis is that LCZ696 will improve functional capacity (NYHA/Ross) and HF 
symptoms (PGIS) and that these two phenotypic characteristics are interrelated (Figure 3-2).
NYHA/Ross
The impact of study drug on the patient’s physical functional status will be assessed using the 
NYHA classification I-IV (older children: 6 to < 18 years old) or Ross HF classification I-IV 
(younger children: l month to < 6 old year). The NYHA and Ross functional class assessments 
are reliable instruments for rating HF patients’ functionality (Criteria Committee NYHA 1994, 
Ross 1992, Packer 2001, Rosenthal 2004). 


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Figure 3-2
Global rank endpoint categories 3, 4, 5 
Patient Global Impression of Severity (PGIS)
The impact of study drug on the patient’s heart failure symptomatic status will be assessed using 
the PGIS which is a static global impression of severity question that will be used to capture the 
patients’ current health status relative to their heart failure over a 7 days recall period. 

Patient (7 to < 18 years old): How would you describe the severity of your heart failure 
symptoms over the past 7 days? (None / Mild / Moderate / Severe / Very Severe) [5-
point response scale]

Parent (for < 5 years old patients): How would you describe the severity of your child’s 
heart failure symptoms over the past 7 days? (None / Mild / Moderate / Severe / Very 
Severe) [5-point response scale]

Patient (5 to < 7 years old): Point to the one face that best shows how your heart problems 
have been over the last 7 days? (Good / Neither Good nor Bad / Bad) [3-point scale]
The PGIS uses a 5-point patient evaluation scale for patients ≥7 years. A 5-point evaluation 
scale is used for parent/caregivers for patients < 5 years of age. A 3-point faces scale will be 
used for patient self-report by children 5 to < 7 years. 
For the Global Rank primary endpoint, a one class change in the PGIS is considered to represent 
a clinically significant change. The parent/caregiver PGIS report will only be used for the 
Global Rank endpoint for patients < 5 years old. The patient PGIS report will be used for the 
Global Rank endpoint for patients ≥5 years old. For additional information, refer to Section 
6.6.1.2 and Appendix 8.
Categories 3, 4, 5 are ranked first on a combination of two measures of efficacy: NYHA/Ross 
functional class and the PGIS. Both measures are simple, comprehensive, and complementary. 
Worsened is defined as worsening in heart failure functional class (NYHA/ Ross heart failure 
classification) at the last reported observation; or worsening of PGIS score at the last reported 


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observation. Improved is defined as a condition that is not worsening, and demonstrating
improvement in heart failure functional class at the last reported observation, and/or 
improvement in PGIS score at last reported observation. Unchanged is defined as neither 
improving nor worsening for both NYHA/Ross and PGIS. 
PedsQL physical functioning domain
Further ranking within Categories 3, 4, 5 as needed (‘tie breaking’) will be based on a subset of 
5 physical functioning domain questions of the PedsQL score (for Group 1 patients 6  to < 18 
years old). For example, patients who are equally ranked based on the NYHA/Ross and the 
PGIS will be further ordered from worst to best by the PedsQL physical functioning assessment. 
The physical functioning domain of questions from the PedsQL focuses on proximal effects of 
health-related quality of life related to heart failure (refer to Section 6.6.1.2 and Appendix 9).
The PedsQL physical functioning domain will only be used for the primary endpoint for Group 
1 since the same age-specific version of the patient-reported PedsQL will be collected for all 
patients in Group 1 (and this does not occur for Groups 2 and 3).
For the duration of Part 2, the same PedsQL, NYHA and Ross instruments based on the age at 
randomization should be used.
3.4
Rationale for patient population
Pediatric heart failure differs from adult HF as it is more heterogeneous and has a different 
etiology. Pediatric HF can be due to: volume overload of the ventricle with preserved systolic 
function (e.g. left to right shunt), pressure overload, persistent arrhythmias, dilated 
cardiomyopathy and systemic disorders that affect myocardial contractile function (Chaturvedi 
2009). This study focuses on studying a subset of pediatric HF with systemic left ventricular 
dysfunction. The rationale for studying this patient population is that it allows for examination 
of a more homogeneous pediatric HF population that also has pathophysiology similar to adult 
HFrEF where LCZ696 has demonstrated a significant mortality and morbidity benefit 
(McMurray 2014) compared to current standard of care (ACEI). In addition, for the Carvedilol 
Pediatric HF study which uses a clinical endpoint similar to this study, there was a potential 
treatment benefit in the subgroup of patients with systemic left ventricle morphology (Shaddy 
2007). When underlying ventricular morphology was taken into account in the Carvedilol 
Pediatric HF study, a significant interaction was seen between treatment and ventricular 
morphology (p=0.02) indicating a possible differential effect of treatment between patients with 
a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left 
ventricle (non-beneficial trend) (Shaddy 2007). 
Numerous small observational studies in children 1.5 days to < 18 years old have suggested that 
ACE inhibition benefits patients with HF caused by systemic ventricular systolic dysfunction, 
left to right shunt, congenital heart disease, and valvular regurgitation (Leversha 1994, 
Rosenthal 2004, Momma 2006). However, the use of ACEI and ARBs in infants with single-
ventricle physiology and adults with systemic right ventricle resulted in no significant benefit 
(Hechter 2001, Dore 2005, Hsu and Pearson 2009b, van der Bom 2013). 
In view of (1) a potential differential effect systemic ventricular morphology may have on 
outcomes (based on the Carvedilol Pediatric HF study ) and (2) studies in children suggesting 
benefit from ACEI in HF due to systemic left ventricular systolic dysfunction but no benefit 


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from ACEI or ARB treatment in HF due to single ventricle or systemic right ventricle 
anatomy/physiology (Bengur 1991, Lewis 1993, Hechter 2001, Rosenthal 2004, Lipshultz 2003, 
Dore 2005, Duboc 2005 and 2007, Hsu and Pearson 2009b, van der Bom 2013), this study will 
examine a more homogeneous population with biventricular hearts and HF due to systemic left 
ventricle with decreased EF. Such an approach will result in a patient population that resembles 
more closely the adult HF population in which LCZ696 has been shown to be more effective 
than enalapril in reducing mortality, HF hospitalization and improving symptoms in patients 
with HF.
Given the concern that use of a RAS blocker may affect kidney development based on 
preclinical rat toxicity studies, children < 1 month old (full term infant) (or < 44 weeks post 
conception for pre-term infant) are excluded from the study. Thus, the study population is 1 
month (or ≥ 44 weeks post conception for pre-term infants) to < 18 years old.
3.5
Rationale for dose/regimen, route of administration and duration 
of treatment
Rationale for dose selection
The approach for dose selection examines safety, PK, and PD responses following 
administration of two doses equivalent to adult LCZ696 50 mg (lowest) and 200 mg (highest) 
doses, respectively. The objective is to select a dose that provides similar exposures of LCZ696 
analytes to that observed in adult heart failure patients and that maximizes neprilysin inhibition.
The PD effect of neprilysin inhibition in children will be assessed through the measurement of 
urine and plasma biomarkers.
For the estimation of precision for pharmacokinetic parameters, data obtained from both dose 
levels will be pooled as pharmacokinetics of LCZ696 analytes is dose-independent (dose 
linearity has been established). Dose-exposure response for pharmacodynamics parameters will 
be compared with available adult data.
Rationale for dose/regimen
Part 1 (PK/PD)
Part 1 (PK/PD) was designed with safety of the trial subjects in mind, sequentially exposing 
older and then younger age groups to LCZ696: 

The dose of LCZ696 0.8 mg/kg corresponds to the LCZ696 50 mg dose for adult subjects
with a body weight of 65 kg. Furthermore, the LCZ696 50 mg dose is the recommended 
starting dose for adult HF patients who are ACEI/ARB naïve, on a low dose of 
ACEI/ARB treatment, have severe renal impairment, or have moderate hepatic 
impairment. The LCZ696 0.8 mg/kg dose delivers valsartan exposure bioequivalent of 0.6 
mg/kg valsartan which is below the starting dose for valsartan in pediatric hypertension 
(1.3 mg/kg). LCZ696 0.8 mg/kg is also expected to have similar tolerability as enalapril 
0.05 mg/kg which is below the recommended daily starting dose of enalapril for pediatric 
heart failure. Note that enalapril doses ranging from 0.1 to 0.5 mg/kg/day are used in the 
treatment of pediatric HF. 


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
To further ensure patient safety, patients must be treated with an ACEI or ARB prior to 
screening. Patients in Group 1 and 2 must be currently treated with a daily dose equivalent 
of at least enalapril 0.2 mg/kg (Table 3-1) prior to the LCZ696 3.1 mg/kg single dose 
assessment, and patients in Group 3 must be currently treated with a daily dose equivalent 
of at least enalapril 0.1 mg/kg (Table 3-1) prior to the LCZ696 1.6 mg/kg single dose 
assessment. For those patients who participated, the LCZ696 0.4 mg/kg or 0.8 mg/kg
single dose assessment must have been tolerated in order to participate in the LCZ696 1.6 
mg/kg or 3.1 mg/kg single dose assessment. 

The LCZ696 3.1 mg/kg dose corresponds to the LCZ696 200 mg dose in adult subjects of 
65 kg body weight. In adult HF patients, no significant impact of body weight on the PK 
of LCZ696 analytes was observed over a range of 41.5 kg to 157.3 kg. Therefore, for 
patients in this weight range, LCZ696 3.1 mg/kg is expected to have similar exposure to 
that observed in adult heart failure patients

Furthermore, simulations using physiologically based PK (PBPK) models and allometric 
scaling techniques indicate exposure similarity between pediatric patients (6 to < 18 years
old) and adult HF patients.

The proposed maximum LCZ696 dose of 3.1 mg/kg delivers valsartan exposure similar to
that observed with 160 mg valsartan marketed tablets which is the target dose 
administered twice daily in adult HF patients. Valsartan at a 2.0 mg/kg dose administered 
orally was studied in children 1 to 16 years old with hypertension (Blumer 2009). In this 
study, with patients (1 – 16 years old) valsartan exposure (Cmax and AUC) did not vary 
significantly with age. The body weight-adjusted CL/F values were also comparable 
across the 1-16 year old children and were similar to those observed in adult subjects.

It should be noted that the LCZ696 3.1 mg/kg single dose for Part 1 (PK/PD) is half the 
LCZ696 200 mg bid (or pediatric equivalent 3.1 mg/kg bid target dose) maximal daily 
dose in Part 2 (Efficacy).

The dose for Group 2 (1 to < 6 years) may be adjusted depending on safety, PK, and PD 
information from Group 1. In Group 2 (1 to < 6 years), the projection is to similarly 
evaluate the LCZ696 0.8 mg/kg and 3.1 mg/kg doses. 

The dose for Group 3 (1 month to <1 year) may be adjusted depending on safety, PK, and 
PD information from Groups 1 and 2. Since the physiologically based pharmacokinetic 
modeling (PBPK) simulations predicts higher exposure in Group 3 (1 month to < 1 year)
compared to older ages, the projection is to evaluate the LCZ696 0.4 mg/kg and 1.6 mg/kg
dose in Group 3.
Safety will be closely monitored during Part 1 of the study. Dosing will be performed in an 
experienced pediatric clinical unit setting with close observation, and patient supine/sitting. 
Part 2 (Efficacy)
For Part 2 randomization, patients are assigned in a blinded manner to enalapril or LCZ696. 
The target dose and dose regimens are outlined in Table 3-5 and Table 3-6. Based on Part 1 
data, the target dose for Group 3 has been increased from the originally planned 1.6 mg/kg to 
2.3 mg/kg as observed exposures in Part 1 Group 3 patients were lower than initially expected. 
The study drug is uptitrated to the target dose  at 2 week intervals, as tolerated. Safety criteria 


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for dose escalation are provided in Table 3-3. The patient should achieve the target dose (dose 
level 4 or 4x, depending upon the age group) by Visit 403 or optional Visit 404 if tolerated. 
Additional safety monitoring for hypotension is required for Group 3 patients with each initial 
dose level up-titration. See Appendix 13 for details. Both scheduled and unscheduled visits can 
be utilized for up-titration/down-titration throughout the study based on Investigator judgment.
The rationale for the projected target dose of LCZ696 3.1 mg/kg bid for Groups 1 and 2 in Part 
2 of the study are:

LCZ696 3.1 mg/kg bid is expected to be consistent with the adult dose target of 200 mg 
bid 

Simulations using physiologically based PK models and allometric scaling techniques 
indicated that a dose of 3.1 mg/kg in pediatric patients of age > 2 years provides similar 
exposure to that observed in adult heart failure patients, therefore justifying administration 
of 3.1 mg/kg in 6 to <18 years age group
The LCZ696 doses used in Part 2 (Efficacy) will be confirmed based on the observed PK, PD
and safety data obtained from Part 1 of the study.
Rationale for duration of treatment
The rationale for the 52-week treatment duration is based on the positive LCZ696 treatment 
effect for relevant clinical endpoints that were evident as early as 4 to 6 months treatment 
duration in the LCZ696 adult PARADIGM-HF study. The 52-week treatment duration will also 
increase the number of clinical events in Categories 1 and 2.

There was a sustained separation of Kaplan-Meier survival curves as early as 6 months for 
the primary composite endpoint consisting of cardiovascular death and time to first HF 
hospitalization.

At four months compared to baseline, there was less worsening of HF symptoms and 
physical limitations compared to enalapril as measured by the KCCQ (p=0.0423).

At four months, there were more improved patients with the Global Assessment, and 
fewer worsened patients for both NYHA and the Global Assessment for the LCZ696 
group compared to the enalapril group (NYHA, p=0.0028; Global Assessment, p=0.0039).
Safety areas of interest such as hypotension, hyperkalemia, renal impairment, angioedema, and 
liver toxicity can be assessed in the 52 week period based on experience from the adult LCZ696 
HF studies.
The study duration will provide 1 year (52 weeks) growth and safety data in growing children.
3.6
Rationale for choice of comparator
Enalapril has been chosen as the comparator as it is the most commonly used renin angiotensin 
system (RAS) blocker in children with HF (The Report on the Expert Group Meeting of 
Pediatric Heart Failure, London, 29 November 2010 (EMA/112144/2011)). Additionally, 
enalapril is considered the standard of care in the treatment of chronic heart failure in most 
geographic areas. Enalapril doses ranging from 0.1 to 0.5 mg/kg/day are used in the treatment 
of pediatric HF.


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The dose of 0.4 mg/kg/day was the target dose in the “Enalapril in infants with single ventricle” 
study published (Hsu 2010), and is the target dose in the ongoing “The labeling of enalapril 
from neonates up to adolescents”, or LENA Study (http://www.lena-med.eu).
In addition, enalapril has a twice daily dosing regimen similar to LCZ696. Two other commonly 
used ACEIs in pediatric HF are captopril and lisinopril. However captopril is typically dosed 
three times daily and lisinopril is typically dosed once daily. 
3.7
Purpose and timing of interim analyses/design adaptations
In Part 1, a review of PK/PD and safety data will be performed for Group 1 and 2 after both 
doses (LCZ696 0.8 mg/kg and 3.1 mg/kg) are administered. For Group 3, this analysis will be 
conducted after both doses (LCZ696 0.4 mg/kg and 1.6 mg/kg) are administered.
The dosing of each corresponding age group can begin in Part 2 after the dose has been
confirmed from Part 1 for that age group. Based on Part 1, these dose regimens may also be 
adjusted. To determine the LCZ696 dose for Part 2: (1) the exposure normalized to dose/body 
weight of pharmacologically active LCZ696 analytes (LBQ657, valsartan) will be compared 
between pediatric patients and adult HF patients; and (2) the exposure-response will be 
examined for neprilysin pharmacodynamic effect.
Interim efficacy analysis of the global rank endpoint
In Part 2 (Efficacy), an interim efficacy analysis and futility analysis is planned when at least 
180 patients (at least 36 patients from each age group) have completed the study (i.e., reached 
a terminal endpoint or completed the 1 year study visit), and at least 40 patients have had an 
event in Category 1 or 2. This interim analysis will be done to allow for early stopping of the 
study in the event that efficacy is observed at the time of the interim analysis or in the event 
that the study is unlikely to demonstrate a benefit for patients. 
In addition, an analysis of sparse PK data collected in a subset of patients in Part 2 Age Group 
2, is planned (see Section 9.6 for details).
 
 
 
 
 
 
3.8
Risks and benefits 
The study will assess the efficacy of LCZ696 in pediatric HF patients. To date no trial has 
demonstrated an outcome benefit of any pharmacotherapy in children with HF. Little progress 
has been made in improving the significant mortality and morbidity associated with 
symptomatic heart failure. In the 1980s, 1-year mortality rates in pediatric HF rates were 20% 


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to 30%, reaching 40% by 5 years. The advent of pediatric heart transplantation has decreased 
mortality in the first year after presentation but only where available (Hsu and Pearson 2009b). 
The mortality and morbidity benefit of LCZ696 compared to the standard of care enalapril for 
the treatment of adult HF with reduced systolic function (HFrEF) is evident from the 
PARADIGM-HF study. Clinical trial data in adults demonstrate that LCZ696 has an overall 
safety profile generally comparable to other RAS inhibiting agents. Hypotension, hyperkalemia, 
renal impairment and angioedema have been identified as possible safety risks in LCZ696 
studies. While the incidence rate of hypotension in study CLCZ696B2314 was higher for 
LCZ696 compared with enalapril, hypotension assessed as severe or serious was not higher in 
the LCZ696 group compared to the enalapril group. Also, no major difference was observed for 
hypotension leading to study drug discontinuation .In contrast, the incidence of hyperkalemia, 
renal impairment and cough was numerically lower in the LCZ696 group compared to the 
enalapril group in study CLCZ696B2314. 
In the PANORAMA-HF study, two patients in the high dose group (1.6 mg/kg) of Part 1 Age 
Group 3 experienced AEs of hypotension. While the risk for hypotension may be lower for this 
age group in Part 2 of the study where study drug will be up-titrated in a step-wise manner 
compared to the single, high-dose setting in Part 1, additional safety measures have been 
implemented in an effort to decrease the risk of, and to monitor for, hypotension in Part 2 Age 
Group 3 patients: (1) lower target dose compared to Age Groups 1 and 2 despite similar 
observed exposures adjusted for dose in Part 1; (2) smaller up-titration steps compared to Age 
Groups 1 and 2; (3) a 4 hour observation period following the initial dose at each dose level to 
monitor vital signs; and (4) an additional phone call at 3 days (+/- 1 day) after each initial dose 
level up-titration step in order to check for symptoms of hypotension.
Results of juvenile studies with valsartan in rats have identified kidney and bone as potential 
targets for adverse effects associated with LCZ696 administration. Renal changes observed in 
rats treated with valsartan are consistent with those observed for other compounds which 
interact with RAAS, and occurred as a result of valsartan administration during a critical period 
of renal development (i.e. completed by post-natal weeks 4-6 weeks) (Zoetis 2003). 
Corresponding renal development is complete in the human by ~35-36 weeks of gestation, 
occasionally extending to 44 weeks. 
Results of juvenile rat studies with sacubitril demonstrated minimal bone changes that are 
considered possibly due to associated body weight reductions. These changes were not 
associated with any changes in bone strength, matrix or growth plate. These findings also did 
not adversely affect the health of the animal. The non-clinical findings described do not 
demonstrate safety findings that preclude studying LCZ696 in the proposed pediatric HF 
population.
In addition, neprilysin is one of multiple pathways involved in the clearance of amyloid β
peptide from the brain and CSF. In a study in young cynomolgus monkeys, administration of 
LCZ696 for 2 weeks resulted in increased total cerebrospinal fluid levels of amyloid β 1-42, 1-
40 and 1-38. In this study, there were no changes in amyloid β levels in brain tissue. There was 
also no evidence for brain amyloid β deposition and plaque formation in a 39-week study in 
cynomolgus monkeys with a dose of LCZ696 that was 6-fold higher than the dose used in the 
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In contrast to the non-clinical study, administration of LCZ696 400 mg once daily for 14 days 
in healthy subjects did not result in changes in cerebrospinal fluid concentrations of amyloid β
1-40 and 1-42, although there was an increase in amyloid β 1-38. The clinical relevance of the 
small increase in CSF Aβ1-38 observed with LCZ696 is unknown. These observations suggest 
that enzymes and disposition pathways other than neprilysin appear to be more important in 
clearance of CSF Aβ in humans. There was also no increased incidence of cognition- or 
dementia-related AEs in the LCZ696 clinical program with up to 5 year LCZ696 exposure in 
the PARADIGM-HF study. The clinical implication of pharmacological changes in CSF 
amyloid β metabolism is unknown (Ryman 2014). Increased CSF amyloid β levels found in
Down’s syndrome patients (Schupf 2002) and associated with specific familial Alzheimer’s 
disease mutations are not associated with dementia symptoms until late in life (> 40 – 50 years 
old) (Wang 2006).
Given the significant morbidity and mortality of pediatric HF patients and the context of the 
current data and knowledge of this issue, the benefit risk assessment is considered to be positive. 
To mitigate potential risks in pediatric study participants, safety parameters will be monitored 
closely, and these parameters will include vital signs, physical exam (including height and 
weight), biomarkers, hematology, blood chemistry, urinalysis tests and ECG.
4
Population
The study population consists of pediatric HF patients 1 month to < 18 years, inpatient or 
outpatient, with systemic left ventricle systolic dysfunction (LVEF ≤45% or a fractional 
shortening ≤22.5%). For inclusion criteria details regarding LVEF and fractional shortening, 
refer to Section 4.1. The study will enroll at least 18 patients in Part 1 and 360 patients in Part 
2 (Efficacy) at centers worldwide. With an expected screen failure rate of 35% for both Part 1 
(PK/PD) and Part 2 (Efficacy), it is estimated that approximately 46 patients will have to be 
screened for Part 1 and 554 patients will have to be screened for Part 2.
For Part 1, at least 18 subjects will be divided across three groups based on age: Group 1: 6 to
< 18 years (6 observations for the LCZ696 0.8 mg/kg dose and 6 observations for the LCZ696 
3.1 mg/kg dose); Group 2: 1 to < 6 years (6 observations for the LCZ696 0.8 mg/kg dose and 
6 observations for the LCZ696 3.1 mg/kg dose); Group 3: 1 month to < 1 year ( approximately 
4 observations for LCZ696 -0.4 mg/kg dose and approximately 4 observations for the LCZ696 
1.6 mg/kg dose). Eligible patients will participate in the LCZ696 0.8 mg/kg and 3.1 mg/kg doses 
in Groups 1 and 2 and in the LCZ696 0.4 mg/kg and 1.6 mg/kg doses in Group 3.  Patients who 
do not participate in the LCZ696 3.1 mg/kg (Group 1 or 2) or 1.6 mg/kg (Group 3) dose will be 
replaced. To ensure that patients are enrolled in both high and low end of the 6 to < 18 years of 
age group, approximately 50% patients will be enrolled who are 6 to 11 years of age in Group 
1.
For Part 2, patients will be stratified by age (Age Groups 1, 2 and 3) and NYHA/Ross class
group (Class I/II, Class III/IV) at randomization to ensure a balanced distribution of treatment 
allocation within each age group. Patients who discontinue from Part 2 will not be replaced.


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4.1
Inclusion criteria
Patients eligible for inclusion in this study (Part 1 and Part 2) must fulfill all of the following 
criteria:
1. Written informed consent by parent(s)/legal guardian(s) for the pediatric patient must be 
obtained before any study-specific assessment is performed.* A consent or assent may 
also be required for some patients depending upon their age and local requirement.
2. Male or female, inpatient or outpatient, 1 month (≥44 weeks post-conception for pre-term 
infants) to < 18 years of age.
3. Chronic heart failure resulting from left ventricular systolic dysfunction, and receiving 
chronic HF therapy (if not newly diagnosed)..
4. NYHA classification II-IV (older children: 6 to less than 18 year old) or Ross HF 
classification II-IV (younger children: less than 6 year old) any time prior to screening. 
[Note: Age Group 1 patients may be NYHA class I at time of screening if there is a prior 
history of NYHA class II-IV. Age Group 2 patients must be Ross class II or higher at time 
of randomization].
5. Systemic left ventricular ejection fraction (EF) ≤ 45% or fractional shortening ≤22.5% 
(assessed by echocardiogram, MRI, MUGA or left ventricular angiogram within 1 month 
before patient begins Part 2). [Note: The study will target enrollment of approximately 
80% patients with a systemic left ventricular ejection fraction (EF) ≤ 40% or fractional 
shortening ≤20% for Part 2 only].
6. Biventricular physiology with systemic left ventricle.
7. For Part 1 PK/PD, patients must be treated with an ACEI or ARB prior to screening. For 
Part 1 PK/PD, patients in Group 1 and 2 must be currently treated with a daily dose 
equivalent of at least enalapril 0.2 mg/kg (Table 3-1) prior to the LCZ696 3.1 mg/kg 
single dose assessment. For Part 1 PK/PD, patients in Group 3 must be currently treated 
with a daily dose equivalent of at least enalapril 0.1 mg/kg (Table 3-1) prior to the 
LCZ696 1.6 mg/kg single dose assessment 
8. HF etiologies include: Congenital Cardiac Malformation with systemic ventricular systolic 
dysfunction; Idiopathic Cardiomyopathy; Familial/Inherited and/or Genetic 
Cardiomyopathy; History of Myocarditis; Neuromuscular Disorder; Inborn Error of 
Metabolism; Mitochondrial Disorder; Acquired (Chemotherapy, Iatrogenic, Infection, 
Rheumatic, Nutritional); Ischemic (e.g. Kawasaki Disease, post-operative); Left 
ventricular noncompaction
*Assessments of HF (e.g. ECHO) in patients that are done according to current local 
institutional/hospital standard protocol or that are part of routine clinical care can be used to 
support patient screening and may have taken place before signing informed consent. An 
informed consent must be obtained from a patient once they become 18 years old during the 
study.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study (Part 1 
and Part 2). No additional exclusions may be applied by the Investigator, in order to ensure that 
the study population will be representative of all eligible patients.


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1. Patients with single ventricle or systemic right ventricle
2. Patients listed for heart transplantation as United Network for Organ Sharing (UNOS) 
Status 1A or hospitalized waiting for transplant while on inotropes or with ventricular 
assist device at time of entry into the study
3. Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy
4. For Part 2 only, patients that have had cardiovascular surgery or percutaneous intervention 
to palliate or correct congenital cardiovascular malformations within 3 months of the 
screening visit. Patients anticipated to undergo corrective heart surgery during the 12 
months after entry into Part 2.
5. Patients with unoperated obstructive or severe regurgitant valvular (aortic, pulmonary, or 
tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch 
obstruction
6. Patients with restrictive or hypertrophic cardiomyopathy
7. For Part 2 only, active myocarditis (diagnosed with presumed or acute myocarditis within 
3 months of enrollment)
8. Symptomatic hypotension or blood pressures (BPs) below the calculated 5th percentile 
systolic BP (SBP) for age at screening visit and as described in Appendix 4
9. Renal vascular hypertension (including renal artery stenosis)
10. Severe pulmonary hypertension (defined by pulmonary vascular resistance (PVR) 
index >6 Wood units-m2) unresponsive to vasodilator agents (such as oxygen, 
nitroprusside or nitric oxide). Note measurement of PVR is not a requirement for study
eligibility
11. History or current clinical evidence of moderate-to severe obstructive pulmonary disease 
or reactive airway diseases (e.g. asthma)
12. Serum potassium >5.3 mmol/L at Visit 1 or at Visit 301
13. Patients with significant renal (eGFR calculated using the modified Schwartz formula < 
30% mean GFR for age, Appendix 10, Table 22-1); hepatic (serum aspartate 
aminotransferase or alanine aminotransferase > 3 times upper limit of normal); 
gastrointestinal or biliary disorders (that could impair absorption, metabolism, or excretion 
of orally administered medications)
14. Concurrent terminal illness or other severe disease (e.g. acute lymphocytic leukemia) or 
other significant laboratory values that, in the opinion of the Investigator, precludes study 
participation or survival
15. Patients with a history of angioedema
16. Patients with allergy or hypersensitivity to ACEI or ARB
17. 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
18. Pregnant or nursing (lactating) women
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of investigational drug and for 7 days after study drug discontinuation. 
Highly effective contraception methods include:


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
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject and if acceptable by the local regulation). Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%); for example hormone vaginal ring or transdermal hormone 
contraception 

In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug
20. Use of other investigational drugs within 5 half-lives or within 30 days of enrollment, 
whichever is shorter
21. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes
22. Any major solid organ transplant recipient
23. History of malignancy of any organ system, treated or untreated, within the past year with 
a life expectancy less than 1 year
24. Any advanced severe or unstable disease that may interfere with the primary or secondary 
study outcome evaluations or put the patient at special risk
25. Any other medical conditions that may put the patient at risk or influence study results in 
the Investigator’s opinion, or that the Investigator deems unsuitable for the study
26. Patient breastfed by a mother taking ACEI
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The sponsor will provide the following study drugs:
Part 1 - PK/PD treatment epoch
All eligible patients that enter Part 1 will receive LCZ696.
The LCZ696 study medication is available as granules or liquid formulation based on age, 
weight, dosing, and patient’s ability to take study medication (Pharmacy Manual).
The following study drug will be provided:


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
LCZ696 3.125 mg granules (packaged in capsules containing 4 or 10 granules) 
Sites will be provided with study drug to administer for single dose Part 1 PK/PD to all eligible 
patients at that site. LCZ696 granules can be ingested after removing from the capsule. The 
liquid formulation can be compounded at the site / pharmacy [Pharmacy Manual].
Patients will be instructed to not use an ACEI for 36 hours after taking the single dose of 
LCZ696 to minimize the potential risk of angioedema due to overlapping ACEI-NEP inhibition. 
Patients should not use an ARB or renin inhibitor on the day of the single dose PK assessment
visit.
At the completion of the single dose PK assessment visit (Visit 101 and/or 201), patients will 
be provided with open-label enalapril or will be instructed to resume their usual care as deemed 
necessary by the Investigator. The open-label enalapril will be obtained from a local commercial 
source by the site and provided to the patient. If needed, based on the patient’s age and/or 
inability to swallow tablets, liquid enalapril may be used. The liquid enalapril is prepared at the 
site’s pharmacy as per local regulations, and can be commercially sourced such as Epaned (if 
available). Patients receiving enalapril liquid formulation must return to the site for resupply at 
intervals dependent on the storage life of enalapril liquid formulation (every 1 month; or every 
2 months if Epaned (enalapril) which has 2 month shelf life, is available and used). 
Part 2 (Efficacy) - Randomized treatment epoch
The LCZ696 study medication is available in three formulations: tablets, granules (mini-tablets) 
or liquid formulation (if patient cannot swallow granules) (refer to Table 5-1). 
The enalapril study medication is available in two formulations: tablets or liquid formulation
(refer to Table 5-2).
Patients will be randomized to initiate study medication at dose levels 1 or 2 for Groups 1 and
2, and 1x or 2x for Group 3, depending on whether they are ACEI/ARB naïve or depending on 
their ACEI/ARB dose prior to randomization (refer to Table 3-4, Table 3-5, Table 3-6). The 
study medication will be titrated at subsequent visits to the target dose. In addition to study 
medication, patients will continue to take optimal background HF therapy as considered 
appropriate by the Investigator and in accordance with standard HF treatment guidelines. The 
exception is that ACEI or ARB will be replaced by study drug. The use of open-label ACEI, 
ARB, or renin inhibitor in addition to randomized study drug is strictly prohibited.
The following study drugs will be provided for Part 2 (Efficacy):

LCZ696 12.5mg (bottle will contain capsules, each capsule contains 4 granules of 
LCZ696 3.125mg)

Placebo to match LCZ696 12.5mg (bottle will contain capsules, each capsule contains 4 
granules of LCZ696 3.125mg matching placebo)

LCZ696 31.25mg (bottle will contain capsules, each capsule contains 10 granules of 
LCZ696 3.125mg)

Placebo to match LCZ696 31.25mg (bottle will contain capsules, each capsule contains 10 
granules of LCZ696 3.125mg matching placebo)

LCZ696 50mg tablets 


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
Placebo to match LCZ696 50mg tablets 

LCZ696 100mg tablets 

Placebo to match LCZ696 100mg tablets 

LCZ696 200mg tablets 

Placebo to match LCZ696 200mg tablets 

Enalapril 2.5mg tablets 

Placebo to match enalapril 2.5mg tablets 

Enalapril 5mg tablets 

Placebo to match enalapril 5mg tablets 

Enalapril 10mg tablets 

Placebo to match enalapril 10 mg tablets
All study medications will be supplied in bottles or blister cards. Capsules of LCZ696/matching 
placebo containing 4 granules or 10 granules per capsule will be provided for oral use. The 
granules can be swallowed (after the removal of the outer capsule) by the patient.
LCZ696/matching placebo liquid formulation will be compounded by the site / pharmacy 
[Pharmacy Manual]. Patients taking < 8 granules (< 25 mg) for a dose will use the liquid 
formulation. The appropriate aliquot of liquid medication corresponding to the patient’s dose 
will be given to the patient. Appropriate oral syringes will be provided to facilitate study drug 
administration as a liquid.
Sufficient medication will be provided for the treatment according to the study protocol (Table 
5-1 and Table 5-2). Medication labels will be in the local language and comply with the legal 
requirements of the country. The labels will include storage conditions for the drug and the 
medication number, and will not include information about the patient.
Patients taking the liquid formulation of LCZ696/matching placebo or enalapril/matching 
placebo must return to the site every 4 weeks for resupply. The enalapril or enalapril placebo -
liquid formulation will be prepared at the site / pharmacy based on the patient’s age and ability 
to swallow adult tablets. The site personnel or the pharmacy at the sites is responsible for 
preparing enalapril liquid formulation (Pharmacy Manual). Given the burden of traveling to the 
site for study visits for patients and families, the parent/caregiver can come to the site without 
the patient for dispensation of study drug. Delivery of study drug to the patient can also be used 
where possible and allowed per local regulations.
Instructions for preparation of the liquid study drugs are provided in the Pharmacy Manual.
Table 5-1
LCZ696 drug supply for Part 1 (PK/PD) and Part 2 (Efficacy)
Study drug – Part 1 PK/PD 
open-label
Strength
Formulation
LCZ696 
3.125 mg
Granules packaged in capsules 
of 4 or 10 granules in bottle
Study drug – Part 2 Efficacy 
double blind
Strength
Formulation
LCZ696 or matching placebo
3.125 mg
Granules packaged in capsules 
of 4 or 10 granules in bottle


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Study drug – Part 1 PK/PD 
open-label
Strength
Formulation
LCZ696 or matching placebo
50 mg
Tablets in bottle
LCZ696 or matching placebo
100 mg
Tablets in bottle
LCZ696 or matching placebo
200 mg
Tablets in bottle
Table 5-2
Enalapril drug supply for Part 2 (Efficacy)
Study drug – Part 2 Efficacy
double blind
Strength
Formulation
Enalapril or matching placebo
2.5 mg
Tablets in bottle/blister
Enalapril or matching placebo
5 mg
Tablets in blister
Enalapril or matching placebo
10 mg
Tablets in blister
Part 1:
The LCZ696 study medication is available as granules or liquid formulation based on age, 
dosing, and patient’s ability to take study medication (Pharmacy Manual).
Part 2:
The LCZ696 study medication is available in three formulations: tablets, granules (mini-tablets) 
or liquid formulation (refer to Pharmacy Manual) (if patient cannot swallow granules) (refer to
Table 5-1). 
The enalapril study medication is available in two formulations: tablets or liquid formulation.
All pediatric formulations of study medication (LCZ696 granules or liquid, enalapril liquid) 
will be made available to all age groups. The adult tablet formulations of LCZ696 and enalapril 
will be available to patients based on the patient’s dosing and ability to swallow adult tablets 
(refer to Pharmacy manual).
Dispensing of medication to the subjects will be controlled by an Interactive Response 
Technology (IRT) system. 
5.1.2
Additional treatment
No additional treatment beyond investigational drug (LCZ696) and active comparator drug 
(enalapril) are included in this trial.
5.2
Treatment arms
Part 1 (PK/PD): All patients will receive open-label LCZ696. Patients completing Part 1 and 
who are willing to participate in Part 2 will be provided open-label enalapril (or their standard 
of care HF regimen) by the study site.
Part 2 (Efficacy): Patients are assigned to one of the following two double blind treatment arms 
in a ratio of 1:1 at the randomization Visit 401:

LCZ696 

Enalapril


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5.3
Treatment assignment and randomization 
At Visit 401, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. Patients will be stratified by age group (Age Groups 1, 2 and 3)
and NYHA/Ross class group (Class I/II, Class III/IV) at randomization to ensure a balanced 
distribution of treatment allocation within each age strata. The Investigator or his/her delegate 
will contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the patient 
to a treatment arm and will specify a unique medication number for the first package of study 
drug to be dispensed to the patient. The randomization number will not be communicated to the 
caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and Investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s). 
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding
Part 1 (PK/PD) involves open-label LCZ696.
Part 2 (Efficacy) is a randomized, double-blind, active controlled study. Patients, Investigator
and staff, persons performing the assessments, and data analysts will remain blind to the identity 
of the treatment from the time of randomization until database lock using the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will 
not be accessible by anyone involved in the study with the following exceptions:
1. The independent and unblinded statistician, programmer and data personnel who are 
involved in preparing safety and efficacy interim analysis reports for the DMC. These 
personnel will not be involved in any other trial conduct related activities
2. The DMC members
3. An unblinded team, which is not involved in the conduct of the study, will evaluate the 
steady-state sparse  PK blood samples collected from approximately 24 patients 
(approximately half of whom are expected to be randomized to LCZ696) in Part 2
Group 2 (Section 9.5.1).
4.
 

A double-dummy design is used because the identity of the investigational treatment 
cannot be disguised, as the drug products are visibly different


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
The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, labeling, schedule of administration, appearance, taste 
and odor
Unblinding will only occur in the case of patient emergencies (Section 5.5.9), at the time of 
interim analyses (Section 9.6), and at the conclusion of the study. 
The randomization codes associated with patients/subjects from whom Part 2 PK samples are 
taken will be disclosed to PK analysts who will keep Part 2 PK results confidential until data 
base lock.
An assessment will be done by the appropriate site personnel and the Medical Lead (or designee) 
for any patient whose treatment code has been broken inadvertently or for any nonemergency 
reason to assess whether or not study treatment/investigational treatment should be discontinued 
and, if applicable, whether the patient can continue in the trial.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the Investigator. Once assigned to a 
patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the Investigator. The Investigator or his/her staff will contact the IRT and provide the requested 
identifying information for the patient to register them into the IRT. The site must select the 
CRF book with a matching Subject Number from the EDC system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening epoch 
Study Disposition case report form (CRF).
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique randomization number is printed on each 
part of this label which corresponds to one of the two treatment arms and dose level. Investigator 
staff will identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the patient, 
Investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number. 


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5.5.3
Handling of study and additional treatment
5.5.3.1
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 designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO 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 patient except for the medication number.
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the Investigator
folder at each site.
Where applicable and as per local regulations, the study medication can be shipped from the 
study site or site pharmacy to the patients home. Pharmacy to home operating procedures will 
be provided to the site by the sponsor.
5.5.3.2
Handling of additional treatment
The Investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded.
The patient should be receiving optimal standard of care medical and surgical treatment for 
their HF and comorbidities. In Part 2 of the study, study drug (LCZ696 vs. enalapril) will be 
used instead of ACEI or ARB.
5.5.4
Instructions for prescribing and taking study treatment
Novartis will supply the Investigators with all study medications required for the course of the 
study. Patients will be provided with bottles and blisters containing study drug corresponding 
to their assigned treatment arm and dose level, sufficient to last until the next scheduled visit. 
Part 1:

LCZ696 granules: 3.125 mg (packaged in capsule containing either 4 or 10 granules)
supplied in a bottle 


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
LCZ696 liquid formulation (compounded by site / pharmacy) (refer to Pharmacy Manual)
Part 2:
Patients will be taking the following as provided in blinded packaging:

LCZ696 tablets: 50 mg or matching placebo, 100 mg or matching placebo, 200 mg or 
matching placebo

LCZ696: 3.125 mg granules or matching placebo, supplied in a bottle containing capsules 
with granules. Each capsule will contain either 4 or 10 granules

LCZ696 liquid formulation (compounded by site / pharmacy) (refer to Pharmacy Manual)
Enalapril liquid formulation(compounded by site / pharmacy) (refer to Pharmacy Manual) 
or matching placebo, 2.5 mg tablets or matching placebo, 5 mg tablets or matching 
placebo, 10 mg tablets or matching placebo
The above Part 2 supplies are provided in blinded packaging.
Details regarding preparation of liquid formulation for LCZ696 and enalapril are provided in 
the [Pharmacy Manual].
For Part 1 (PK/PD), the site will provide the single dose open-label LCZ696 to the patient for 
administration. For Part 2 (Efficacy), patients 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. The LCZ696 granules can be administered as solid or mixed with soft food. LCZ696 can 
also be administered as a liquid form [Pharmacy Manual]. If the patient misses taking any study 
drug dose, s/he should take it as soon as possible, unless it is almost time for the following 
scheduled dose. In this case, the patient should skip the missed dose and return back to his/her 
regular study drug administration schedule.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record (DAR) CRF. All kits of study treatment 
assigned by the IRT will be recorded in the IRT.
The Investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the Investigator if he/she is 
unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
The study drug is up-titrated every 2 weeks as tolerated to target dose (level 4 for Group 1 and 
2, and 4x for Group 3) as outlined in (Table 3-5 and Table 3-6) based on the safety monitoring 
criteria (Table 3-3). Additional safety monitoring will be required for Age Group 3 patients 
with each initial dose level up-titration. See Appendix 13 for details. Following up-titration, the 
maximum tolerated or target dose will then be maintained for the duration of the study. Both 
scheduled and unscheduled visits can be utilized for up-titration/down-titration throughout the 
study based on Investigator judgment.


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For patients who are unable to tolerate the protocol-specified dosing scheme, dose level 
adjustments and interruptions of study treatment are permitted in order to keep the patient on 
study drug. The following guidelines should be followed: 

The Investigator should adjust doses of concomitant medications if it is believed that they 
are the most likely cause of an adverse effect

If adjustment/elimination of concomitant medications is not possible or does not alleviate 
the side effects of concern, the Investigator may down titrate to the next lower study drug 
dose level down (Table 3-5 and Table 3-6) to temporary or permanent discontinuation of 
study drug 

The patient should be rechallenged with 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 temporarily or permanently discontinued, then the patient should 
continue to attend the study visits and be followed until the completion of the study
Patients may be seen at any time for unscheduled visits during the randomized treatment epoch 
for reevaluation 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. Local laboratory assessments of serum sodium, 
potassium, creatinine, and eGFR (calculated based on the modified Schwartz formula (Schwartz 
2009) will be utilized. Refer to Appendices 15, 16, and 17 for treatment guidelines for renal 
dysfunction, management of hypotension and hyperkalemia, respectively.
Adjustment of study drug dose level
During the double-blind treatment epoch, down titration of the study drug at any time is allowed 
based on the safety and tolerability criteria defined in (Table 3-3). If down titration is necessary, 
the patient should be down titrated to a lower study drug dose level (Table 3-5 and Table 3-6).
The Investigator may down titrate to the next lower study drug dose level. If the tolerability 
issues are not alleviated despite down titration by multiple dose levels, the Investigator may 
temporarily discontinue study drug. Once the patient’s condition is stable, s/he can be up-
titrated to the next higher dose level every 1 to 4 weeks in an attempt to bring back the patient 
gradually to the target study drug dose level (dose level 4 for Group 1 and 2, and 4x for Group 
3). The Investigator may choose the next dose level for down- or up-titration according to his 
or her judgment (Table 3-5 and Table 3-6). 
All changes should be recorded on the DAR CRF. In addition, IRT should be contacted to 
register any changes in the patient’s study drug dose level, in cases of temporary and permanent 
discontinuation of the study drug, and to obtain the medication numbers of the study drug 
supplies required for the new study drug dose level. 
Study drug restart after temporary treatment interruption
Patients who have temporarily discontinued study drug should be restarted as soon as possible 
as deemed appropriate by the Investigator. The Investigator should restart the patient on the 
study drug at the most appropriate dose level (Table 3-5 and Table 3-6) as per the Investigator’s 
clinical judgment. Patients must discontinue their ACEI medication(s) 36 hours prior to re-
starting study drug to allow for an ACEI-free washout period. If the patient does not tolerate 


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the newly restarted study drug dose level, s/he may be down titrated again (if appropriate) or 
the study medication may be temporarily discontinued again.
Patients restarted on the study drug will retain their original randomization and study 
identification numbers. 
Investigators may discontinue the study drug due to serious or intolerable AEs suspected to be 
causally related to study drug. If study drug is discontinued for any reason, the exact time and 
date of study drug discontinuation must be recorded on the DAR CRFs. In addition, patients 
who discontinue study drug should continue to be followed at all study visits as defined in the 
protocol (Table 6-1 and Table 6-2). 
The use of an open-label ACEI, ARB or a renin inhibitor during a period in which the patient 
may be off study drug is discouraged. However, if a patient off study drug has started open-
label treatment with an ACEI, the ACEI must be discontinued ≥36 hours prior to restarting 
study drug. Patients 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 started. These changes must be recorded on the DAR and Concomitant Medication CRFs.
If the patient is discovered to be pregnant during the course of the study, the patient should 
discontinue study drug immediately. Meanwhile, the patient should continue to attend 
scheduled study visits.
Refer to (Section 6.5.7 and Section 7.7) for further details on pregnancies and reporting 
guidelines.
5.5.6
Rescue medication
If in the opinion of the Investigator, the patient does not tolerate the assigned study medication, 
the Investigator should consider whether non disease-modifying medication (e.g. CCBs, 
diuretics, α-blockers) can be reduced to rectify the situation.
Guidance on handling renal dysfunction, hypotension, and hyperkalemia are provided to 
Investigators in (Appendix 3, Appendix 4, and Appendix 5) respectively. 
The Investigator may prescribe any medications and/or supportive care during the study based 
on clinical needs. Use of rescue medication and/or supportive care must be recorded on the 
Concomitant medications CRF.
5.5.7
Concomitant medication
The Investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the concomitant medications / 
procedures (significant non-drug therapies) CRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.


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5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-3 is NOT allowed while taking study drug after 
randomization due to safety reasons. If the medications displayed in Table 5-3 must be used, 
study drug must be discontinued and the actions specified below must be taken.
Table 5-3
Prohibited treatment by medication class
Medication
Action taken
Any ACEI
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 patient 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 
should be stopped 36 hours prior to starting open-label ACEI. Study drug should be stopped 
prior to starting open-label ARB or renin inhibitor. 
Similarly, if study drug is to be restarted, the open-label ACEI should be stopped >36 hours 
prior to resuming study drug. Open-label ARB or renin inhibitor should be stopped prior to 
resuming study drug.
5.5.9
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The Investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the Study Team that the code has 
been broken.
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator
will provide:

protocol number

study drug name (if available)

patient number


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In addition, oral and written information to the subject must be provided on how to contact the 
investigator’s backup in cases of emergency, or when the investigator is unavailable, to ensure 
that un-blinding can be performed at any time. 
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
Continuing care should be provided by Investigator and/or other caring physician. The patient 
should be placed on an ACEI or ARB for HF treatment as determined by the caring physician.
5.6.2
Discontinuation of study treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. 
The emergence of the following circumstances will require permanent study drug 
discontinuation:

Withdrawal of informed consent

Investigator believes that continuation would be detrimental to the patient’s well-being

Suspected occurrence of angioedema; a patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the Investigator
The emergence of the following circumstances will require temporary or permanent 
discontinuation (study drug may be restarted once these circumstances no longer exist):

Use of an open-label ACEI, ARB or renin inhibitor

Pregnancy and post-pregnancy during lactation period (Section 7.7)
Study drug may be discontinued at the Investigator’s discretion if any of the following occurs:

Any severe or suspected drug-related AE

Any other protocol deviation that results in a significant risk to the patient’s safety
The appropriate personnel from the site and Novartis will assess whether study drug should be 
discontinued for any patient whose treatment code has been broken inadvertently for any reason.
If permanent discontinuation of study treatment occurs and the patient/parents/guardians have 
not withdrawn consent, the patient should NOT be considered withdrawn from the study. The 
patient should return to the clinic as soon as possible, after discontinuation of study drug, for a 
study treatment discontinuation visit. Treatment discontinuation visit assessments detailed in 
the “unscheduled treatment discontinuation visit” (UNS) in Table 6-1 and Table 6-2 should be 
completed and recorded in the CRF. The Investigator must determine the primary reason for 
the patient’s premature discontinuation of study treatment and record this information on the 
Dosage Administration CRF. 
After study treatment discontinuation, the following minimum data should to be collected at 
clinic visits or via telephone visits: 

new / concomitant treatments


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
adverse events/serious adverse events
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, caregiver/parent, or with a person pre-designated by the 
patient. This telephone contact should preferably be done according to the study visit schedule. 
The Investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent
Parents/guardians may voluntarily withdraw consent for their child to participate in the study 
for any reason at any time. Withdrawal of consent occurs only when a parent/guardian:

Does not want the child to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the Investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the parent/guardian's decision to withdraw his/her consent for 
their child and record this information in the CRF. 
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 patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in Table 6-
1 and Table 6-2.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For European Union and Rest of World: All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements. Any child's request to be withdrawn from the study 
should be respected and discussed in detail with parents/guardians and the local Investigator
before acting upon the request.
5.6.4
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the Investigator should show "due diligence" by 


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documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed. 
An assessment of the child's well-being must be made if the family is non-compliant with study 
visits. Appropriate referral to local social services should be considered based on safety 
concerns for the child.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, the patient 
must be seen as soon as possible and treated as a prematurely discontinued patient. The 
Investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The Sponsor will be 
responsible for informing the Investigator, the national competent authority and Institutional 
Review Board/Independent Ethics Committee (IRBs/IECs) of the early termination of the trial
as per local regulations. In some countries and based on local regulations, the sponsor may 
delegate to the Investigator the duty to inform the ECs about the early termination.
6
Visit schedule and assessments
Table 6-1 and Table 6-2 lists all of the assessments and indicates with an “x” when the visits 
are performed.
After identifying a potential patient, an informed consent form (ICF) and assent (if applicable) 
must be signed by the parent(s)/legal guardian(s) and by the patient (as applicable) before 
performing any study-related procedures that are not considered standard of care for pediatric 
HF patients at that site. Procedures that are part of a site’s standard of care for a pediatric patient 
may pre-date the signed ICF. The AE and SAE reporting period will begin at the time the ICF 
is signed. 
Part 1 of the study consists of Visits 1 to 299. After screening (Visit 1), there are two LCZ696 
single dose PK/PD assessments (Visit 101 and Visit 201). There are telephone visits (Visit 102
and 202) followed by a sequence of telephone visits monthly in between the in person visits 
every 3 months (Visits 103 to 120, Visits 203 to 220).
Patients taking open-label liquid enalapril should obtain study drug from the site monthly until 
Part 2 begins (due to the 1 month storage life of liquid enalapril). If the patient is taking Epaned 
liquid enalapril that has a 2 month storage life, patients must obtain open-label enalapril every 
2 months until Part 2 begins. If the parent/caregiver comes to the site without the patient to pick 
up the open label liquid enalapril, a telephone call to the patient (≥6 years old) can be used in 
conjunction with the parent/caregiver visit. At the telephone visits for Part 1, the following 
assessments will not be performed: vital signs, abbreviated physical exam, weight, abbreviated 
laboratories and urine pregnancy.
Visit 199 and 299 are end of LCZ696 PK/PD first dose visit and second dose visit, respectively. 
For the patient that only participates in the LCZ696 PK/PD first dose, the Visit 199 may occur 


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on the same day as Visit 301, if patient is going to participate in Part 2. For the patient that 
participates in the LCZ696 PK/PD first and second PK doses, Visit 199 may occur on the same 
day as Visit 201. For the patient that only participates in the LCZ696 PK/PD second dose, Visit 
299 may occur on the same day as Visit 301, if patient is going to participate in Part 2. Visit 
301 is a pre-randomization screening visit for Part 2.Part 2 of the study consists of Visits 301 
to 499. Visit 401 (randomization) will be considered the reference visit for all study visits during 
Part 2 (Efficacy). Regardless of the occurrence of any unscheduled visits, scheduled visits 
should be performed within the specified timeframe in relation to Visit 401. 
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. Patients/subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF.
After Visit 406 (12 weeks), patients using the adult formulation will be seen at 12 week intervals. 
The liquid formulation of study drug (LCZ696/matching placebo or enalapril/matching placebo) 
and LCZ696 granules have a limited shelf life. Therefore, Visits 407, 408, 410, 411, 413, 414
are visits intended primarily to permit dispensation of study drug for patients who are using 
blinded liquid enalapril/matching placebo and/or LCZ696/matching placebo granules. Given 
the burden of traveling to study visits for patients and families, the parent/caregiver can come 
to the site for dispensation of study drug. If the parent/caregiver comes to the visit without the 
patient, a telephone call to the patient (≥ 6 years old) can be used in conjunction with the 
parent/caregiver visit for the visit assessments (all can be performed verbally). Delivery of study 
drug to the patient can also be used where possible and allowed per local regulations. At these 
visits (407, 408, 410, 411, 413, and 414), the following assessments are performed: concomitant 
medications, AE/SAEs, dosage administration record, study medication compliance, endpoint 
collection (for additional details refer to Table 6-2). Urine pregnancy testing will be done for 
females of childbearing potential (for additional details see Table 6-2). IRT will be contacted if 
study medications are dispensed.
Visits 407, 408, 410, 411, 413, 414 are telephone visits for patients using the adult formulation
of study drug. The assessments listed for these visits (Table 6-2) can be performed by telephone. 
Patients who prematurely discontinue the investigational treatment will remain in the study and 
should undergo all the assessments illustrated in Table 6-2. If a patient/parent(s)/legal 
guardian(s) withdraws from participation in the study, refuses to return for study assessments 
or is unable to do so, every effort should be made to contact them or a knowledgeable informant 
by telephone and/or other measures to determine the patient’s survival status 52 weeks from 
randomization (Visit 499). 
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment. 


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Table 6-1
Part 1 Assessment Schedule
Epoch
Scree
ning
Period 1
First Dose PK
Period 2
Second Dose PK
Pre-
Randomizat
ion
Visit
1
101
102
(telephone 
visit)
103 to 
120*
UNS
PK/PD
199**
201
202
(telephone 
visit)
203 to 
220*
UNS
PK/PD
299**
301**
(Part 2
Screening)
Week
♦
♦
♦
♦
♦
up to -3
Obtain Informed Consent (parent (s)-legal 
guardian (s)/consent-assent (patient, as 
applicable)13
x, S
x, S
Demography
x
x1
Inclusion/Exclusion Criteria
x
x
Medical History
x
x1
Pediatric Heart Failure History
x
x1
Concomitant Medications
x
x
x
x
x
x
x
x
x
x
x
x
Alcohol & Smoking History
x
x1
Vital Signs (BP and pulse)
x
x2
x9
x2
x
x2
x 9
x2
x
x
Height
x
x
x
x
Weight3
x
x
x9
x
x
x
x 9
x
x
x
Head Circumference (≤ 3 years old)
x
x
x
x
Physical Examination (complete)
S
S
Physical Exam (abbreviated)
S
S9
S
S
S
S9
S
S
ECG
x
x
x
x
ECHO, LVEF or fractional shortening 
measurement4
x
x
Urinalysis
x
x
x
x
Serum/Urine Pregnancy Test5
x
x
x9
x
x
x
x9
x
x
x
Complete Laboratories6
x
x
x
x
Abbreviated Laboratories7
x
x9
x
x
x9
x
PK Blood Samples
x
x
x
x
Plasma Biomarkers/PD8
x
x
x
x


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Epoch
Scree
ning
Period 1
First Dose PK
Period 2
Second Dose PK
Pre-
Randomizat
ion
Visit
1
101
102
(telephone 
visit)
103 to 
120*
UNS
PK/PD
199**
201
202
(telephone 
visit)
203 to 
220*
UNS
PK/PD
299**
301**
(Part 2
Screening)
Week
♦
♦
♦
♦
♦
up to -3
Urine cGMP8
x
x
x
x
NYHA/ Ross Classification 
x
X
x
x
AEs/SAEs
x
x
x
x
x
x
x
x
x
x
Dosage Administration Record
x
x
Study Medication Compliance10
S11
S
S
S11
S
S
Contact IRT
x
x
x
x
x
x
x
x
Dose Open-Label LCZ (single dose)
x
x
x
x
Dispense Open-Label Enalapril12
x
x
x
x
x
x
Screening Disposition (Parts 1 and 2)
x
x
Part 1 Disposition
x
x
UNS PK/PD = Unscheduled PK/PD visit. Only one unscheduled visit either in Period 1 or Period 2 should be conducted. 
S = assessment to be recorded on source documentation only
♦Visit 101 will occur approximately up to three weeks after Visit 1. Visit 201 may occur approximately up to three weeks after Visit 1 if patient is directly going to second dose PK 
assessment from Visit 1. The Visit 102/202 are telephone visits that occur 2 weeks after completion of Visit 101/201 respectively.
* Visits 103 to 120 / 203 to 220 are combination of in person and telephone visits. Telephone visits will occur monthly between the every 3 month in person visits. At these telephone 
visits the following assessments will not be performed: vital signs, abbreviated physical exam, weight, abbreviated laboratories and urine pregnancy
** For the patient that participates in the second PK/PD dose, Visit 299 may occur on the same day as Visit 301, if the patient is going to participate in Part 2. For the patient that only 
participates in the first dose PK/PD assessment, the Visit 199 may occur on the same day as Visit 301, if the patient is going to participate in Part 2. If the patient participates in both first 
and second PK/PD doses Visit 199 may occur on the same day as Visit 201.  
1 Demography, medical history, pediatric HF history alcohol & smoking history are only obtained at Visit 301 for patients who did not participate in Part 1.
2 Patients who have PK done at Visit 101/201/ unscheduled PK/PD will have vital signs (blood pressure and heart rate/pulse) collected at 0, 30 min, 1 hr, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 
7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs, 18 hrs and 24 hours post-dose. Vital signs at 11 hrs, 12 hrs and 18 hrs are optional unless the patient physically stays on-site. The 24-hr post 
dose vital signs will be measured if the patient either stays on-site or returns to the site the next day.
3 Weights are measured for safety and for dose administration at V101 and/or V 201 or UNS PK/PD (if this visit occurs). 
4 For Part 1, patients are to meet inclusion criteria regarding ECHO, LVEF or fractional shortening measurement (i.e. Systemic left ventricular ejection fraction (EF) ≤ 45% or fractional 
shortening ≤22.5%), by history at any time prior to screening (V1). If there is no history of LVEF or fractional shortening measurements an ECHO can be performed at screening (Visit 1).
(see Section 4.1, Inclusion criteria).


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Epoch
Scree
ning
Period 1
First Dose PK
Period 2
Second Dose PK
Pre-
Randomizat
ion
Visit
1
101
102
(telephone 
visit)
103 to 
120*
UNS
PK/PD
199**
201
202
(telephone 
visit)
203 to 
220*
UNS
PK/PD
299**
301**
(Part 2
Screening)
Week
♦
♦
♦
♦
♦
up to -3
5 For child bearing potential females (CHBP) only. Urine pregnancy test is analyzed locally and done at all visits on all female patients ≥11 years of age and all female patients who are 
<11 years of age if they are menstruating. In addition, a serum pregnancy test is performed and analyzed locally at Visit 1 and Visit 301. 
6 Complete laboratory evaluations will be performed by local lab for Part 1. 
7 Abbreviated laboratories will be collected and sent to the local lab at specified visits for all patients. Abbreviated laboratories consist of sodium, potassium, creatinine, eGFR (modified 
Schwartz formula). Abbreviated laboratories may be performed at any visit based on the Investigator’s clinical judgement. At Visit 101, 201 or/and UNS PK/PD (if occurs) the 
abbreviated labs will be collected at the end of the visit.
8 At Visit 101, 201, or/and UNS PK/PD (if this visit occurs), samples will be collected for plasma NTproBNP, plasma and urine cGMP, and plasma BNP. Central laboratory will be used 
for these biomarkers.
9 For Visits 103 -120 / 203 – 220 vital signs, abbreviated physical exam, weight, abbreviated laboratories and urine pregnancy test are performed every 3 months when the patient 
comes to the site for a visit.
10 For Part 1, only applicable for patients taking open-label enalapril. For Parts 1 and 2, dosage administration record and compliance will be performed when the study drug is dispensed 
and when the last dispensed study drug is presented to the site for tablet/granule count or liquid assessment.
11 Patients will be asked via telephone if they completed a 36-hour washout period after the single dose LCZ696 PK and prior to starting enalapril (or ACEI). This information will be 
captured in the source document.
12 Patients who are taking open-label enalapril will be provided enalapril medication at the completion of visit 101 or/and 201. Patient will be instructed to take it after 36 hour washout 
period. Compliance will be evaluated at Visit 102 or/and 202 via telephone call.
13 Patient Assent document is captured as a source document and not stored in the clinical database.


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Table 6-2
Part 2 Assessment Schedule
Epoch
Pre-
Randomiza
-tion
Double-blind
Visit
301**
(Part 2 
Screening)
401
401JPNJ
402
403
404 Optional
405
406
407†
408†
409
410†
411†
412
413†
414†
415
UNS/
TD
UNS
416/ 
499(PSD)
Week
up to -3
0
1
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
Obtain Informed Consent (parent (s)-legal 
guardian (s)/consent-assent (patient, as 
applicable)2
x, S
Demography
x1
Inclusion/Exclusion Criteria
x
Medical History
x1
Pediatric Heart Failure History
x1
Concomitant Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Alcohol & Smoking History
x1
Vital Signs (BP and pulse)17
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Height
x
x
Weight3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Head Circumference (≤ 3 years old)
x
x
Physical Examination (complete)
S
S
Physical Exam (abbreviated)
S
S
S
S
S
S
S
S
S
S
S
S
ECG
x
x
ECHO, LVEF or fractional shortening 
measurement4
x
Urinalysis
x
x
x
x
Serum/Urine Pregnancy Test5
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete Laboratories6 , 13
x
x
x
x


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Epoch
Pre-
Randomiza
-tion
Double-blind
Visit
301**
(Part 2 
Screening)
401
401JPNJ
402
403
404 Optional
405
406
407†
408†
409
410†
411†
412
413†
414†
415
UNS/
TD
UNS
416/ 
499(PSD)
Week
up to -3
0
1
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
Abbreviated Laboratories7
(x)
x
(x)
x
x
x
x
(x)
18
(x)
18
Population PK Blood Samples13, 15
x
X15
(x)
18
X15, 
19
Sparse PK blood Samples (Group 2 Subset 
of patients)13, 14
x14
(x)
14
Plasma Biomarkers/PD8, 13
x
x
x
(x)
18
X
Plasma Biomarker/PD (Sparse PK Group 2 
Subset of patients) 13, 16
x16
(x)
16
NYHA/ Ross Classification 
x
x
x
x
x
x
(x)
18
x
PGIS (Global Impression of Severity): 
Patient9
x
x
x
x
x
(x)
18
x
PGIS: Parent/Care-giver9
x
x
x
x
x
(x)
18
x
PedsQL: Patient10
x
x
x
x
(x)
18
x


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Epoch
Pre-
Randomiza
-tion
Double-blind
Visit
301**
(Part 2 
Screening)
401
401JPNJ
402
403
404 Optional
405
406
407†
408†
409
410†
411†
412
413†
414†
415
UNS/
TD
UNS
416/ 
499(PSD)
Week
up to -3
0
1
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
AEs/SAEs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dosage Administration Record11
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
(x)
(x)
x
Study Medication Compliance11
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
(S)
(S)
S
Contact IRT
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dispense Double-Blind Study Medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
(x)
Screening Disposition (Parts 1 and 2)
x
Endpoints
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Efficacy Study Treatment Disposition (Part 
2)
x
End of Study Treatment Discontinuation 
(Part 2)
x
UNS = Unscheduled visit
S = assessment to be recorded on source documentation only
TD = Study treatment discontinuation and patient continues study visits;
PSD = Premature subject/patient discontinuation
(x) / (S) = optional assessment
Visit 404 Optional = Investigators have the option to schedule a patient for an additional visit (Visit 404) for up titration.
** A patient may be screened and randomized the same day for Part 2. Visits 299 and 301 (for patient in second dose PK) and Visits 199 and 301 (for patient only going to take first 
dose PK) may occur on the same day if patient is participating in Part 2. Any assessments should not be repeated if visits occur on the same day. 


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Epoch
Pre-
Randomiza
-tion
Double-blind
Visit
301**
(Part 2 
Screening)
401
401JPNJ
402
403
404 Optional
405
406
407†
408†
409
410†
411†
412
413†
414†
415
UNS/
TD
UNS
416/ 
499(PSD)
Week
up to -3
0
1
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
† Visits 407, 408, 410, 411, 413, 414 are telephone visits. Patients who are dispensed LCZ696 liquid formulation/matching placebo, liquid enalapril/matching placebo and 
LCZ696/matching placebo granules will come to the site for dispensation of study drug. If the parent/caregiver comes to the site without the patient, a telephone call to the patient 
(≥6 years old) can be used in conjunction with the parent/caregiver visit for the visit assessments. IRT will be contacted only if study drug is dispensed.
J Visit 401JPN (week 1) is applicable only to patients enrolled at sites in Japan.
1 Demography, medical history, pediatric HF history alcohol & smoking history are only obtained at Visit 301 for patients who did not participate in Part 1.
2 Patient Assent document is captured as a source document and not stored in the clinical database.
3 Weights are measured for safety. For patients 1 month to < 1 year old, last available study weight measurement will be used to ascertain dose. For patients 1 to < 6 years old, 
weight measurements every 3 months will be used for dose determination. For patients who are ≥ 6 years old, weight measurement every 6 months will be used for dose 
determination.
4 This must be performed within 1 month of Visit 301 (Part 2). Patients who have participated in Part 1 (PK) and remain in study for Part 2 (efficacy) need a repeat assessment of 
LVEF or fractional shortening to determine eligibility for Part 2 if the assessment is greater than 1 month prior to Visit 301 (see Section 4.1, Inclusion criteria).
5 For child bearing potential females (CHBP) only. Urine pregnancy test is analyzed locally and done at all visits on all female patients ≥11 years of age and all female patients who 
are <11 years of age if they are menstruating. In addition, a serum pregnancy test is performed and analyzed locally at Visit 301 and centrally at Visit 416/499 respectively. Urine 
pregnancy tests will not be done at visit 401JPN (i.e. week 1 visit, which is applicable only to patients enrolled at sites in Japan). Note: In addition to the testing done in the clinic, all 
female subjects ≥11 years of age and all female subjects who are <11 years of age if they are menstruating, will be given a urine pregnancy test kit for each month between in-
person study visits and will be instructed to do a urine pregnancy test at home, for each visit designated to be a telephone visit (i.e. Visits 407, 408, 410, 411, 413 and 414). 
Patients will be instructed to save the pregnancy test kits in a container (e.g. plastic) and bring them to the next in-person clinic visit. Study site personnel are to review the 
pregnancy test kits the patients bring to the clinic and record the results in the source documentation and on the appropriate CRF. If, according to local requirements, pregnancy 
tests cannot be done at home, the patient can have the test done at the study site or an alternative venue (additional details are included in the Central Lab Manual). Patients will 
be instructed to come to the clinic for a serum pregnancy test if the urine pregnancy test is positive.
6 Local laboratories should be used for all laboratory tests at Visit 301. Central lab should only be used for Visit 301, if local lab is unavailable using unscheduled visit. Central 
laboratory should be used at Visits 401, 409, and 416/499 for all patients, where possible.
7 Abbreviated laboratories will be collected and sent to the local lab at specified visits for all patients. Abbreviated laboratories consist of sodium, potassium, creatinine, eGFR 
(modified Schwartz formula). Abbreviated laboratories may be performed at any visit based on the Investigator’s clinical judgement. Central lab should only be used for abbreviated 
lab testing only if local lab is unavailable, using unscheduled visit. Note: The Abbreviated laboratories scheduled at Visit 402 (week 2) and Visit 404 (week 6) are optional if it is 
considered safe and where the patient is not being up-titrated (applicable to Visit 402 and 404). For Age Group 3 patients who turn 1 year old during the study and who are up-
titrated to Group 3 Dose Level 5x (if applicable) at a scheduled visit or at an unscheduled visit, abbreviated labs are to be done at the additional up titration visit.


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Protocol No. CLCZ696B2319
Epoch
Pre-
Randomiza
-tion
Double-blind
Visit
301**
(Part 2 
Screening)
401
401JPNJ
402
403
404 Optional
405
406
407†
408†
409
410†
411†
412
413†
414†
415
UNS/
TD
UNS
416/ 
499(PSD)
Week
up to -3
0
1
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
 
9 Patient or parent/caregiver will complete the PGIS
, depending on the age of patient.
11 For Part 1, only applicable for patients taking open-label enalapril. For Parts 1 and 2, dosage administration record and compliance will be performed when the study drug is 
dispensed and when the last dispensed study drug is presented to the site for tablet/granule count or liquid assessment.
 
13 For countries where blood samples cannot be shipped out of the country due to local regulations, the PK blood samples and Plasma Biomarkers/PD are not required. In these 
countries, complete laboratories at visit 401, 409 and 416/499 will be collected and sent to the local lab. 
14 In approximately 24 patients in Age Group 2, sparse PK blood samples will be collected at steady-state, at 3 time-points on the same day, at Visit 405 or at a subsequent 
scheduled or unscheduled visit (with the exception of Visit 406 and 416/499), Please refer to Section 6.6.2 and Table 6-5 for instructions regarding sample collection.  
15 For the subset of patients who participate in the sparse PK sampling visit, blood samples for Population PK will NOT be required to be collected at Visits 406 and 416/499.
16  For the subset of patients who participate in the sparse PK sampling visit, 
(e.g. visit 405 or a 
scheduled or unscheduled visit with the exception of visits 406 and 416/499).
17 For Part 2 Group 3 patients, starting with the first dose of study medication, vital signs need to be checked for up to 4 hours after the initial dose at each dose level. Patients are 
to remain in the study site clinic for this 4-hour post-dose Vital Sign monitoring period. Vital signs (i.e. blood pressure and heart rate) are to be measured pre-dose (time 0), and 
post-dose at 0.5, 1, 2, 3 and 4 hours for the initial study medication dose at each dose level. See Appendix 13 for details.
18 For patients impacted by the urgent safety measure (USM), additional evaluations are to be done at the visit that is used to discontinue study medication (see Appendix 15 for 
details). PK
 
must be collected, and NYHA/Ross Classification and all PROs (PedsQL, PGIS, 
) must be completed, at this visit.
19 For patients impacted by the USM and who transitioned to SOC before the EoS visit, a sample for Population PK should NOT be collected.


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6.1
Information to be collected on screening failures
All patients who have signed informed consent for Part 1 (PK/PD) and/or Part 2 (Efficacy), but 
have not entered into the next epoch will have the study completion page for the screening 
epoch, demographics, inclusion/exclusion, and SAE data collected. Adverse events that are not 
SAEs will be followed by the Investigator and collected only in the source data.
A patient who has failed screening may have abnormal test findings that occurred prior to the 
informed consent. Investigators have the discretion to record these abnormal test findings on 
the CRF.
Re-screening
A patient who enters screening but is determined not to be eligible for the study will be 
considered a screen failure. The Investigator may consider rescreening the patient at a later time 
if he/she believes that the patient’s condition has changed and they may potentially be eligible. 
In this case, a new patient number will be allocated to the subject and he/she will need to 
perform all screening Visit 1 (Part 1- PK/PD) or Visit 301 (Part 2 Efficacy-Pre-
randomization/Screening) procedures again. A patient may be rescreened up to two times. A 
minimum of 2 weeks must elapse between rescreening. The parent(s)/legal guardian(s) for the 
pediatric patient must provide new written informed consent before each time the patient is 
rescreened. Patients required to provide assent must also provide new assent before being 
rescreened.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: year 
of birth, age, sex, race, ethnicity, concomitant medications, alcohol/smoking history, 
NYHA/Ross class, pediatric heart failure history, vital signs, weight and height. Relevant 
medical history/current medical condition data includes data until the start of study drug.
Rationale for collecting race and ethnicity data: Race and ethnicity data are collected for patients 
in this study, as available. The rationale for this is noted in a 2016 FDA Guidance document 
“Collection of Race and Ethnicity Data in Clinical Trials,” which states “…evidence must be 
reviewed to establish whether or not there are potentially clinically important sex-and 
racial/ethnic-based differences in the anticipated effects of the intervention.” ICH E5 is also 
cited in this Guidance document and states that the “Question and Answer Addendum to E5 
introduces the multi-regional clinical trial study design as one means to evaluate treatment 
response heterogeneity and extrapolation. Multi-regional clinical trials may present special 
situations for the collection and self-reporting of race and ethnicity.” (FDA 2016)
6.3
Treatment exposure and compliance
This information should be captured in the source document at each visit and specific CRFs. 
All study treatment dispensed and returned must be recorded in the Drug Accountability Log. 
Compliance will be assessed by the Investigator and/or study personnel using pill counts, liquid 
study medication assessment and information provided by the caregiver. This information 


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should be captured in the source document and specific CRFs. All study treatment dispensed 
and returned must be recorded in the Drug Accountability Log. The Investigator and/or study 
personnel should counsel the patient and his/her parent(s)/legal guardian-caretaker(s), as 
appropriate, if compliance is below 80% at any time during the study. Study drug accountability 
will be determined by the site monitor while performing routine site visits and at the completion 
of the study.
The duration of randomized treatment exposure will be calculated based upon the start and stop 
dates recorded in the CRF.
6.4
Efficacy
6.4.1
Efficacy assessment
The efficacy of LCZ696 compared to enalapril after 52-week of double-blind treatment is 
assessed using a global rank endpoint as outlined below (Table 6-3) (see Appendix 15 for USM 
exception). Clinical events (Categories 1 and 2) are adjudicated by an external independent 
adjudication committee. The NYHA/Ross classification (Criteria Committee NYHA 1994,
Ross 1992, Rosenthal 2004), PGIS, and PedsQL are conducted at randomization and end of 
study (and during the study as shown in Table 6-2 assessment schedule).
Table 6-3
Primary endpoint algorithm using ranked analysis
Category
Sub-category
Description
Ranking algorithm
1
Death; UNOS status 1A listing for heart transplant or equivalent; 
VAD/ECMO/mechanical ventilation/intra-aortic balloon pump requirement for 
life support at end of study.
A
Category 1: Death; 
UNOS status 1A listing 
for heart transplant or 
equivalent; 
VAD/ECMO/mechanica
l ventilation/intra-aortic 
balloon pump
requirement for life 
support at end of study.
Rank within this 
category by time to first 
event. All Category 1 
events are considered 
equal.
2
Worsening HF (WHF); defined by signs and symptoms of WHF that requires 
an intensification of HF therapy.


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Category
Sub-category
Description
Ranking algorithm
B
Worsening heart failure 
hospitalization with 
intensive care unit stay 
(HFH-ICU).
Within Category 2, the 
patients will be ranked 
first by event 
subcategory, and then 
by number of events 
within each 
subcategory. Further 
ranking by time to first 
event in the worst 
subcategory.
C
Worsening heart failure 
hospitalization without 
intensive care unit stay 
(HFH-No ICU).
Within Category 2, the 
patients will be ranked 
first by event 
subcategory, and then 
by number of events 
within each 
subcategory. Further 
ranking by time to first 
event in the worst 
subcategory.
D
Worsening heart failure 
without hospitalization
(WHF-No Hosp). 
Within Category 2, the 
patients will be ranked 
first by event 
subcategory, and then 
by number of events 
within each 
subcategory. Further 
ranking by time to first 
event in the worst 
subcategory.
3
Worsened; worse NYHA/Ross or worse Patient Global Impression of 
Severity (PGIS); and further ranking by PedsQL physical functioning 
domain.
E
NYHA/Ross or Patient
Global Impression of 
Severity (PGIS) 
worsened based on 
last available 
assessment compared
to baseline.
Rank by combination of 
NYHA/Ross and PGIS
degree of change. 
Within a group of the 
same degree of 
NYHA/Ross and PGIS 
change, further rank by 
PedsQL (physical 
functioning domain)
change from baseline.
4
Unchanged; unchanged NYHA/Ross and unchanged PGIS; and further 
ranking by PedsQL physical functioning domain.


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Category
Sub-category
Description
Ranking algorithm
F
NYHA/Ross and PGIS 
unchanged based on 
last available 
assessment compared 
to baseline.
Worst baseline 
combination of 
NYHA/Ross functional 
class and PGIS without 
change is ranked 
worse than a better 
baseline NYHA/Ross 
functional class and 
PGIS. Within a group of 
the same baseline 
NYHA/Ross and PGIS, 
further rank by PedsQL 
(physical functioning 
domain) change from 
baseline. 
5
Improved; improved NYHA/Ross or improved PGIS (neither can be worse); 
and further ranking by PedsQL physical functioning domain).
G
NYHA/Ross or PGIS 
improved based on last 
available assessment 
compared to baseline
Rank by combination of 
NYHA/Ross and PGIS 
degree of change. 
Within a group of the 
same degree of 
NYHA/Ross and PGIS 
change, further rank by 
PedsQL (physical 
functioning domain) 
change from baseline.
Changes in heart transplant status should be documented by completing a new ‘Heart Transplant 
Listing Endpoint’ CRF.
Worsening HF is defined as new or worsening symptoms and signs of HF that require an 
intensification of HF therapy. The symptoms of WHF include but are not limited to: dyspnea 
on exertion; dyspnea at rest; orthopnea; paroxysmal nocturnal dyspnea; decreased exercise 
tolerance due to fatigue; abdominal bloating/discomfort; tachypnea with feeding; diaphoresis 
with feeding; fatigue with feeding; feeding intolerance/emesis/weight loss and fluid retention. 
The signs of WHF include but are not limited to: pulmonary edema or rales; tachypnea or rapid 
respiration rate; increased jugular venous pressure; peripheral hypoperfusion; radiographic 
evidence of pulmonary edema, radiographic evidence of pulmonary vascular congestion, 
radiographic evidence of pleural effusion; hypoxemia; growth failure or failure to thrive; 
peripheral edema; hepatomegaly and any other sign consistent with heart failure. 
Treatments for worsening heart failure include intravenous diuretics, intravenous vasodilators, 
intravenous vasopressors, intravenous inotropes, mechanical fluid removal (e.g., ultrafiltration 
or dialysis), ventricular assist device, extracorporeal membrane oxygenation (ECMO), intra-
aortic balloon pump, mechanical ventilation, non-invasive ventilation, surgical or catheter-
based interventions. Treatment for worsening heart failure with oral medication includes the 
initiation or intensification of standing oral diuretics. Intensification of oral diuretics must be a 
50% increase or more of the daily maintenance dose for at least 2 weeks duration. For worsening 
heart failure characterized by growth failure or failure to thrive, treatments can include feeding 


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tube placement or parenteral nutrition (Section 3.3). Further details are documented in the 
Clinical Endpoint Committee (CEC) charter.
Primary endpoint Categories 3, 4 and 5 are ranked by NYHA/Ross class and PGIS score. The 
combined change from the end of study compared to baseline for both the NYHA/Ross class 
and the PGIS score will be used to rank patients from worst to best within categories 3, 4 and 
5. Within a group of patients with the same degree of combined NYHA/Ross and PGIS change, 
the PedsQL (physical functioning domain) change from baseline will be used to further rank 
these patients from worst to best. Further ranking within Categories 3, 4, 5 as needed (‘tie 
breaking’) will be based on a subset of 5 physical functioning domain questions of the PedsQL 
score (for patients 6 to < 18 years old). The PedsQL will not be used for the youngest two age 
strata (1 month to < 1 year and 1 to < 6 years), as the patient reported PedsQL data will not be 
collected for all patients in these strata. (Note: Patient < 5 years old only have a parent report 
for the PedsQL).
6.4.2
Secondary efficacy endpoints
The secondary efficacy endpoints include:

To determine whether LCZ696 is superior to enalapril in delaying time to first occurrence 
of the composite of either Category 1 or 2 events (e.g. death, worsening HF)

To determine whether LCZ696 is superior to enalapril for improving NYHA/Ross 
functional class

To determine whether LCZ696 is superior to enalapril for improving the Patient Global 
Impression of Severity (PGIS) score

To characterize the population PK of LCZ696 exposure in pediatric patients with HF. Also 
to further confirm the LCZ696 target dose for Age Group 2 using a population PK approach 
with steady-state sparse PK blood samples (i.e. 3 samples per patient drawn on the same 
day) collected from approximately 24 patients, approximately half of whom are expected to 
be randomized to LCZ696. Therefore, blood samples from approximately 12 patients 
randomized to LCZ696 will be used in the PK analysis.
 
 
 
 
6.5
Safety 
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety profile 
of the study drugs. Such information may include diagnostic procedure reports, discharge 


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summaries, autopsy reports, and other relevant information that may help in assessing the 
reported AE. All additional information is de-identified prior to collection by Novartis or its 
agents. In addition to AE/SAEs, the following safety related data will be collected:

Physical examinations

Vital signs

Height, weight, and head circumference (head circumference is only collected in patients 
≤3 years of age at enrollment)

Laboratory evaluations

Electrocardiograms (ECG)

Pregnancy

Angioedema
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
A complete physical examination will be performed at the screening visits for Part 1 (Visit 1) 
and Part 2 (Visit 301), and also the end of study Visit 416/499. An abbreviated physical 
examination will be performed at other in person visits as shown in Table 6-1 and Table 6-2. 
An abbreviated physical exam will include the examination of general appearance and vital 
signs (BP and pulse) as well as other examinations based on Investigator discretion.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the patient’s CRF. Significant findings made after 
signing the informed consent which meet the definition of an AE must be recorded on the AE 
section of the CRF. 
6.5.2
Vital signs 
Vital signs include BP and pulse measurements and are assessed when a complete or 
abbreviated physical examination is performed. BP will be measured in the sitting position after 
5 minutes of rest using an automated validated device (e.g. OMRON) or a standard 
sphygmomanometer with an appropriate size cuff on the non-dominant arm. Supine BP instead 
of sitting BP will be measured in patients who are infants or who cannot sit comfortably. 
Guidelines for the management of hypotension are provided in Appendix 4.
Vital signs (blood pressure and heart rate/pulse) will be collected at Visit 101, 201 during PK 
assessment (and unscheduled PK/PD visit if it occurs) at: 0, 30 min, 1 hr, 2 hrs, 3 hrs, 4 hrs, 5 
hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs, 18 hrs, and 24 hours post-dose LCZ696.
Vital signs at 11 hrs, 12 hrs and 18 hrs are optional unless the patient physically stays on-site. 
The 24-hr post dose vital signs will be measured if the patient either stays on-site or returns to 
the site the next day. The vital signs will be collected in Part 1 and Part 2 of the study as depicted 
in the assessment schedule (Table 6-1 and Table 6-2).


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For Part 2 Age Group 3 patients, starting with the first dose of study medication, vital signs 
need to be checked for up to 4 hours after the initial study medication dose at each dose level. 
Patients are to remain in the study site clinic for this 4-hour post-dose Vital Sign monitoring 
period. Vital signs are to be measured pre-dose (time 0), and post-dose at 0.5, 1, 2, 3 and 4 hours 
for the initial study medication dose at each dose level.
Clinically notable vital signs for this patient population are defined in Appendix 1.
6.5.3
Height/length, head circumference and weight 
Height/length in centimeters (cm) will be measured using a standard device at Visit 1 (Part1 
PK/PD- Screening), Visit 199 and/or Visit 299, Visit 301 (Part 2 Efficacy- Pre-
randomization/Screening), and Visit 416/499 (Week 52/Final Visit). Use of a stadiometer for 
standing height measurements is recommended.
For patients ≤ 3 years, head circumference in centimeters (cm) is measured at Visit 1 (Part 1 
PK/PD-Screening), Visit 199
and/or
Visit 299, Visit 301 (Part 2 Efficacy-Pre-
randomization/Screening), and Visit 416/499 (Week 52/Final Visit).
Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) is measured 
at every in-person visit. Body weight during hospitalization is to be recorded only if available 
as per standard of care. For patients 1 month to < 1 year old, last available study weight 
measurements will be used to ascertain dose. For patients who are 1 to < 6 years old, weight 
measurements every 3 months will be used for dose determination. For patients who are ≥6 
years old, weight measurement every 6 months will be used for dose determination.
6.5.4
Laboratory evaluations
Complete laboratory evaluations (hematology, blood chemistry, and urine) as outlined in Table 
6-4 are performed in Part 1 at Visit 1 (Screening), Visit 199 and/or 299, and in Part 2 at Visit 
301 (Screening), Visit 401 (Randomization), Visit 409 and Visit 416/499 (Week 52/Final Visit). 
Local laboratory should be used for Visit 1, 199, 299 and 301 for complete laboratory 
evaluations. Central laboratory should only be used for Visit 301, if local lab is unavailable 
using unscheduled visit. Central laboratory must be used for Visit 401, 409 and 416/499 for 
complete laboratory evaluations for all patients. Details on the collections, shipment of samples 
and reporting of results by the central laboratory will be provided to the Investigators in the 
laboratory manual. Patient can be randomized based on safety laboratory results from Visit 
199/299/301 unless the Investigator feels the need to wait for laboratory results from Visit 401.
Abbreviated safety laboratory evaluation consists of serum sodium, potassium, creatinine, and 
eGFR. Abbreviated safety laboratories should be performed locally. If the local laboratory is 
unavailable (either for abbreviated or complete labs), the central laboratory should be used as 
an unscheduled visit. Abbreviated laboratory evaluations are to be performed at Part 1 PK/PD 
Visits 101, 201, 103 to 120 (when patient comes to the site for a visit about every three months), 
203 to 220 (when patient comes to the site for a visit about every three months), UNS PK/PD; 
and Part 2 (Efficacy) Visits 402 (Abbreviated labs are optional if considered safe and where 
patient is not being up-titrated), 403, 404 (optional visit; Abbreviated labs are optional if 
considered safe and where patient is not being up-titrated), 405, 406, 412, 415 and as an optional
assessment at UNS TD, and UNS. For those patients who have Visits 299 and 301 on the same 


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day (for second PK dose patient) or Visits 199 and 301 on the same day (for the first PK dose 
only patient), laboratories will be performed only once. Local laboratory results will allow 
Investigators to proceed with study visit procedures without the need to wait for central 
laboratory results. The local laboratory results must be recorded in the appropriate CRF. Given 
limitations of blood volume, the local laboratory assessments will be a priority for urgent 
medical decision making (including for study drug dose titration). 
Local and central laboratory results need not agree in order for the Investigator to qualify a 
patient for the trial or make a dose titration decision. A patient enrolled in the study based on 
local laboratory results and subsequently determined to be above an exclusion criteria based on 
central laboratory results may be continued or discontinued from the study at the discretion of 
the Investigator. The Investigator should use his/her clinical judgment on how best to manage 
the study drug dose level in the event a dose titration decision based on a local laboratory results 
is subsequently found to be discrepant with central laboratory results. If the central laboratory 
is used, it may take up to 72 hours or more to obtain the results.
For child bearing potential females only, serum pregnancy testing will be performed at Visit 1 
(Part 1 PK/PD - Screening), Visit 301 (Part 2 Efficacy- Pre-Randomization/Screening) and Visit 
416/499 (Part 2 Week 52/End of Study). Child-bearing potential females (CHBP) are defined 
as all female patients ≥ 11 years of age and all female patients who are <11 years of age if they 
are menstruating. Patients with a positive urine/serum pregnancy at any time in the study must 
be excluded. Urine pregnancy test is analyzed locally and done at all visits on all CHBP female 
patients (for additional details regarding urine pregnancy testing requirements for visits 407, 
408, 410, 411, 413, and 414, please see Table 6-2). Serum pregnancy test will be analyzed 
centrally (for Visit 416/499) or locally (for Visits 1 and 301). A positive urine pregnancy test 
should be confirmed with a serum pregnancy test.
Table 6-4
Laboratory examinations
Hematology
Biochemistry
Urine measurements**
Hematocrit 
Alanine aminotransferase (ALT)
Specific gravity
Hemoglobin
Albumin (Alb)
pH
Platelet count
Alkaline phosphatase (ALP)
Glucose
Red blood cell count (RBC)
Aspartate aminotransferase 
(AST)
Protein (Total)
White blood cell count (WBC)
Blood urea nitrogen (BUN)
Ketones
WBC differential
Calcium
Bilirubin
Magnesium
Urobilinogen
Phosphate
Hemoglobin (blood)
Red blood cell distribution width 
(RDW)
Chloride
Leukocyte esterase
Mean corpuscular volume 
(MCV)
Creatinine*
Nitrite
Mean corpuscular hemoglobin 
concentration (MCHC)
Glucose
WBC
Potassium*
RBC sediments
Sodium*
Hyaline casts


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Hematology
Biochemistry
Urine measurements**
Bicarbonate
Granular casts
Total bilirubin (TBL)
Waxy casts
Fractionated bilirubin (if total 
bilirubin >2x ULN)
WBC casts
Total protein
RBC casts
Uric acid
eGFR*
*Abbreviated laboratory evaluations must include these parameters
**Urinalysis with dipstick includes specific gravity, pH, glucose, total protein, bilirubin, ketones, 
urobilinogen, nitrite, leukocytes esterase and hemoglobin (blood). Other urine measurements listed are 
not required. If a urine dipstick is positive, other urine measurements such as a qualitative microscopic 
determination of WBC, RBC sediments (and casts) will also be measured.
Study procedures may be performed without restriction while the central laboratory results are 
pending. In these cases, the Investigator or his/her designee should review the central laboratory 
results as soon as they become available to decide on whether any adjustments in the patient’s 
study drug or non-study drug regimen are needed.
Abnormal laboratory values (as defined in Appendix 1) may require additional laboratory 
evaluations be performed, as judged appropriate by the Investigator. If the laboratory 
abnormality induces clinical signs or symptoms, or requires therapeutic intervention, then the 
diagnosis or medical condition must be entered on the AE page of the patient's CRF. 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 from the 
study drug (temporarily or permanently), the patient must be followed until the abnormality 
resolves or until it is judged to be permanent. This investigation may include continued 
monitoring by repeat laboratory testing or by performing additional laboratory tests as deemed 
necessary by the Investigator or the Novartis medical monitor.
A table which provides the maximum, allowable blood-draw volumes by weight can be found 
in Appendix 6. 
There are countries where plasma potassium is used instead of serum potassium for routine 
clinical care. Plasma potassium can be used instead of serum potassium in this study. Serum 
potassium thresholds in the study protocol, including those values cited in Appendix 1 and 
Appendix 5, can be converted to plasma potassium thresholds for the study by subtracting 0.4 
mmol/L from the serum potassium threshold (Hartland 1999).
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, MCV, MCHC, RDW, white blood cell count 
with differential counts, and platelet count are to be measured as part of the complete laboratory 
assessments (Table 6-4) at scheduled study visits (Table 6-1 and Table 6-2). Results from the 
local laboratory are to be recorded in the CRF.


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6.5.4.2
Clinical chemistry
Blood urea nitrogen (BUN), serum creatinine, total bilirubin, fractionated bilirubin (if total 
bilirubin >2x ULN (upper limit of normal)), AST, ALT, alkaline phosphatase, sodium, 
potassium, chloride, calcium, phosphate, magnesium, bicarbonate, total protein, albumin, uric
acid, glucose are measured as part of complete laboratory assessments (Table 6-4) at scheduled 
study visits (Table 6-1 and Table 6-2). Results from local laboratory are to be recorded in the 
CRF.
6.5.4.3
Estimated GFR
Estimated glomerular filtration rate (eGFR) as per Schwartz formula (Schwartz 2009) will be 
calculated and reported by the central laboratory whenever a serum creatinine is performed by 
the central laboratory. eGFR must be calculated by the laboratory or the Investigator for local 
labs.
The calculation is based on the following formula:
eGFR (ml/min/1.73m2) = 0.413 x height (cm) / serum creatinine (mg/dl)
Height will be provided by the site to the local and/or central lab.
For eGFR, baseline value for the decrease from baseline criterion for the analysis will be 
calculated from screening for local labs and from randomization for central labs.
6.5.4.4
Urinalysis
Urinalysis with dipstick includes specific gravity, pH, glucose, total protein, bilirubin, ketones,
urobilinogen, leukocyte esterase, nitrite and hemoglobin (blood). If a urine dipstick is positive, 
other urine measurements such as a qualitative microscopic determination of WBC and RBC 
sediments (and casts) will also be measured. 
Urinalysis will be performed for all patients at Visit 1 (Part 1 PK/PD - Screening), Visit 199
and/or 299 and Part 2 (Efficacy) Visit 301, Visit 401, Visit 409, and Visit 416/499 (Week 
52/End of Study). For those patients who have visits 299 and 301 (for second dose PK), or Visit 
199 and Visit 301 (for the first dose PK) on the same day, urinalysis will be performed only 
once.
6.5.4.5
Biomarkers
 
 
 
 
 
In Part 1 (PK/PD) (in the absence of the above-mentioned collection / sample handling issues): 
plasma BNP, plasma and urine cGMP and plasma NTproBNP samples are collected at Visits 
101, 201 and UNS PK/PD (if performed). Plasma BNP and plasma cGMP are collected at pre-
dose, 4 hour and 8 hour time points post-dose. Plasma NTproBNP is collected at pre-dose and 
24 hours post-dose (optional). Urine cGMP is collected at pre-dose and between 4-8 hours. 


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At Visit 101, 201 or UNS PK/PD (if performed), infants who weigh < 15.5 kg will only have
plasma cGMP and BNP collected; infants who weigh ≥ 15.5kg, will have three biomarker 
(plasma BNP, cGMP and plasma NTproBNP) samples collected as long as blood volume 
restriction allows.
Urine cGMP should be collected in Part 1 (PK/PD) at Visit 101, 201 and UNS PK/PD (if 
performed) at pre-dose and once at any time between 4 to 8 hours after LCZ696 single dose 
administration. 
Details about biomarker prioritization when blood volumes are restrictive; blood volume 
requirements for each of the biomarkers; sample collection, processing and storage are provided 
in the laboratory manual.
Details about blood sample collection for biomarkers in Part 1 are also provided in Table 3-2. 
 
6.5.5
Electrocardiogram (ECG) 
ECGs are conducted at Visit 1 (Part 1 PK/PD - Screening), Visit 199 and/or 299, and Visit 301 
(Part 2 Efficacy - Pre-Randomization/Screening) and Visit 416/499 (Week 52/End of Study). 
ECGs are interpreted locally for study entry and for purpose of safety assessment. For those 
patients who have Visit 299 and Visit 301 (for second dose PK) or Visit 199 and Visit 301 (for 
the first dose PK) on the same day, ECG will be performed only once.
ECGs must be recorded in the supine position, after at least 10 minutes rest if possible to ensure 
a stable baseline. The preferred sequence of cardiovascular data collection during study visits 
is ECG collection first, followed by vital signs, and blood sampling The Fridericia QT 
correction formula (QTcF = (QT/[RR]0.33)) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs, appropriately signed by the ECG reader, 
must be collected and archived at the study site.
Each ECG tracing must be labeled with study number, subject initials, subject number, date and 
time, and filed in the study site source documents. For any ECGs with subject safety concerns, 
two additional ECGs must be performed to confirm the safety finding. Clinically significant 
ECG findings at baseline must be discussed with the sponsor before administration of study 
treatment.
Clinically significant ECG abnormalities must be recorded on the relevant section of the 
medical history or adverse event CRFs as appropriate.
6.5.6
Left ventricular ejection fraction (LVEF) or fractional shortening 
assessments
All patients entering Part 1 (PK/PD) will require a qualifying LVEF or fractional shortening 
assessment by echocardiogram, MRI, MUGA or left ventricular angiogram. If a qualifying 
LVEF or fractional shortening assessment is not available, the patient may enter the study based 
on a qualifying echocardiogram performed during the screening epoch between Visit 1 and 


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before patient receives the first dose of open label LCZ696 (Visit 101or V 201). Patients who
have participated in Part 1 (PK/PD) and continue to Part 2 (Efficacy) need a repeat assessment 
of LVEF or fractional shortening in order to determine eligibility for Part 2 (Efficacy) unless 
the most recent assessment is
within 1 month prior to Visit 301
(Part 2 Pre-
Randomization/Screening). 
Patients entering directly into Part 2 (Efficacy) will require a LVEF or fractional shortening 
assessment obtained within 1 month prior to Visit 301 (Part 2 Pre-Randomization/Screening). 
If a qualifying LVEF or fractional shortening assessment (echocardiogram, MRI, MUGA, or 
left ventricular angiogram) within 1 month of Visit 301 is not available, the patient may enter 
the study based on a qualifying echocardiogram performed during screening before the patient 
receives study treatment.
6.5.7
Pregnancy and assessments of fertility 
Pregnancy test (urine) is analyzed locally and done at all visits on all female patients ≥11 years 
of age and all female patients who are <11 years of age if they are menstruating (for additional 
details regarding urine pregnancy testing requirements for visits 407, 408, 410, 411, 413, and 
414, see Table 6-2). In addition, serum pregnancy test is only conducted at Visit 1 (Part 1 PK/PD 
- Screening), Visit 301 (Part 2 Efficacy-Pre-Randomization/Screening) and Visit 416/499 (Part 
2 at Week 52/End of Study); and serum pregnancy test will be analyzed centrally (for Visit 
416/499) or locally (for Visits 1 and 301). A positive urine pregnancy test should be confirmed 
with a serum pregnancy test.
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 with the patient and her 
parents/caregivers are therefore best performed by Investigators familiar with the pediatric 
patient 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 patient and her parents/caregivers. The 
privacy of the patient should be considered in accordance with the local law and ethics.
Any patient with a positive pregnancy test must discontinue study drug immediately and the 
patient should remain in study and continue to attend scheduled study visits.
6.5.8
Angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise. 
It is important that the Investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the Investigator will complete angioedema case report forms to summarize the 
event, its treatment, and its ultimate outcome. This report along with the requisite medical 


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documentation must be submitted to Novartis as soon as possible. Follow-up reports must be 
communicated to Novartis as soon as new information regarding the event becomes available. 
All hospital records related to the event must be communicated to Novartis. 
The Investigator may also be contacted by Novartis and complete specific forms regarding AEs 
that may resemble an angioedema-like event. The Investigator or his/her delegated staff must 
complete the required forms and provide the required medical records for all such events, 
regardless of whether the Investigator views the event in question as angioedema or not.
All angioedema reports will be forwarded to an external independent Angioedema Adjudication 
Committee by Novartis for assessment. 
Information regarding this committee is outlined in Section 8.4. Details on the procedures for 
reporting angioedema events will be provided to Investigators in a manual.
6.5.9
Appropriateness of safety measurements 
The safety assessments selected for this trial are standard assessments for demonstrating safety 
in this pediatric patient population, based on safety data from adult LCZ696 studies 
(Investigator Brochure), and in accordance with guidelines (ICH E11 Clinical Investigation of 
Medicinal Products in the Pediatric Population). 
6.6
Other assessments
6.6.1
Clinical outcome assessments (COAs)
6.6.1.1
Clinician reported outcomes (ClinRO)
The impact of study drug on the patient’s physical functional status will be assessed using the 
NYHA classification I-IV (older children: 6 to < 18 years old) or Ross HF classification I-IV 
(younger children: l month to < 6 years old). The NYHA and Ross functional class assessments 
are reliable instruments for rating HF patients’ functionality (Criteria Committee NYHA 1994, 
Ross 1992, Packer 2001, Rosenthal 2004). 
The NYHA functional class system is commonly used and is a clinically important system for 
staging the severity of HF (Spertus 2005). Similar to NYHA, the Ross classification system is 
a common system for grading the severity of HF in infants (Ross 1992). The most recent 
pediatric HF Guidelines from the International Society of Heart and Lung Transplant (ISHLT)
mention both NYHA and Ross as Heart Failure Severity Classifications (Kirk 2014). A one 
class change in the NYHA or Ross functional class scale is considered to represent a clinically 
significant change (Ross 1992, Madsen 1994) based on the fact that the four stages in each 
classification differ considerably in severity.
Assessment of NYHA/Ross class will be conducted at screening visits for Part 1 (Visit 1) and 
Part 2 (Visit 301); randomization for Part 2 (Visit 401); end of study for Part 2 (Visit 416/499), 
and other visits as per Table 6-1 and Table 6-2.
For the duration of Part 2, the same PedsQL, NYHA and Ross instruments based on the age at 
randomization should be used.


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6.6.1.2
Patient reported outcomes (PRO)
The impact of HF on the patient’s status will be assessed by the following measures:

Patient global impression of severity (PGIS)

Pediatric quality of life inventory (PedsQL) 4.0 generic scales
All questionnaires will be completed in the language most familiar to the respondent, and at the 
scheduled study visit prior to the patient seeing the Investigator for any clinical assessment or 
evaluation. The patient should be given sufficient instruction, space, time and privacy to 
complete the questionnaire. The study coordinator should check the responses to the 
questionnaire for completeness and encourage the patient to complete any missing responses.
A detailed training manual relating to the administrative procedures of the questionnaires will 
be provided to the sites. The Investigator enters the data from the questionnaire into the CRFs. 
The original questionnaire will be kept with the patient’s file as the source document. 
In Part 2 the patient or parent/caregiver will complete the patient reported outcome (PGIS,
and PedsQL) evaluations based on age at randomization.
Patient global impression of severity (PGIS)
The patient global impression of severity (PGIS) is a static global impression of severity 
question that will be used to capture the patients’ current health status relative to their heart 
failure over 7 days recall period.

Patient (7 to < 18 years old): How would you describe the severity of your heart failure 
symptoms over the past 7 days? (None / Mild / Moderate / Severe / Very Severe)

Parent (for < 5 years old patients): How would you describe the severity of your child’s 
heart failure symptoms over the past 7 days? (None / Mild / Moderate / Severe / Very 
Severe)

A 3-point faces scale (corresponding/coded to Good / Neither Good nor Bad/ Bad) will be 
used for patient self-report by children 5 to < 7 years (Appendix 8). 
For the global rank primary endpoint, a one class change in the PGIS is considered to represent 
a clinically significant change. The patient PGIS report will be used for the Global Rank 
endpoint for patients ≥ 5 years old.
Given the nature of heart failure symptoms, the PGIS will be performed when the patient is at 
rest and at the same location during the study visit. Additionally, instructions will be provided 
to the child and/or parent/caregiver that describe several symptoms of heart failure for 
consideration while responding to the PGIS. When the pediatric patient is completing the PGIS, 
the parent/caregiver will be instructed to not interfere with the child’s response. There will be 
standardized instructions for patient and parent/caregiver to complete the PGIS. If a child is 
unable to complete the PGIS, this will be noted. If a patient 5 years and older is unable to 
complete the assessment, the assessment will be considered not done. The parent/caregiver 
PGIS report will only be used for the Global Rank endpoint for patients < 5 years old because 
patients < 5 years old are not considered mature enough to complete the patient PGIS self-report.


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Parents and caregivers should be instructed to minimize any interaction, assistance and 
influence on the patient while the patient is completing the PGIS.
Patient or parent/caregiver will complete the PGIS at randomization for Part 2 (Visit 401); end 
of study for Part 2 (Visit 416/499), and other Part 2 visits as per Table 6-1 and Table 6-2.
Pediatric quality of life inventory (PedsQL)
The PedsQL is a patient-reported outcome instrument that evaluates health related quality of 
life in healthy children and adolescents and in pediatric patients with acute and chronic health 
conditions (Varni 2003, 2011). The PedsQL has published data in over 25,000 children and 
adolescents in multiple disease areas including pediatric cardiology (Varni 2003; Uzark 2008). 
The PedsQL has been validated in multiple pediatric disease populations and has demonstrated 
responsiveness to meaningful clinical change (Uzark 2008, Uzark 2013, Desai 2014). The 
PedsQL is the most widely used pediatric patient reported outcome assessment, and it is 
currently being used in the PEDIMACS (pediatric mechanical circulatory support devise) 
registry (INTERMACS protocol 2014) and in an observational study of pediatric solid organ 
transplant recipients (ClinicalTrials.gov 2008).
 
The physical functioning domain of questions that focuses on 
proximal effects of health-related quality of life related to heart failure will be used for the 
Global Rank primary endpoint. The responsiveness of the PedsQL physical functioning domain 
in pediatric patients with cardiovascular disease has been demonstrated in several studies. In a 
prospective study of 475 families including 347 children with cardiovascular disease, the 
PedsQL score for physical functioning by patient self-report was significantly lower than the 
norms for healthy children (Uzark 2008). In this study, PedsQL physical functioning scores 
were also significantly lower for patients with more severe cardiovascular disease compared to 
milder cardiovascular disease. In a study of 126 families from Sweden with congenital heart 
disease, the PedsQL physical functioning scores were significantly lower for patients with more 
severe compared to mild/moderate congenital heart disease; and PedsQL physical functioning 
scores were also significantly lower comparing non-operated to operated congenital heart 
disease (Sand 2013). PedsQL physical functioning scores were significantly lower for children 
who received a heart transplant compared to healthy peers and children who received curative 
heart surgery (Uzark 2012). Another study demonstrated that children with the more severe 
condition of hypoplastic left ventricle had significantly lower PedsQL physical functioning 
scores compared to the less clinically severe tetralogy of Fallot pediatric patients (Eagleson 
2013).
The PedsQL is administered to both the patient via child self-report and the patient’s 
parent/legal guardian-caretaker via parent proxy-report. The PedsQL requires on average 5 
minutes for completing. A 5-point response scale is used for 8-18 years old patients; while a 3-
point scale is used for 5-7 years old patients. 
 
 
 
The patients’ self-report will be used for the primary endpoint for patients 
≥ 6 years. 
 


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Parents and caregivers should be instructed to minimize any interaction, assistance and 
influence on the patient while the patient is completing the PedsQL. The patient’s age at 
randomization (Part 2 Efficacy - Visit 401) will be utilized to determine the corresponding 
PedsQL questionnaire to be administered at that visit and all subsequent visits.
The PedsQL will be completed at randomization for Part 2 (Visit 401); end of study for Part 2 
(Visit 416/499), and other Part 2 visits as per Table 6-2.
 
 
 
 
 
 
 
 
 
 
 
 
 
6.6.2
Pharmacokinetics
Part 1 (PK/PD)
At Visit 101, 201 and UNS PK/PD the PK samples will be collected at the following intervals 
for the various age groups:

Patients >6 years of age: Blood samples  are collected at pre-dose (pre-dose sample for all 
patients) 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing

Patients <6 years of age: Blood samples  are collected at pre-dose (pre-dose sample only 
from those patients who are on valsartan) 1, 2, 4, 10, and at an optional 24 hours post 
dosing
The exact time of the treatment administration, dose of LCZ696, sample number, and time of 
sample collection are recorded for each sample collected in the CRF. Sampling problems are to 


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be documented in the CRF and may include but are not limited to hemolyzed samples, 
insufficient sample volumes, and/or a lack of sample collections.
The plasma levels of LCZ696 analytes are determined using a validated LCMS/MS method 
with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, 
and 10 ng/mL for valsartan. The detailed method description of analysis will be included in 
bioanalytical report.
The following PK parameters will be determined for LCZ696 analytes (sacubitril, LBQ657, and 
valsartan) using Phoenix version 6.2 or higher using non-compartmental methods: Cmax, Tmax, 
AUClast, AUCinf, T1/2, Cl/F, and other relevant PK parameters (data permitting). In case of data 
limitations for estimating PK parameters using non-compartmental methods, a population PK
approach will also be used to estimate exposure of LCZ696 analytes.
The information about pharmacodynamic parameters (biomarkers) is provided in Table 3-2 and
Section 6.5.4.5.
Part 2 (Efficacy)
Population PK data collection:
Pre-dose PK blood samples will be collected at Visit 403, Visit 406, and Visit 416/499 for 
population PK analysis (see Appendix 15 for USM exception). Every effort should be made to 
collect PK samples at all three visits. If a PK sample is not obtained at Visit 403 or 406, the PK 
sample can be collected at a subsequent scheduled or unscheduled visit. A population PK blood 
sample should only be obtained if permissible by blood volume limits (Appendix 6). 
Steady-state sparse PK data collection (Group 2 patients only): 
In approximately 24 patients (approximately half of whom are expected to be randomized to 
LCZ696) in Group 2 (1-<6 years old), sparse PK blood samples will be collected at steady-state, 
at approximately 3 time-points on the same day, at Visit 405 or at a subsequent scheduled or 
unscheduled visit (with the exception of Visit 406 and 416/499), when the patient is on Dose-
Level 4 or at his/her highest tolerated dose for at least 1 week. The study site personnel are to 
confirm that blood volume restrictions for each patient are not an issue for the patient before 
blood sampling for steady-state sparse PK Visit is started. Patients will be instructed to hold 
their morning dose the day of the steady-state, sparse PK Visit to enable the collection of a pre-
dose blood sample. The time of the last dose taken the day before the sparse PK visit will be 
recorded in the CRF. Patients will take their morning dose at the study site after the pre-dose
blood sample is collected. Two additional blood samples will be collected at 2 hours post dose 
and 6 hours post dose. In this sub-set Age Group 2 patients, collection of additional PK blood 
samples for Population PK at Visits 406 and 416/499 will not be required.
Table 6-5
Sparse PK Assessment Schedule Part 2 Group 2 Subset
Timepoint
Visit 405 (week 8)
# Visit 409,412,415, UNS
Pre-dose
X
X#
2 hours post-dose
X
X#
6 hours post dose
X
X#


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# If sparse PK blood samples cannot be collected at V405 than one of the following visits can be used 
for collection of the sparse PK samples: Visit 409, Visit 412, Visit 415 or an UNS visit.
Steady state concentrations of valsartan, sacubitril, and LBQ657 will be analyzed by graphical 
methods to determine an appropriate structural PK model to fit the data. Data obtained from 
Part 1 will also be included in this PK modeling. Following this, a population PK model will be 
developed using the data obtained from this study and/or in combination with PK data obtained 
from other studies to quantify PK of valsartan, sacubitril, and LBQ657. Significant covariates 
that influence PK properties of these analytes will also be examined.
Patients/caregivers should be instructed not to take their morning dose of study treatment during 
the PK blood sample collection visits. 
For the Population PK blood samples that are to be collected at Visits 403, 406, and 416/499, 
if a patient takes his or her morning study drug dose prior to obtaining the PK blood sample, 
the PK blood sample must still be collected and the actual time of study drug dosing and sample 
collection time must be recorded. 
For the sparse PK samples that are to be collected at the sparse PK Visit for Age Group 2 
patients, if a patient takes his or her study drug dose the morning of this sparse PK Visit, the 
patient will be asked to return at a later date to complete the sparse PK blood sample collection 
Visit.
All samples are given a unique sample number and a collection number (laboratory manual). 
The exact time of the treatment administration, study drug dose, sample number, and time of 
sample collection are recorded for each sample collected on the CRF. Whether the patient fasted 
prior to the single dose PK assessment should also be collected in the CRF. Sampling problems 
may include but are not limited to hemolyzed samples, insufficient sample volumes, and/or a 
lack of sample collections are to be documented in the CRF. PK samples are to be collected 
when the patient is expected to be at steady state, i.e., patient has been receiving the study drug 
regularly on the same dose levels as prescribed for at least 1 week.
PK blood sample handling
The PK section of the (Laboratory Manual) for this study will provide details regarding sample 
handling including collection, labeling, processing, storage and shipping. The Laboratory 
Manual will also provide details regarding which samples to exclude if blood volume is an issue.
7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.


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The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant 

they require therapy
Clinically significant abnormal laboratory values or test results 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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the AE CRF under the signs, symptoms or diagnosis 
associated with them, accompanied by the following information:

the severity grade 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

investigational treatment dosage adjusted/temporarily interrupted 

investigational treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (refer to Section 7.2 for definition 
of SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 


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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 has then to be discussed with the patient.
The Investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the Investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
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:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (refer to Annex IV, ICH-E11D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (refer to Annex IV, ICH-E11D Guideline).


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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days 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.). Any SAEs experienced after the 30 day period after the 
last study visit should only be reported to Novartis if the Investigator suspects a causal 
relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations
regarding reporting timelines prevail.). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signatures are to be found 
in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Drug Safety and Epidemiology 
Department associate may urgently require further information from the Investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
Investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.


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7.3
Protocol specific unblinding rules
7.3.1
Adverse events that are commonly seen in the study population 
Investigators will report AEs or SAEs that are commonly seen in the study population, but they 
will not be unblinded and will not be reported as SUSARs to regulatory agencies, ethics 
committees (ECs), or Investigators during the study (Table 7-1). 
These SAEs will be reviewed by an external independent DMC (Section 8.3) appointed to 
monitor the safety of study participants. If the DMC observes a clinically important imbalance 
in the AEs or SAEs, it will inform Novartis. Novartis will then inform all health authorities, 
ECs, and Investigators in an expedited manner and implement any additional actions required.
These events will be presented in the clinical study report (CSR) at the end of the study.
Table 7-1
Adverse events (AEs) 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
Study-specific unblinding rules for SUSARs that are disease related and 
present efficacy endpoints
The integrity of this study may be compromised, if the blind is systematically broken for 
SUSARs that could also be efficacy endpoints [for relevant EU guidance please refer to the 
European Commission ENTR/CT 12 Guideline (2006), FDA Guidance 2012]. Therefore, the 
rules for unblinding will apply as follows.

A SUSAR will not be unblinded, if it could represent one of the following pre-specified 
disease related endpoints:

Death (All cause, Cardiovascular, Non-cardiovascular), Ventricular Assist 
Device/ECMO/Mechanical Ventilation/Intra-aortic Balloon Pump requirement, 
Worsening HF (with and without hospitalization)
In addition, no report to competent authorities and relevant EC and no issuance of an 
Investigator Notification (IN) will occur. An external independent DMC (Section 8.3) has been 
previously appointed and will review efficacy and safety data of the ongoing trial on a regular 
basis. DMC opinion and recommendations will be notified by Novartis as soon as possible to 
the competent authorities and the ECs where they qualify for expedited reporting.
If specifically requested by a local Health Authority (HA), pre-specified endpoints (see above) 
that also meet the criteria for SUSARs will be expedited to this HA as blinded reports. INs will 
not be issued for these events.


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Any other SUSAR that will not meet the pre-specified disease related endpoints as mentioned 
above will be unblinded and a report to competent authorities and relevant ethics committees 
and issuance of an IN will occur.
7.4
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities/AEs have to be considered during the course of 
the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the Investigator or designated personal at the trial site as summarized below. 
Follow up information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at the central laboratory as soon as 
possible. If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate
For the liver events:

repeating the LFT to confirm elevation as appropriate

discontinuation of the investigational drug if appropriate

hospitalization of the patient if appropriate

a causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)

an investigation of the liver event which needs to be followed until resolution
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultation. These investigations can be performed based on Investigator’s 
discretion. All follow-up information, and the procedures performed should be recorded on 
appropriate CRF pages, including the liver event CRF pages.


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7.5
Renal safety monitoring 
To ensure patient safety and enhance reliability in determining the nephrotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
renal events has to be followed. 
The following two categories of renal AEs have to be considered during the course of the study:
1. Serum event:

Confirmed (after ≥ 24h) decrease in estimated glomerular filtration rate (eGFR) of ≥ 
25% compared to baseline during normal hydration status as estimated by Schwartz 
equation AND eGFR <90 mL/min/1.73m2
2. Urine event:

New onset (≥1+) proteinuria, hematuria or glucosuria

New onset of proteinuria should be confirmed by urinary protein creatinine ratio 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the Investigator or designated personnel. 
7.6
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, patient 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 collected in 
the DAR CRF irrespective of whether or not associated with an AE/SAE and reported to Safety 
only if associated with an SAE (Table 7-2). Misuse or abuse will be collected and reported in 
the safety database irrespective of it being associated with an AE/SAE.
Table 7-2
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration 
(DAR) CRF (Yes/No)
Document in AE 
CRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE.
Only if associated with an 
SAE.
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE.
7.7
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 


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the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications (with up to 12 months follow up after the birth of the baby, where 
consent is provided).
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
Investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
Site monitoring
Before study initiation, at a site initiation visit, or at an Investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the Investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the CRFs, the 
adherence to the protocol and to GCP, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The Investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients/subjects 
will be disclosed.


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8.1
Data collection
Designated Investigator staff will enter the data required by the protocol into the clinical 
database system. Designated Investigator site staff will not be given access to the system until 
they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated Investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the Investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.2
Database management and quality control
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
Investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will make 
the correction to the database. The signed copy of the Data Query Form is kept at the 
Investigator site.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Laboratory samples processed centrally will have results sent electronically to Novartis.
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated Clinical Research Organization (CRO)).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded 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.
8.3
Data monitoring committee (DMC)
An external and independent DMC will evaluate the unblinded data during the course of study, 
which will be provided by an independent and external Statistical Data Analysis Center. Data 


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may also be provided to Health Authorities, if required for an ongoing marketing authorization 
application regulatory review and Novartis will inform the DMC should this occur.
In addition, the DMC will review efficacy data from one prespecified interim efficacy and 
futility analysis when at least 180 patients and at least 36 patients from each age group have 
completed the study (i.e. reached a terminal endpoint or completed the 1 year study visit), and 
at least 40 patients have had an event in Category 1 or 2. Further details about interim analyses 
are provided in Section 9.6. 
As necessary, the DMC may also review the data associated with the analysis of sparse PK 
steady state data from a subset of patients in Part 2 Group 2 (Section 9.5.1).
Both the DMC and Novartis (Section 8.5) will be responsible for the review of Part 1 PK/PD
data and dose determination for Part 2 (Efficacy). Any major recommendation from the DMC 
will be communicated to the study Executive Committee and must be reviewed and ratified by 
the study Executive Committee in consultation with Novartis prior to its enactment. Further 
information is provided in the DMC Charter.
8.4
Adjudication committee 
Clinical endpoint committee
All clinical events, which could potentially fulfill the Category 1 or 2 endpoints will be assessed 
during the study and reported to the Clinical Endpoint Committee for adjudication.
The CEC will review and adjudicate events including but not limited to deaths (CV and non-
CV death), circulatory and/or respiratory mechanical assistance for life support, listing for heart 
transplantation, and clinical worsening of heart failure (with or without hospitalization) for 
endpoint determination. The detailed definitions of the endpoints, required documentation, and 
the adjudication process will be included in a separate CEC Manual. 
Sites are instructed to take a conservative approach when reporting endpoints. If the Investigator
suspects an endpoint may have occurred, it is best to report the event in the endpoint CRF. 
Angioedema adjudication committee
If an angioedema or angioedema-like event occurs, the Investigator will complete case report 
forms for angioedema adjudication. Details on the process of reporting angioedema and 
angioedema-like events are outlined in a manual provided to Investigators.
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
If an angioedema-like event satisfies the definition of an SAE, the Investigator must submit an
SAE report in addition to the adjudication report for an angioedema-like event.
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites.
8.5
Part 1 PK/PD data review
As described in Section 3.1, the age groups will be enrolled sequentially from Group 1 to Group 
3. For the oldest age group (Group 1: 6 to < 18 years), the PK, PD, and safety data obtained 
from all 12 observations will be reviewed by the DMC prior to starting Group 2 in Part 1 and 


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to support the dose recommendation before patients will be enrolled into Part 2 of the same age 
group. Similarly, for Group 2 (1 to < 6 years), the PK, PD, and safety data obtained from all 12 
observations will be reviewed by the DMC prior to starting Group 3 in Part 1 and to support the 
dose recommendation for Part 2 of the same age group. For Group 3 (1 month to < 1 years) the 
PK, PD, and safety data obtained from approximately 8 observations will be reviewed by the 
DMC to support the dose recommendation for Part 2 in the same age group. All suspect 
abnormalities will be discussed before enrollment into the next dose group/age group is allowed. 
The decision on the dosing for Part 2 (Efficacy) for each age group will be made jointly by 
Novartis and the DMC.
Data review is anticipated to include the following, when available: 

AEs and SAEs and their causal relationship to the study drug

Evidence of pharmacodynamic interactions between LCZ696 and co-medications

Vital signs 

Blood chemistry and hematology

PK and PK/PD response
9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the Investigator should be submitted to Novartis before publication 
or presentation.
9.1
Analysis sets
For Part 1: All subjects with at least one dose of study drug will be included in safety analysis 
set. All subjects with evaluable PK/PD data will be included in the PK/PD data analysis.
For Part 2 (Efficacy), the following populations will be used for the statistical analyses 
The full analysis set (FAS) will consist of all randomized patients with the exception for those 
patients who have not been qualified for randomization and have not received study drug, but 
have been inadvertently randomized into the study. Following the intent-to-treat principle, 
patients will be analyzed according to the treatment to which they were assigned at 
randomization. Efficacy variables will be analyzed based on the FAS as the primary population.
The Safety Population (SAF) will consist of all patients who received at least one dose of study 
drug and have at least one post-baseline safety assessment. Of note, the statement that a patient 
had no AEs also constitutes a safety assessment. Patients will be analyzed according to the 
treatment actually received. The safety population will be used for the analyses of safety 
variables. 
The Per-Protocol (PP) population will be a subset of the FAS which will consist of the patients 
who do not have major deviations from the protocol procedures in the double-blind study stage. 
Major protocol deviations will be pre-specified prior to unblinding treatment codes for analyses. 
This supplemental efficacy population will be used to support the primary analysis results.


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9.2
Patient demographics and other baseline characteristics
Summary statistics for Part 1 (PK/PD) and Part 2 (Efficacy) will be provided by treatment group 
for demographics and baseline characteristics, including age, age group (Group 1: 6 to < 18 
years; Group 2: 1 to < 6 years; Group 3: 1 month to < 1 year), modified age group (Group 1: 6 
to < 18 years; Group 2a: 2 to < 6 years; Group 3a: 1 month to < 2 years), sex, race, ethnicity, 
weight, height, body mass index (BMI), category of prior HF medication, HF etiology, prior 
HF hospitalization, NYHA/Ross class,
 and vital signs. BMI will be calculated as 
weight (kg) / height2 (m2) from the collected height and weight at the Screening visit. 
Continuous variables will be summarized using n, mean, standard deviation, median, minimum, 
and maximum. Categorical variables will be summarized using frequency and percentage. 
Additionally, summary statistics will be provided by treatment and age group, and by treatment 
and modified age group, for demographics and baseline characteristics for both Part 1 and Part 
2.
For Part 2 (Efficacy), baseline value is defined as the last non-missing assessment prior to the 
first dose of randomized study medication unless specified otherwise. 
For Part 1 (PK/PD), all subjects with at least one dose of study drug will be included in the 
above analyses. For Part 2 (Efficacy), the FAS set will be the patient population for the above 
analyses.
9.3
Treatments
Part 1 (PK/PD)
The study drug administration (single dose of LCZ696 in mg/kg) will be summarized for 
subjects who received study drug during Part 1 (PK/PD). The summary will be conducted by 
age group and overall; and the summary will use mean, standard deviation, median, minimum, 
and maximum. The number and percentage of patients will be summarized by age group and 
dose levels (mg/kg).
Concomitant medications will be summarized by therapeutic class, preferred term (PT) and 
dose level for each age group and overall for all subjects who received study drug in Part 1 
(PK/PD). 
Part 2 (Efficacy)
The overall duration of the double-blind study drug will be summarized for the SAF population 
by treatment group using mean, standard deviation, median, minimum, and maximum. 
Additionally, the number and percentage of patients will be summarized by treatment group for 
duration category. 
Concomitant medications will be summarized by therapeutic class, preferred term (PT), 
treatment group for the SAF population.
Additionally, all analyses conducted above for Part 2 (Efficacy) will be summarized by 
modified age group. 


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9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
Part 1 (PK/PD)
The objective of Part 1 of the study is to characterize PK and PD of LCZ696 in pediatric patients 
and compare PK, PD, and exposure-response with observed data in adult heart failure patients 
in order to determine the dose for Part 2 (Efficacy) of the study. In Part 1 (PK/PD) of the study, 
the pediatric patient population is divided into three age groups; Group 1: 6 to < 18 years old, 
Group 2: 1 to < 6 years old, and Group 3: 1 month to < 1 year old. 
Considering various factors including factors such as ontogeny of enzymes/transporters, the 
variability in PK parameters is assumed to be similar between adult and pediatric HF patients 
(>3 months). Since LBQ657 is a metabolite, clearance and volume of distribution were not 
estimated in earlier clinical trials and coefficient of variation% (CV%) of total exposure was 
considered for sample size estimation. From previous clinical study in adult HF patients, the 
observed CV% for body-weight normalized LBQ657 exposure was 37.1% and the observed 
CV% for body-weight normalized clearance and volume of distribution of valsartan was 39.4% 
and 49.6%, respectively (CLCZ696A2117). Therefore 49.6% of CV% was assumed for sample 
size estimations. The sample size is up to 12 observations per age group (except Group 3 where 
N= 8 observations) to achieve 95% CI for geometric mean of PK parameters to fall between 
60% and 140% range (95% CI: 71 – 141%) with 80% coverage probability. 
A population PK model will be developed to describe incoming data from pediatric patients 
based on an established model developed for the adult HF population. The fidelity of the 
developed PK model will be cross validated for its robustness and precision to the observed 
data. The steady state population PK parameters including clearance, volume of distribution, 
Ka, T1/2, Cmax, Cmin, and AUC will be estimated. The impact of covariates such as eGFR, 
age, body weight, NYHA/Ross class, TBL, and AST levels will be evaluated.
Pharmacodynamic evaluations will include analysis of change in plasma cGMP, plasma BNP, 
plasma NTproBNP and urine cGMP. Dose and exposure-response relationship will be 
evaluated based on changes in plasma cGMP levels (and also plasma NTproBNP, plasma BNP, 
urine cGMP).
PKPD modeling of Part 1 data may be carried out, depending on the robustness of both the PK 
and biomarkers to be used to inform the dose justification for Part 2.
Part 2 (Efficacy)
The global rank primary endpoint is constructed through 2 steps: 

Step 1: Patients are classified into the 5 ordinal categories based on the logic described in 
Table 6-3 in Section 6.4.1.

Step 2: Within each category, patients are ranked from worst to best based first on the 
subcategory if applicable, and then the ranking algorithm as explained in Table 6-3.


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9.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint comparing the distributions for patients receiving LCZ696 and patients 
receiving enalapril will be assessed using a stratified Wilcoxon rank-sum analysis (Kawaguchi 
2011), stratifying by modified age group (Group 1: 6 to < 18 years; Group 2a: 2 to < 6 years; 
Group 3a: 1 month to < 2 years) and NYHA/Ross class group (Class I/II; Class III/IV). The 
overall significance level (Type 1 error) of 0.05 (2-sided) will be used. In addition, the 
proportion of patients falling into each of the 5 ordered categories of the primary endpoint will 
be presented by treatment group. These proportions will be provided both hierarchically (only 
worst category counted for each patient), as the endpoint is defined, and overall, not accounting 
for whether a patient also had a worse event. Full analysis set will be used for these analyses.
In addition, the number and percentage of patients in each category will be provided by 
treatment group for each age group, each modified age group, and for overall.
Due to unresolvable technical reasons in study drug supply, the unforeseen intercurrent events 
of the USM leading to study treatment discontinuations are not related to disease progression, 
are not related to the assigned study treatment, and do not reflect a real-world setting. The 
exposure to the study treatment and study follow-up are reasonably long. Therefore, the on-
treatment approach is considered to be more appropriate for the handling of USM-impacted 
patients in the primary analysis, utilizing the relevant components of the global rank endpoint 
including Category 1 and Category 2 status at the time of treatment discontinuation.
9.4.3
Handling of missing values/censoring/discontinuations
Part 1 (PK/PD)
All concentrations below the lowest limit of quantitation (LLOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LLOQ will be treated as 
zero in summary statistics and for the calculation of PK parameters.
The statistical analysis will include all subjects with valid PK parameters.
Part 2 (Efficacy)
All efforts should be made to collect all information including vital status for all patients at the 
52 week visit, or the last on-treatment assessment visit for the USM impacted patients. 
For the primary efficacy endpoint, missing information will be handled as follows.
Patients will be classified into the worst possible category, based on available and retrievable 
information for the patient. Within Categories 1 and 2, patients will be further ranked according 
to the day of the last reliable information (for example, last day of contact). If the patient is not 
classified as Categories 1 or 2 (e.g. patient is alive and is documented to not have any WHF 
events), the same principle will be followed for ranking the patient.
If the 52 weeks measurements, or the last on-treatment assessment visit for the USM impacted 
patients, of NYHA classification or Ross classification and the PGIS score are missing then the 
last-observation-carried-forward (LOCF) technique will be used to impute the missing post-
randomization values (for patients who do not experience any events in Category 1 or 2). Only 
post-randomization values will be used for imputation.


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Categories 3, 4, and 5 will be determined based on available information if the NYHA/Ross, 
PGIS, and PedsQL physical functioning domain are not complete. When ranking these patients, 
the ranking algorithm will place the patients at the median for the missing assessment 
component(s).
9.4.4
Sensitivity analyses
In addition to the primary analysis, the primary efficacy endpoint will also be analyzed using 
the same primary analysis model in the PP population.
For the USM-impacted patients, the full data, including the off-treatment part, from the 
impacted patients will be included as a sensitivity analysis.
 
9.4.5
Supportive analyses
To characterize the treatment difference between LCZ696 compared to enalapril, an ordered 
categorical endpoint with 5 categories, as used for deriving the primary endpoint variables, will 
be analyzed using a stratified Wilcoxon rank-sum test. The number and percent of patients 
within each individual category will be summarized by treatment group.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
Part 1 (PK/PD)
The objective of this part is to characterize the PK and PD of LCZ696 in pediatric patients with 
HF. Primary variables are described in Section 9.4.1. There are no specific secondary variables
in Part 1. 
Part 2 (Efficacy)
To determine whether LCZ696 is superior to enalapril, Part 2 (Efficacy) variables include

Time to first Category 1 or 2 event

Change from baseline (randomization visit) for NYHA/Ross class

Change from baseline (randomization visit) for PGIS

Population PK of LCZ696 exposure in pediatric patients with HF, including an assessment 
of steady-state sparse PK data in a subset of Group 2 patients, to further confirm the 
LCZ696 target dose for Group 2.
The full analysis set will be used in analyses for secondary endpoints.
With the same reasons described for the primary analysis, for the USM-impacted patients, the 
relevant assessments at the time of treatment discontinuation will be utilized in the secondary 
analyses (on-treatment approach).
For the USM-impacted patients, the full data, including the off-treatment part, from the 
impacted patients will be included as the sensitivity analyses. 


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The time to event endpoints will be analyzed using Cox’s proportional hazards model with 
treatment as fixed-effect factor stratified by modified age group (Group 1: 6 to < 18 years; 
Group 2a: 2 to < 6 years; Group 3a: 1 month to < 2 years). The estimated hazards ratio and the 
corresponding two-sided confidence interval will be provided. 
NYHA/Ross class and PGIS will be compared for LCZ696 and enalapril at week 52,
respectively. Change from baseline at week 52 for these assessments will be analyzed based on 
a proportional cumulative odds model, stratified by modified age group (Group 1: 6 to < 18 
years; Group 2a: 2 to < 6 years; Group 3a: 1 month to < 2 years) in which treatment will be 
included as fixed-effect factors and baseline value as a covariate. The treatment comparison 
between LCZ696 and enalapril for the secondary objective is to be made at week 52. This 
model assumes that the treatment effect sizes across measurement categories are the same. The 
effect size estimates and their 95% confidence intervals will also be provided.
Part 2 Age Group 2 (PK)
The population PK Model will be updated with sparse PK data from a subset of Part 2 Group 2 
patients for the purpose of further confirming the target dose for Age Group 2. This will be 
performed prior to database lock and requires unblinding, and as such will be done by an 
unblinded team who is not involved in the conduct of the study.  
9.5.2
Safety variables 
Safety data from Part 1 (PK/PD) and Part 2 (Efficacy) will be presented separately.
The assessment of safety will be based primarily on the frequency of AEs, SAEs, and laboratory 
abnormalities. Other safety data, such as specific adverse events of interest (i.e. hypotension, 
hyperkalemia, renal impairment, angioedema), will be summarized as appropriate. 
The incidence of treatment-emergent AEs (new or worsened) will be summarized by primary 
system organ class, preferred term, severity, and relationship to study drug. In addition, the 
incidence of death, SAEs, and AEs leading to discontinuation will be summarized separately 
by primary system organ class and preferred term.
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data 
and change from baseline values (mean, medians, standard deviations, ranges) and by the 
flagging of notable values in data listings.
Data from other tests (e.g. vital signs) will be descriptively summarized as appropriate by 
presenting absolute values and change from baseline at each assessment time point. Any other 
information collected will be listed as appropriate. 
Safety analyses will be performed based on all patients who received study drug during Part 1 
and the safety population for Part 2 (Efficacy). There will be no formal statistical inference 
analysis.


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9.5.3
Biomarkers
Data for each biomarker will be summarized by treatment group and time point using 
descriptive statistics (n, mean, median, SD, min, max, n below LLOQ, n above ULOQ, 
geometric mean and 95% confidence interval around the geometric mean). Summary statistics 
for change from baseline at each time point will also be presented.
 
 
 
 
 
 
 
 
 
 
 
 
In addition, as a supportive analysis, the same MMRM analysis as above will be performed 
using data from all post-baseline scheduled visits (Week 4, Week 8, Week 12 and Week 52).
9.5.4
PK/PD
The relationship between LBQ657 exposure to changes in plasma BNP, plasma NTproBNP and 
plasma cGMP will be explored using exposure-response models. 
  
 
 
 
 
 
 
 
 
 


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9.6
Interim analyses
An external DMC will monitor patient safety data during the course of the study. For this study, 
the DMC will review safety data on a regular frequency, e.g. every six months. DMC may 
request additional safety data review. Such safety analyses do not inflate the type I error for the 
primary efficacy hypothesis testing and thus require no multiplicity adjustments.
Part 1 (PK/PD)
The available PK, PD and safety data from each age group will be analyzed to confirm the dose 
for that age group in Part 2 and to start the next younger age group in Part 1. A sample size of 
up to 12 observations per age group for Groups 1 and 2 is prospectively planned to evaluate 
the PK and PD of LCZ696 analytes following single dose administration of LCZ696 0.8 mg/kg 
(N=6 observations) and LCZ696 3.1 mg/kg (N=6 observations). For Group 3 a sample size of 
up to 8 observations is prospectively planned to evaluate the PK and PD of LCZ696 analytes 
following single dose administration of LCZ696 0.4 mg/kg (N= approximately 4 observations) 
and LCZ696 1.6 mg/kg (N= approximately 4 observations). Since the pharmacokinetics of 
LCZ696 is demonstrated to be dose independent, dose-normalized PK parameters from both 
dose cohorts will be combined. If no age effect on PK is observed, then data from two different 
groups may be pooled. 
Part 2 (Efficacy)
Interim efficacy analysis of the global rank endpoint
It is planned to have a formal interim efficacy analysis. The interim efficacy analysis is planned 
when at least 180 patients (at least 36 patients from each age group) have completed the study
(i.e., reached a terminal endpoint or completed the 1 year study visit), and at least 40 patients 
have had an event in Category 1 or 2. Some adjustment to the time of interim analysis may be 
made to coincide with the regular DMC meetings. One-sided tests will be performed and
appropriate statistical adjustments for the interim efficacy analysis actually performed will be 
made to ensure the overall one-sided type I error of 0.025 (Lan-DeMets spending function to 
match an O’Brien-Fleming stopping boundary). For the interim efficacy analysis, the analysis 
dataset will comprise all patients who completed the study by the cut-off date.
The trial may only be concluded early for efficacy, if a significant difference between two 
treatment arms for the primary efficacy endpoint is achieved by crossing the pre-specified 
boundary at the interim efficacy analysis and the overall risk/benefit profile is considered 
positive. A futility analysis will also be incorporated into the interim analysis plan, whereby the 
study can be stopped if there is evidence that the study is unlikely to have a positive outcome. 
Details of the stopping rules for the futility analysis will be described in the interim analysis 
statistical plan.


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The interim analysis will be performed by an external independent statistician at an external 
data analysis center, who will not be involved in the study conduct. The results will be reviewed 
by the independent DMC. Investigators and others who are involved in the conduct of the trial 
and in the analysis of the final trial results, or who have contact with study centers, will remain 
blinded to the treatment codes and interim analysis results until all monitoring decisions have 
been made and the database has been unblinded for final analysis. Additional details of the 
interim analysis plan for efficacy and safety will be described in the [DMC charter].
If the study is stopped early at interim analysis due to overwhelming efficacy, then the pre-
specified percentage of patients will be used for this analysis. Additional sensitivity analysis for
the primary global rank endpoint (and components) will be performed at time points of 30 days, 
90 days, and 180 days. For time to event endpoints, annualized event rates will be calculated.
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7
Sample size calculation
Part 1 (PK/PD)
From a prior clinical study in adult HF patients, the observed CV% for body-weight normalized 
LBQ657 exposure was 37.1%, and the observed CV% for body-weight normalized clearance 
and volume of distribution of valsartan was 39.4% and 49.6%, respectively (Study 
CLCZ696A2117). Therefore, 49.6% of CV% was assumed for sample size estimations. A 
sample size of 12 observations (except Group 3 where N=–approximately 8 observations) is 
expected to have 80% probability that the 95% CI of the point estimate for the geometric mean 
estimates of clearance and volume of distribution will be between 60% and 140% range (95% 
CI: 71 – 141%).


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Part 2 (Efficacy)
In the Carvedilol Pediatric HF study (Shaddy 2007) for the subgroup of systemic left ventricle 
patients, the improvement rate of the placebo group was 51%, while the improvement rate in 
the carvedilol group was 64%. This was a 13% increase in absolute improvement rate over 8 
month treatment period. Most of the patients in the carvedilol and placebo groups received 
ACEI treatment.
Table 9-1 presents the assumed underlying probabilities for each category of the primary 
endpoint in Part 2 (Efficacy) using data from the Carvedilol Pediatric HF study data (Shaddy 
2007). It is assumed that the probability for patients receiving LCZ696 and enalapril who will 
have an event of death, circulatory and/or respiratory mechanical support or UNOS 1A heart 
transplant listing (Category 1) is similar to what was observed for the carvedilol and placebo 
groups in the Carvedilol Pediatric HF study. It is also assumed that the probability of patients 
experiencing Worsening HF (Category 2) is similar to Hospitalization for HF observed in the 
Carvedilol Pediatric HF study. Thus, for Categories 1 and 2, the events percentages are based 
on the Carvedilol Pediatric HF study (Shaddy 2007). The probability of an improved outcome 
for enalapril patients is assumed to be the same as for the placebo group in the carvedilol study, 
and the probability for the LCZ696 patients is assumed to be the same as observed for carvedilol 
patients in the Carvedilol Pediatric HF study. The probabilities for the worsened and unchanged 
categories are formed by splitting the remaining probability approximately equally for these 
two categories. 
Table 9-1
Assumed percentage of patients in each category of the primary 
efficacy endpoint in Part 2 by treatment group at Month 8 (Week 32)
Category
LCZ696 (%)
Enalapril (%)
1. Clinical event – death / heart transplant listing / mech. support
6
9
2. Clinical event – WHF 
10
13
3. Worsened functional class: NYHA/ Ross Classification or 
worsened PGIS
9
14
4. Unchanged functional class: NYHA/ Ross Classification and 
unchanged PGIS
11
13
5. Improved functional class: NYHA/ Ross Classification or 
Improved PGIS
64
51
The projected event percentages presented in Table 9-1 are based on the 8 month treatment 
period estimates. For a 52 weeks treatment period (Table 9-2), for Categories 1 and 2, the 
anticipated events percentages are calculated based on an exponential distribution assumption, 
extending from Month 8 to Month 12; and the remaining percentages within each treatment 
group are shared by Categories 3, 4, 5 according to their corresponding proportions at Month 8
(i.e. according to Table 9-1, 9 : 11 : 64 for the LCZ696 group, and 14 : 13 : 51 for the enalapril 
group). The treatment difference represented in Table 9-2 represents a Mann-Whitney-
Wilcoxon Odds of 0.753.


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Table 9-2
Assumed percentage of patients in each category of the primary 
efficacy endpoint in Part 2 by treatment group at Month 12 (Week 52)
Category
LCZ696 (%)
Enalapril (%)
1. Clinical event – death / heart transplant listing / 
mech. support
9
13
2. Clinical event – WHF 
15
19
3. Worsened functional class: NYHA/ Ross 
Classification or worsened PGIS
8.1
12.2
4. Unchanged functional class: NYHA/ Ross 
Classification and unchanged PGIS
10.0
11.3
5. Improved functional class: NYHA/ Ross 
Classification or Improved PGIS
57.9
44.5
The primary efficacy analysis will be a stratified Wilcoxon rank-sum test with alpha level of 
0.05%, (two-sided). For the analysis of an ordered categorical endpoint with an underlying 
distribution as presented in Table 9-2, there is approximately 70% power with a sample size of 
177 patients per group (354 total patients). Sample size calculations for the ordered categorical 
test (ordered categorical Mann-Whitney/Wilcoxon rank sum test) were determined using 
nQuery. Using a global ranked endpoint, the power under the same assumptions is expected to 
increase. While the exact increase in power is dependent on the distribution of the ranking 
within each category, simulation studies have demonstrated that the power for the global rank 
endpoint increases 10-20% more than with the ordered categorical analysis when the power of 
the ordered categorical endpoint is more than 50% (Sun 2012). Based on the assumptions stated, 
the power is estimated to be at least 80% for this study. 
The sample size is further increased to account for a single planned interim analysis to be 
performed when approximately 50% of the patients (and at least 36 patients from each age 
group) have completed the study (50% information fraction). This interim analysis will be done 
to allow for early stopping of the study in the event that overwhelming positive efficacy is 
observed at the time of the interim analysis. Using the Lan-DeMets alpha spending function of 
the O’Brien-Fleming stopping boundary, a sample size of 180 patients per group (360 patients 
total) will provide at least 80% power for a test of the primary endpoint including a planned 
interim analysis. Further simulations will be performed to ensure that the estimated sample size 
maintains the targeted power when accounting for the interim analysis.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki.


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10.2
Informed consent procedures
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent and child assent where applicable must be 
documented in the patient source documents. 
Novartis will provide to Investigators in a separate document a proposed informed consent form 
and age appropriate assent forms that comply with the ICH GCP guideline and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the Investigator must be agreed to by Novartis before submission to the 
IRB/IEC, and a copy of the approved version must be provided to the Novartis monitor after 
IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study and for 7 days after study drug discontinuation. If there is any question that the patient 
will not reliably comply, they must not be entered in the study.
10.3
Responsibilities of the Investigator and IRB/IEC
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g.
advertisements) and any other written information to be provided to patients/subjects. Prior to 
study start, the Investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the Investigator must inform Novartis immediately that 
this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.


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11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients/subjects should 
be administered as deemed necessary on a case by case basis. Under no circumstances is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
(References available upon request).
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disease in childhood: A prospective study in the United Kingdom and Ireland. Circulation; 
117:79-84.
Anker SD, Ponikowski P, Mitrovic V, et al. (2015) Ularitide for the treatment of acute 
decompensated heart failure: From preclinical to clinical studies. Eur Heart J; 36(12):715-23.
Bengur AR, Beekman RH, Rocchini AP, et al. (1991) Acute hemodynamic effects of 
captopril in children with a congestive or restrictive cardiomyopathy. Circulation; 83:523.
Blumer J, Batisky DL, Wells T, et al. (2009) Pharmacokinetics of valsartan in pediatric and 
adolescent subjects with hypertension. J Clin Pharmacol; 49:235-241.
Chang S, Davidson PM, Newton PJ, et al. (2015) Composite outcome measures in a 
pragmatic clinical trial of chronic heart failure management: A comparative assessment.
International Journal of Cardiology; 185: 62–68.
Chaturvedi V, Saxena A (2009) Heart failure in children: Clinical aspect and management. 
Indian Journal of Pediatrics; 76:195-205.
ClinicalTrials.gov (2008) Quality of life in pediatric transplant recipients.
NCT00678002.Medical College of Wisconsin.


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Committee for human medicinal products (CHMP), European Medicines Agency (EMA). 
(2004) ICH Topic E 2 D: Post approval safety data management, London, UK.
Criteria Committee of the New York Heart Association (1994) Functional capacity and 
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CLCZ696A2117 (2009) An open label, non-randomised study to explore safety/tolerability, 
pharmacokinetics and pharmacodynamics of LCZ696 in patients with stable heart failure. 
Novartis Internal Document.
CVAL 489K2304 (2011) Physician survey of clinical management and uses of medicinal 
products in paediatric patients with heart failure survey protocol. Diovan pediatric heart 
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Desai AD, Zhou C, Stanford S, et al. (2014) Validity and responsiveness of the pediatric 
quality of life inventory (PedsQL) 4.0 generic core scales in the pediatric inpatient setting. 
JAMA Pediatrics; 168:1114-21.
Dore A, Houde C, Chan KL, et al. (2005) Angiotensin receptor blockade and exercise 
capacity in adults with systemic right ventricles: A multicenter, randomized, placebo-
controlled clinical trial. Circulation; 112:2411–2416.
Duboc D, Meune C, Lerebours G, et al. (2005) Effect of perindopril on the onset and 
progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll 
Cardiol; 45:855.
Duboc D, Meune C, Pierre B, et al. (2007) Perindopril preventive treatment on mortality in 
Duchenne muscular dystrophy: 10 years' follow-up. Am Heart J; 154:596.
Eagleson KJ, Justo RN, Ware RS, et al. (2013) Health-related quality of life and congenital 
heart disease in Australia: Journal of Paediatrics and Child Health; 49:856-64.
European Medicines Agency (EMA). (2010) Report on the expert group meeting of pediatric
heart failure, London, UK.
European Commission. ENTR/CT3 (2006) Detailed guidance on the collection, verification 
and presentation of adverse reaction reports arising from clinical trials on medicinal products 
for human use.
Favilli S, Fresnos S, Lasagni D, et al. (2009) The use of B-type natriuretic peptide in pediatric
patients: A review of the literature. J Cardiovasc Med; 10: 298-302.
FDA (2012) Guidance for Industry and Investigators: Safety reporting requirements for INDs 
and BA/BE studies.
Felker GM, Maisel AS (2010) A global rank end point for clinical trials in acute heart failure. 
Circ Heart Fail; 3:643-646.
FDA (2016) Guidance for Industry and Food and Drug Administration Staff: Collection of 
Race and Ethnicity Data in Clinical Trials. Document issued on October 26, 2016.
Hartland AJ, Neary RH (1999) Serum potassium is unreliable as an estimate of in vivo plasma 
potassium. Clin Chem; 45:1091-1092.
Hechter SJ, Fredriksen PM, Liu P, Veldtman G, et.al. (2001) Angiotensin-converting enzyme 
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Howie SR (2011) Blood sample volumes in child health research: review of safe limits. Bull 
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multicenter randomized trial. Circulation; 122:333-340.
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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Table 13-1
Clinically notable laboratory values
Parameter
Conventional
Alert Value
Conventional
Units
SI Alert
Value
SI
Units
Hematology
Red Blood Cell 
Count 
>50% 
increase, >30% 
decrease
x10E6/uL
>50% 
increase, >30% 
decrease
x10E12/L
Hemoglobin
>50% 
increase, >30% 
decrease, or any 
value <7
g/dL
>50% 
increase, >30% 
decrease, or any 
value <70
g/L
Hematocrit
>50% 
increase, >30% 
decrease
%
>50% 
increase, >30% 
decrease
L/L
White Blood Cell 
Count 
>50% 
increase, >50% 
decrease
x10E3/uL
>50% 
increase, >50% 
decrease
x10E9/L
Platelet Count
>75% 
increase, >50% 
decrease
x10E3/uL
>75% 
increase, >50% 
decrease
x10E9/L
Chemistry
BUN
>50% increase
mg/dL
>50% increase
mmol/L


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Parameter
Conventional
Alert Value
Conventional
Units
SI Alert
Value
SI
Units
Creatinine
>50% increase
mg/dL
>50% increase
umol/L
Albumin
<2
g/dL
<20
g/L
Glucose
>50% 
increase, >50% 
decrease, or any 
value <60
mg/dL
>50% 
increase, >50% 
decrease, or any 
value <3.3
mmol/L
Total Bilirubin
>100% increase
mg/dL
>100% increase
umol/L
AST (SGOT)
>150% increase
U/L
>150% increase
U/L
ALT (SGPT)
>150% increase
U/L
>150% increase
U/L
Sodium
>5% increase, or 
any value >150
mEq/L
>5% increase, or 
any value >150
mmol/L
Potassium
>20% 
increase, >20% 
decrease, or any 
value >5.3 
mEq/L
>20% 
increase, >20% 
decrease, or any 
value >5.3 
mmol/L
Chloride
>10% 
increase, >10% 
decrease
mEq/L
>10% 
increase, >10% 
decrease
mmol/L
Calcium
>10% 
increase, >10% 
decrease
mg/dL
>10% 
increase, >10% 
decrease
mmol/L
Uric Acid
>50% increase
mg/dL
>50% increase
mmol/L
Table 13-2
Criteria for clinically notable vital signs
Age
HR [min-1]
SBP [mmHg]
DBP [mmHg]
RR [min-1]
1-<3 months
<90, >160
<60, >95
<40, >50
<25, >60
3-<6 months
<80, >130
<60, >100
<40, >60
<20, >50
6-<12 months
<70, >130
<60, >110
<45, >70
<15, >45
1-<3 years
<60, >120
<76, >115
<45, >75
<14, >35
3-<6 years
<55, >120
<82, >120
<50, >80
<12, >30
6-<12 years
<50, >105
<90, >130
<50, >80
<10, >27
≥12 years
<45, >95
<90, >145
<55, >90
<8, >23


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14
Appendix 2: Liver event and laboratory trigger definitions 
and follow-up requirements
Table 14-1
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)
Test for hemolysis (e.g. reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
Investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.


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15
Appendix 3: Specific renal alert criteria and actions
Table 15-1
Specific renal alert criteria and actions
Serum event
Estimated GFR* decrease
≥25% compared to baseline AND eGFR 
< 90 mL/min/1.73m2 
Confirm ≥25% decrease AND eGFR*
< 90 mL/min/1.73m2 after 24-48 hours (h). 
If it persists follow up with repeat, if possible, 
within 2-5 days. 
Then do some frequent monitoring (preferably 
weekly) until event resolves or stabilizes. 
If event does not resolve or stabilize consider 
consulting nephrologist and/or drug interruption.
Acute Kidney Injury: Serum estimated GFR* 
decrease 50 % compared to baseline
Follow up within 24-48h if possible.
If value persists, consider consulting nephrologist 
and/or drug interruption.
Urine event
Confirm by urinary protein creatinine ratio. 
If it persists, consider consulting nephrologist 
and/or drug interruption.
New dipstick proteinuria ≥ 1+
Confirm value after 24-48 h, if possible.
If dipstick value confirmed: 
a) perform urinary protein creatinine ratio (PCR) 
within 2-5 days, if possible. If PCR > 0.2 then:
b) perform urine microscopy and evaluate.
If PCR > 0.2 and /or urine microscopy has 
findings (e.g. crystals, casts , dysmorphic RBC, 
leukocytes), consider consulting nephrologist or 
drug interruption or discontinuation
New dipstick glucosuria ≥ 1+ not due to diabetes
Confirm value after 24-48 h, if possible.
If it persists: 
a) perform, blood glucose (fasting)
b) perform urinary protein/creatinine ratio. 
If PCR ratio > 0.2 and blood glucose abnormal 
consider consulting nephrologist and /or drug 
interruption or discontinuation
New dipstick hematuria ≥ 1+ not due to trauma
Confirm value after 24-48 h, if possible.
If it persists:
a) perform urinary protein creatinine ratio (PCR) 
within 2-5 days on a first morning urine collection 
b) perform urine microscopy and evaluate.
If PCR > 0.2 and /or urine microscopy has 
findings (e.g. crystals, casts , dysmorphic RBC, 
leukocytes) consider consulting nephrologist or 
drug interruption or discontinuation
* eGFR is calculated using a modified Schwartz formula 
Urine samples for testing for renal monitoring, and particularly those for the PCR ratio determination, 
must be collected at the first morning void.
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed.


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Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: estimated GFR within 20% of baseline and > 90 mL/min/1.73m2 or PCR < 0.2;
Event stabilization: estimated GFR within 20% of baseline OR > 90 mL/min/1.73m2 or PCR < 0.3.
15.1
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 randomization.
Two types of response to serum creatinine increase are described:
1. Surveillance situation
If, at any time after randomization, eGFR%* decreases by ≥ 50% from baseline (Visit 301 for 
Part 2), the Investigator will check for potentially reversible causes of renal dysfunction such 
as:

non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
cause creatininemia

volume decrease, including that resulting from excessive dosing of diuretics

urinary infection

urinary tract obstruction

study medication.
2. Action situation
If a patient eGFR* decreases by ≥ 50% from baseline (Visit 301 for Part 2) (or if serum 
creatinine concentration rises above 3 mg/dL (265 μmol/L), the Investigator will check for 
potentially reversible causes of renal dysfunction (see above). If the Investigator judges that 
study medication has to be stopped, he/she will have to contact the Novartis medical monitor 
or his/her designee. Thereafter, serum creatinine assessments will have to be repeated at least 
each week until levels return to acceptable values. If study medication was stopped, every effort 
will 
be 
done 
to 
restart 
it 
again, 
according 
to 
clinical 
conditions.
*eGFR is calculated using a modified Schwartz formula


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16
Appendix 4: American heart association (AHA) pediatric 
advanced life support (PALS) guidelines 
Table 16-1
5th percentile systolic blood pressure 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


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16 years
5th
90
17 years
5th
90
* AHA PALS guidelines 2010 (Kleinman 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 BP 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: 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.
16.1
Guidelines for the management of blood pressure
1. Investigator should monitor blood pressure closely.
2. If symptomatic hypotension occurs:

Correct any treatable cause, e.g. hypovolemia

If hypotension persists, any antihypertensive drug and non-disease-modifying 
drugs, such as diuretics, calcium channel blockers (CCBs), nitrates, and α-
blockers, should be down-titrated or stopped first before down-titration of the 
study drug is considered

If hypotension persists, the study drug should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medications adjust guidelines described in 
Section 5.5.5 should be adhered to as much as possible.


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17
Appendix 5: Treatment guidelines for elevated potassium 
and hyperkalemia (serum potassium greater than or equal to 
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 less than or equal to 5.4 mmol/L
Confirm potassium concentration in a non-hemolyzed sample.
Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. 
orange juice, melon, bananas, low-salt substitutes etc.).
Review medical regimen (including dietary supplements and over-the-counter medications) for 
agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of these 
agents:

Aldosterone antagonists (if they are believed to be the most likely cause of hyperkalemia)

Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics

Potassium supplements, e.g. potassium chloride

Salt substitutes

Non-steroidal anti-inflammatory drugs (NSAIDs)

Cyclo-oxygenase-2 (COX-2) inhibitors

Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and 
Septra® (trimethoprim/sulfamethoxazole fixed combination)

Herbal Supplements: For example, Noni juice, alfalfa (Medicago sativa), dandelion 
(Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, 
lily of the valley, Siberian ginseng, hawthorn berries.
Repeat serum potassium measurement within 3 to 5 days. If serum potassium remains > 5.2 and 
≤ 5.4 mmol/L, regularly monitor serum potassium levels to ensure stability suggested once 
monthly.
Consider down-titration of study medication, according to Investigator’s medical judgment.


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Serum potassium > 5.4 and < 6.0 mmol/L
Confirm potassium concentration in a non-hemolyzed sample.
Consider down-titration or temporarily discontinue study drug according to Investigator
medical judgment.
Apply all measures outlined for serum potassium > 5.2 and ≤ 5.4 mmol/L.
Repeat serum potassium measurement after 2-3 days.

If serum potassium < 5.4 mmol/L, consider resumption of study drug at lower dose with
repeat potassium within 5 days.
Serum potassium greater than or equal to 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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Appendix 6: Reference table - blood volume by weight
Table 18-1
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
20
1600
40
80
20.5
1640
41
82
21
1680
42
84


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


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Appendix 7: NYHA/Ross classification
For older children 6 to less than 18 years old, the Investigator will determine the appropriate 
NYHA class of heart failure. Classification criteria are as follows:

NYHA Class I: No limitation - ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation

NYHA Class II: Slight limitation of physical activity - comfortable at rest, ordinary 
physical activity results in fatigue, palpitation, dyspnea, or angina

NYHA Class III: Marked limitation of physical activity - comfortable at rest, less than 
ordinary activity will lead to symptoms

NYHA Class IV: Inability to carry on any physical activity without discomfort -
symptoms of congestive failure present even at rest; with any physical activity, increased 
discomfort is experienced
For younger children less than 6 years old, the Investigator will determine the appropriate Ross 
class of heart failure. Classification criteria are as follows:

Ross Class I: 
No limitation or symptoms.

Ross Class II: 
No growth failure.  
Mild tachypnea with feeds in infants and/or
Mild diaphoresis with feeds in infants and/or
Dyspnea on exertion in older children.

Ross Class III: 
Growth failure. Prolonged feeding time in infants.
Marked tachypnea with exertion or with feeding.
Marked diaphoresis with exertion or with feeding.

Ross Class IV: 
Symptomatic at rest with the following sign/symptom(s):
Tachypnea and/or
Retractions and/or
Grunting and/or
Diaphoresis.


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Appendix 8: Patient global impression of severity (PGIS)
For patients 7 to < 18 years old:

How would you describe the severity of your heart failure symptoms over the past 7 
days? (None / Mild / Moderate / Severe / Very Severe)
For parents/caregivers of patients < 5 years of age:

How would you describe the severity of your child’s heart failure symptoms over the past 
7 days? (None / Mild / Moderate / Severe / Very Severe)
For patients 5 to < 7 years old:

Point to the one face that best shows how your heart problems have been over the past 7 
days?


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21.1
Teen report (ages 13-18)


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21.3
Child report (ages 8-12)


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21.5
Young child report (ages 5-7)


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Appendix 10: GFR by age
Table 22-1
GFR by age for initiation/up-titration and exclusion criteria
Age range*
≥30% mean GFR for 
age (mL/min/1.73m2)**
< 30% mean GFR for 
age (mL/min/1.73m2)***
1 month to < 3 months
≥14
< 14
3 months to < 6 months
≥17
< 17
6 months to < 12 months
≥23
< 23
12 months to < 19 months (1 year, 7 
months) 
≥31
< 31
19 months to < 18 years
≥38
< 38
* Age rounded to nearest whole number
** Initiation/up-titration criteria
*** Exclusion criteria
Source: (Peters 1999)


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25
Appendix 13: Safety Monitoring for Age Group 3 patients 
This Appendix applies only to Part 2 Age Group 3 patients (i.e. patients who are 1 month to <1 
year old at randomization) and provides Safety Monitoring requirements for the initial up-
titration portion of the study for Part 2 Age Group 3 patients.
25.1
Safety Monitoring for Age Group 3 patients:
Starting with the first dose of study medication, vital signs must be checked for up to 4 hours 
after the initial dose at each study drug dose level (i.e. dose levels 1x through 4x, as applicable). 
(Note: This does not apply for up-titrations following study drug interruptions or down-
titrations, up to the prior achieved maximal dose level.) Patients are to remain in the study site 
clinic for this 4-hour post-dose Vital Sign monitoring period. Vital signs (i.e. blood pressure 
and heart rate) are to be measured pre-dose (time 0), and post-dose at 0.5, 1, 2, 3 and 4 hours.
These data are to be recorded on the CRFs as well as in the source documentation.
The Investigator is to follow up with the parents of the Part 2 Group 3 patient by phone, 3 days 
(+/- 1 day) after the initial dose of the study medication at each dose level, checking for 
symptoms of hypotension. This does not apply for up-titrations following study drug 
interruptions or down-titrations. up to the prior achieved maximal dose level.
Examples of signs and/or symptoms of hypotension in infants: 
•
Not feeding or eating as they usually do
•
Not breast-feeding or drinking milk from a bottle (as it applies) as they usually 
do
•
Acting more fussy or tired than usual
•
More difficult than usual to arouse from a nap or sleep
•
Breathing faster than normal 
•
Unusually cold arms, legs, hands and/or feet: change from how they usually are
•
Change in appearance of skin: pale or mottled skin (spotted, blotchy, varicolored 
skin)
•
Decrease in amount of urine made; producing very little urine or not at all
If any signs and/or symptoms of hypotension are reported by the parents/guardians, the 
parents/guardians should be instructed to have their child seen by their local provider or at the 
study site as quickly as possible, so their vital signs can be assessed.


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Appendix 14: Up-titration dosing instructions for patients in 
Age Group 3 (1 month to <1 year at randomization) who turn 
1 year old during Part 2
This Appendix applies only to Part 2 Age Group 3 patients (i.e. patients who are 1 month to <1 
year old at randomization) and provides Up-titration instructions for patients randomized into 
Age Group 3. who turn 1 year old during Part 2 of the study.
26.1
Up-titration instructions for Age Group 3 patients who turn one 
year old during Part 2
Randomized, ongoing, Part 2 Age Group 3 patients who are safely tolerating Age Group 3 Dose 
Level 4x (i.e. LCZ696/Placebo, 2.3 mg/kg bid / Enalapril/Placebo 0.15 mg/kg bid) for at least 
2 weeks, and who turn 1 year old during the study, may be up-titrated, if it is the patient’s best 
interest to be up-titrated based on the medical judgement of the investigator. Under these 
circumstances, the patient may be further up-titrated to Age Group 3 Dose Level 5x (i.e. 
LCZ696/Placebo, 3.1 mg/kg bid / Enalapril/Placebo 0.2 mg/kg bid).
See Table 26-1 for dose level up-titration information for Age Group 3 patients who have turned 
1 year old during Part 2 of the study.
Table 26-1
Part 2 (Efficacy): Study drug dose level for double-blind enalapril and 
LCZ696 for Age Group 3 patients who turn 1 year old during the study
Dose levels for pediatric formulation
Enalapril dose^
LCZ696 dose^
Dose Level 5x for Age Group 3 patients who turn 
1 year old during the study
0.2 mg/kg bid.
3.1 mg/kg bid.
^Note: The maximum LCZ696 dose and enalapril dose allowed for patients who turn 1 year old during 
the Part 2 study, is Dose Level 5x (3.1 mg/kg bid and 0.2 mg/kg bid, respectively).
A subsequent planned study visit or an unscheduled visit (see Table 6-2 Part 2 Assessment 
Schedule) can be utilized for the additional up-titration visit for the Age Group 3 patients that 
turn 1 year old during the study. The timing of the up-titration visit, where applicable, will vary 
from patient to patient.
Abbreviated safety labs: For Age Group 3 patients who are ≥1 year old and who are further up-
titrated to Dose Level 5x, at a scheduled visit or at an unscheduled visit, abbreviated safety labs 
are to be done at this up-titration visit for Dose Level 5x.
All safety requirements for dose up-titration (and down titration), that are outlined in the
protocol in Section 5.5.5, Permitted dose adjustments and interruptions of study treatment,
apply to the above described dose up-titration for patients that have turned 1 year old during 
part 2.


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27
Appendix 15: Urgent safety measure (USM) 
This appendix describes the USM implemented in consideration of a quality event affecting the 
active comparator used in this study, effective 26 October 2021. An out of specification (OOS) 
result for an unspecified degradation product (observed: 0.3% vs. requirement: ≤ 0.2%) for both 
enalapril maleate 5 mg and 10 mg, packaged in alu-alu blisters by Novartis for this clinical trial, 
was observed in representative batches during supportive stability testing. As a result, the 
assigned shelf-life of 24 months of enalapril 5 mg and 10 mg in alu-alu blisters can no longer 
be supported for the current batches in use in the study and only a shelf-life of 12 months and 
18 months, respectively, is supported. This finding impacts the batches currently in use in the 
trial of enalapril 5 mg and 10 mg as well as one batch of enalapril 5 mg and 10 mg used earlier 
in the study. The current clinical trial supply of enalapril 5 mg is beyond the revised supported 
12-month shelf-life (expiry date was 31 March 2021). The current supply of enalapril 10 mg 
has a revised supported expiry date of 18 months lasting up to 31 October 2021. The finding 
only relates to enalapril 5 mg and 10 mg in alu-alu blister packs. The placebo of enalapril 5 mg
and 10 mg, as well as all LCZ696/placebo and Enalapril/placebo 2.5 mg, are not impacted.
What follows outlines the safety measures that have been implemented for the 31 patients who 
were ongoing and receiving study medication at the time the USM was initiated.
The USM includes the following:

Investigational medicinal product (IMP) dispensation was blocked in the IRT system by 
Novartis

All patients who were receiving study medication at the time the USM was initiated, 
had to discontinue study treatment by 31 October 2021 and change to local standard of 
care, respecting any required washout periods. These patients were to attend an 
unscheduled visit at the site by 31 October 2021, or as soon as possible thereafter, for 
safety and efficacy assessments (see Section 27.1 for additional details).

It was requested for all patients to return IMP in their possession by 31 October 2021.

All IMP is to be removed from the sites for destruction per local practices.
27.1
Instructions for patients impacted by the USM 
For patients who discontinued study treatment for other reasons before the USM was 
implemented but were being followed in the study at the time the USM was initiated,
instructions are as follows:
o
Patients to remain off study medication permanently and continue to be treated with 
SOC
o
Patients to be followed to their originally planned EOS visit (week 52 ± 2 weeks).
For patients who were receiving study medication, with an EOS visit originally planned for a 
date up to and including 14 November 2021, instructions are as follows:
o
Patients to have an EOS visit by 31 October 2021 enabling visit to be within 2 weeks 
of their originally planned EOS visit. 


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For patients who were receiving study medication with an EOS visit originally planned for after
14 November 2021, instructions are as follows: 
o
Patients to come to the study site for an unscheduled visit (or regularly scheduled 
visit) by 31 October 2021 and perform the following: 

Discontinue study medication

Transition to local SOC, respecting the required washout period

Complete the following additional assessments with all data maintained 
in source documentation (see Table 6-2 Part2 Assessment schedule, 
visits UNS/TD and UNS and footnotes 18 and 19 for details):
 
•
Unscheduled PK
•
Unscheduled abbreviated labs 
•
NYHA/ROSS class evaluation 
•
PGIS patients or parent/caregiver 
 
 
o
These patients should continue to be followed in the trial until the planned EOS
visit (week 52 ± 2 weeks).
o
Full EOS visit assessments (with the exception of PK) are to be conducted at the 
planned EOS visit (week 52 ± 2 weeks)
27.2
USM implications regarding data collection and study results 
As described in the sections above, due to unresolvable technical reasons regarding study drug 
supply, all patients on study medication at the initiation of the USM will have to discontinue
study drug treatment by 31October2021, which is up to two months prior to the scheduled study 
end for the last patient. This early study drug discontinuation is not expected to compromise the 
scientific integrity of the study due to the limited number of patients impacted. 
The early study drug discontinuation affects a maximum of 31 patients, who were on-treatment 
as of 26 October 2021, with a current follow-up between 297 days to 395 days. The total on-
treatment follow-up time lost is expected to be <1%.
Regarding CRF documentation, the reason for the treatment discontinuation is to be reported
on the End of Treatment (EOT) CRF as ‘Technical problems’. If a patient withdraws from study 
participation after the study drug discontinuation due to the USM and before they have 
completed 52 weeks (± 2 weeks) of follow up, the reason for the study phase discontinuation 
on the EOS CRF, is also be documented as ‘Technical problems’. 
Every effort is to be made to keep patients in the study until the planned 52-week follow up and 
to ensure study integrity. While the current statistical analysis plan (SAP) includes off-treatment 


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data after treatment discontinuations in the primary analysis (reflecting a real-world setting), 
this does not seem appropriate for the study drug discontinuations in the context of this USM. 
The unforeseen intercurrent events of the USM leading to study treatment discontinuations are 
not related to disease progression, are not related to the assigned study treatment and do not 
reflect a real-world setting. The exposure to the study treatment and study follow-up are 
reasonably long. Therefore, an on-treatment approach is considered to be more appropriate for 
the handling of USM-impacted patients in the primary analysis, utilizing the relevant 
components of the global rank endpoint including Category 1 and 2 status at the time of 
treatment discontinuation. The full data, including the portion off-treatment from the impacted 
patients, will be included in a sensitivity analysis. The SAP will be amended to reflect this.

SAP_001.pdf: 
Clinical Development
LCZ696/Entresto®
CLCZ696B2319 / NCT02678312
Multicenter, open-label, study to evaluate safety, 
tolerability, pharmacokinetics and, pharmacodynamics of 
LCZ696 followed by a 52-week randomized, double-blind, 
parallel group, active-controlled study to evaluate the 
efficacy and safety of LCZ696 compared with enalapril in 
pediatric patients from 1 month to < 18 years of age with 
heart failure due to systemic left ventricle systolic 
dysfunction
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
 
Document type:
SAP Documentation
Document status:
Final
Release date:
29-Oct-2021
Number of pages:
73
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CLCZ696B2319


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SAP
CLCZ696B2319
Document History – Changes compared to previous final version of SAP
Date and 
SAP 
version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
23-Nov-
2016
Part 1
Prior 
to 
DB
Initial
NA
NA
03-Mar-
2017
Part 2
Prior 
to 
DB
Initial
NA
NA
27-Oct-
2020
Part 1
Amendment 
1
Prior 
to 
DB
Protocol amendment
Updated per protocol 
amendment 6
All 
sections
03-Nov-
2020
Part 2
Amendment 
1
Prior 
to 
DB
Protocol amendment
Updated per protocol 
amendment 6
All 
sections
29-Oct-
2021
Combined 
Part 1 and 
Part 2
Amendment 
2
Prior 
to 
DB
Combine Part 1 and Part 
2 SAP
Part 1 and Part 2 combined
All 
sections
Part 1 period covers long 
duration
Part 1 period changed: remove 
treatment period, dose 
associated treatment period; 
added the dose associated 
period to be two visits whichever 
occurred first
2.1.1
Subgroup changes
NYHA/ROSS at baseline added;
COVID-19 period added;
Baseline eGFR removed;
Race added;
Prior ACEI/ARB use added.
2.2.1
COVID-19 related 
analysis added
COVID-19 disposition, PD 
summary added
2.3.1
Demographics added
age adjusted percentile 
parameters added
2.3.2
Compliance category 
added
Added < 90%, 90% to < 
110%, >110%.
2.4.1
Adult dose level specified 
clear
Adult dose (≥ 57 kg)
2.4.1


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SAP
CLCZ696B2319
Date and 
SAP 
version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
Randomization date 
changed to first dose date 
for time to first dose and 
permanent 
discontinuation of the 
drug
Randomization date changed to 
first dose date
2.4.1
Clarification for the prior 
medication and 
concomitant medication 
definition 
Changed to the general 
description.
2.4.2
SGLT2i added
SGLT2i ATC code added
2.4.2
Analysis cutoff date 
added 
analysis cutoff date will be set to 
58 weeks, i.e. 406 days
2.6.1
2.6.3
2.6.4
2.7.2
2.7.3
 
 
Missing baseline and 
post-baseline 
assessment handling for 
PGIS added for global 
rank 
While ranking, if the baseline is 
missing, then the baseline will be 
imputed using the median 
assessment within each stratum. 
If all the post-randomization 
assessments is missing, then the 
post randomization assessment 
will be imputed to the worst case 
at week 52
2.6.3
Supportive analysis for 
primary analysis added
Add supportive analysis
2.6.4
Randomization 
stratification(NYHA/ROSS 
group) added as 
covariate
Cox proportional hazard model, 
MMRM, proportional cumulative 
odds model, LWYY added 
covariate for randomization 
stratification
2.7.1
2.7.2
2.7.3
2.8.1
2.8.2
2.8.3
2.8.4
4
 
 
Safety summary changes
Part 2: 4 risks expanded to AESI;
Added summary by SMQ; 
added baseline eGFR ≤ / > 170 
mL/min/1.73 m2 seperate 
analysis for renal event;
2.9


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SAP
CLCZ696B2319
Date and 
SAP 
version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
Clinical notable criteria for 
laboratory values updated;
Central lab and local lab 
combined for events summary;
Change from baseline in height 
Z-score added;
PK and PD analysis 
description adjustments
2.5.1
2.5.2
2.10
2.11
 
PD for PPS updated
PD for PPS updated
5.3
Implementation of an 
Urgent Safety Measure 
(USM) 
Analysis updated per USM 
2.6
2.7
2.8


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Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................14
2.2
Analysis sets ..........................................................................................................18
2.2.1
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................20
2.3.1
Patient disposition.................................................................................20
2.3.2
Background and demographic characteristics.......................................22
2.3.3
Medical history......................................................................................23
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................23
2.4.1
Study treatment / compliance................................................................23
2.4.2
Prior, concomitant and post therapies...................................................30
2.5
Analysis of the primary objective for Part 1..........................................................31
2.5.1
Analysis of the PK parameters..............................................................31
2.5.2
Analysis of the PD parameters..............................................................32
2.5.3
Handling of missing values/censoring/discontinuations.......................33
2.6
Analysis of the primary objective for Part 2..........................................................33
2.6.1
Primary endpoint...................................................................................33
2.6.2
Statistical hypothesis, model, and method of analysis..........................39
2.6.3
Handling of missing values/censoring/discontinuations.......................39
2.6.4
Supportive and sensitivity analyses ......................................................40
2.6.5
Subgroup analyses.................................................................................42
2.7
Analysis of the secondary objectives for Part 2.....................................................42
2.7.1
Time to first adjudicated Category 1 or 2 event....................................42
2.7.2
NYHA/ROSS class change...................................................................43
2.7.3
PGIS change..........................................................................................43
2.7.4
Handling of missing values/censoring/discontinuations.......................44
2.7.5
Subgroup analysis for secondary endpoints..........................................45
2.8
45
46


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48
49
49
2.9
Safety analyses.......................................................................................................50
2.9.1
Adverse events (AEs)............................................................................50
2.9.2
Death .....................................................................................................53
2.9.3
Laboratory data .....................................................................................53
2.9.4
Vital signs..............................................................................................58
2.9.5
Electrocardiogram (ECG) .....................................................................59
2.10
Pharmacokinetic (PK) endpoints...........................................................................59
2.11
Pharmacodynamics (PD) and PK/PD analyses......................................................59
2.12
Patient-reported outcomes .....................................................................................60
2.13
Biomarkers.............................................................................................................60
60
2.15
Interim analysis......................................................................................................60
3
Sample size calculation .....................................................................................................62
3.1
Sample size for Part 1............................................................................................62
3.2
Sample size for the primary analysis for Part 2.....................................................62
3.3
Sample size re-estimation for Part 2......................................................................64
4
Change to protocol specified analyses ..............................................................................65
5
Appendix ...........................................................................................................................66
5.1
Imputation rules.....................................................................................................66
5.1.1
Missing or partially missing AE or concomitant medication 
start/end date .........................................................................................66
5.1.2
Missing visit date ..................................................................................66
5.1.3
Event date missing or partially missing ................................................66
5.2
Statistical models...................................................................................................66
5.2.1
Primary analysis....................................................................................66
5.2.2
Futility analysis .....................................................................................68
5.2.3
Sample size calculation and blinded re-estimation...............................69
5.3
Rule of exclusion criteria of analysis sets..............................................................71
6
Reference...........................................................................................................................73


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List of abbreviations
AE
Adverse Event
ADaM
Analysis Data Model
AGB
ADaM Governance Board
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CRF
Case Report Form
CSR
Clinical Study Report
CV
Coefficient of variation
DMC
Data Monitoring Committee 
LLOQ
Lowest Limit of Quantitation
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NOVDTD
Novartis Drug and Therapy Dictionary
PK
Pharmacokinetics
PD
Pharmacodynamics
PDS
Programming datasets specifications
SAP
Statistical Analysis Plan
SOC
System Organ Class
UNS PK/PD
Unscheduled PK/PD
ULOQ
Upper Limit of Quantitation
USM
Urgent Safety Measure


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1
Introduction
This document includes the analysis details of study CLCZ696B2319. Data will be analyzed 
according to CLCZ696B2319 protocol v06 Section 9 (Data analysis). Statistical methods are 
described in the following Section 2 (Statistical methods) and sample size considerations are 
provided in the following Section 3 (Sample size calculation).
The analysis results will be summarized in the clinical study report (CSR).
1.1
Study design
This study uses a seamless design which consists of two parts.
Part 1 is a multi-center, open-label, study to evaluate safety, tolerability, pharmacokinetics (PK)
and pharmacodynamics (PD) of LCZ696 in pediatric patients (1 month to <18 years) with heart 
failure due to systemic left ventricle systolic dysfunction (left ventricular ejection fraction
[LVEF] ≤ 40% or fractional shortening ≤ 20%). Eligible patients will be placed into three age 
groups (Age Group 1: 6 years to < 18 years, Age Group 2: 1 year to < 6 years, and Age Group 
3: 1 month to < 1 year). Patient enrollment will start sequentially from the eldest age group to 
the youngest age group.
For each age group, available PK/PD and safety data will be reviewed to confirm or modify the 
doses. After completion of the PK/PD assessment visit, patients can either be maintained on 
open-label enalapril or their standard of care HF medical regimen until Part 2. Patients in each 
age group can enroll in Part 2 after the target dose for that age group is determined based on 
Part 1 data for the corresponding age cohort. Patients that discontinue from Part 1 (PK/PD) will 
be allowed to screen and enroll for participation in Part 2.
Part 2: This is a randomized, double-blind, parallel-group, active controlled, 52-week study to 
evaluate the efficacy, safety, and tolerability of LCZ696 compared to enalapril in pediatric HF 
patients (1 month to < 18 years). A screening epoch of up to 3 weeks will be used to assess 
eligibility. Three hundred and sixty eligible patients will be randomized to one of the two 
treatment arms (LCZ696 vs. enalapril) and continue treatment for 52 weeks duration. Both 
hospitalized patients and outpatients are eligible. Chronic HF patients that are either previously 
treated for HF or newly diagnosed are eligible. 
An interim efficacy analysis is planned to be performed when at least 180 patients (at least 36 
patients from each age group) have completed the study (i.e., reached a positively adjudicated 
event in Category 1 or completed the 1 year study visit), and at least 40 patients have had an 
event in Category 1 or 2. Further details about interim analysis are provided in Section 2.15.
If not stopped early for efficacy or futility based on the interim analysis, Part 2 will continue 
until at least 360 patients have completed the study and at least 80 patients have an event in 
Category 1 or 2. If necessary, study enrollment will continue beyond 360 patients in order to 
obtain at least 80 patients with an event in Category 1 or 2, based on event prediction.
A penalty-free blinded sample size adjustment may be made in the latter part of the study to 
ensure a power of 80% for the study.


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1.2
Study objectives and endpoints
Table 1-1 summarizes the study objectives and the endpoints for the objectives.
Table 1-1
Objectives and related endpoints
OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure
Section
Part 1
Primary
To determine the 
pharmacokinetics (PK) and 
pharmacodynamics (PD) of 
LCZ696 in pediatric HF patients
Title: PK and PD of LCZ696 after single dose 
treatment
Unit of measure: PK: Cmax (ng/mL); Tmax (h); 
AUClast, AUCinf (h▪ng/mL); Cl/F (L/h); T1/2 (h);
PD: plasma BNP, plasma NTproBNP, plasma 
cGMP, urine cGMP change from baseline 
geometric mean ratio (GMR) after single dose 
treatment
Description: Part 1 PK assessment: The samples 
will be collected at the following intervals for the 
various age groups:

Patients ≥6 years of age: Blood samples 
are collected at pre-dose (pre-dose 
sample for all patients), 0.5, 1, 2, 4, 8, 
10, and optional 24 hours post dosing

Patients < 6 years of age: Blood samples 
are collected at pre-dose (pre-dose 
sample only from those patients who are 
on valsartan), 1, 2, 4, 10, and optional 24 
hours post dosing
Part 1 PD assessments: The blood samples will be 
collected at pre-dose, 4, 8 and optional 24 hours 
post dosing. The urine samples will be collected at 
pre-dose and once between 4 to 8 hours post 
dosing.
Time Frame: Single dose PK/PD visit
Section 2.5
Secondary
To assess the safety and 
tolerability of LCZ696 in pediatric 
patients with HF
Title: Safety and tolerability of LCZ696 in Part 1
Unit of Measure: Multiple
Description: Safety and tolerability including AEs, 
laboratory, vital signs
Time Frame: Single dose PK/PD visit
Section 2.9
Part 2
Primary
To determine whether LCZ696 is 
superior to enalapril for the 
treatment of HF as assessed 
Title: Global Rank endpoint through 52 weeks of 
treatment
Section 2.6


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure
Section
using a global rank endpoint in 
pediatric HF patients
Unit of Measure: The mean global rank endpoint 
does not have a unit. Patients are ranked from 
worst to best. The ranking is based on clinical 
events such as death, listing for urgent heart 
transplant, mechanical life support requirement at 
end of study, worsening HF, NYHA/ROSS, patient 
global impression of severity (PGIS), pediatric 
quality of life (PedsQL) physical functioning 
domain. 
Description: The effects of LCZ696 and enalapril 
will be assessed using the Global Rank endpoint 
as outlined below through 52 weeks of double-
blind treatment. The primary endpoint will be 
derived based on 5 categories ranking worst to 
best outcome:

Category 1: Death; UNOS status 1A 
listing for heart transplant or equivalent; 
VAD/ECMO/mechanical ventilation/intra-
aortic balloon pump requirement for life 
support at end of study

Category 2: Worsening HF (WHF); 
defined by signs and symptoms of WHF 
that require an intensification of HF 
therapy

Category 3: Worsened; worse 
NYHA/ROSS or worse PGIS; and further 
ranking by PedsQL physical functioning 
domain

Category 4: Unchanged; unchanged 
NYHA/ROSS and unchanged PGIS; and 
further ranking by PedsQL physical 
functioning domain

Category 5: Improved; improved 
NYHA/ROSS or improved PGIS (neither 
can be worse); and further ranking by 
PedsQL physical functioning domain
Within each category, patients are ranked from 
worst to best based on pre-defined criteria.
PedsQL physical functioning will only be used for 
the global rank endpoint for Age Group 1.
Time Frame: 52 Weeks 
Secondary
To determine whether LCZ696 is 
superior to enalapril in delaying 
time to first occurrence of the 
composite of either Category 1 or 
2 events (e.g. death, worsening 
HF)
Title: Time to first occurrence of Category 1 or 
Category 2 event through 52 weeks of treatment
Unit of Measure: Days
Section 0


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure
Section
Description: Time to first occurrence of Category 1 
or Category 2 event will be compared for LCZ696 
and enalapril through 52 weeks of double-blind 
treatment
Time Frame: 52 Weeks
To determine whether LCZ696 is 
superior to enalapril for improving 
NYHA/ROSS functional class
Title: NYHA/ROSS functional class change from 
baseline through 52 weeks of treatment
Unit of Measure: NYHA/ROSS classification
Description: NYHA/ROSS functional class will be 
compared through 52 weeks of double-blind 
treatment
Time Frame: 52 Weeks
Section 2.7.2
To determine whether LCZ696 is 
superior to enalapril for improving 
the PGIS score
Title: PGIS score change from baseline through
52 weeks of treatment
Unit of Measure: PGIS scale
Description: PGIS scale will be compared for 
LCZ696 and enalapril through 52 weeks of 
double-blind treatment
Time Frame: 52 weeks
Section 2.7.3
To characterize the population 
PK of LCZ696 exposure in 
pediatric patients with HF
Title: Population PK of LCZ696
Unit of Measure: ng/mL/kg, ng*h/mL/kg, L/h/kg, 
L/kg, and 1/h
Description: During Part 2 Efficacy, population PK 
will be assessed with chronic dosing. Population 
PK allows us to estimate clearance and total 
exposure.
Time frame: week 2, 12, 52
Separate 
document
To assess the safety and 
tolerability of LCZ696 compared 
to enalapril in pediatric patients 
with HF
Title: Safety and tolerability through 52 weeks of 
treatment
Unit of Measure: Multiple
Description: Safety and tolerability including AEs, 
laboratory, ECG, vital signs data through 52 
weeks of double-blind treatment
Time Frame: 52 weeks
Section 2.9


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OBJECTIVE
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure
Section
2
Statistical methods
2.1
Data analysis general information
Unless otherwise specified, data will be analyzed according to the study protocol using SAS 
9.4 or higher.
An external DMC will monitor patient safety data during the course of the study. For this study, 
the DMC will review safety data on a regular frequency of every six months. DMC may request 
additional safety data review.
In addition, the safety, tolerability, pharmacokinetic, and pharmacodynamic data from open 
label use of LCZ696 will be evaluated by Novartis and the DMC to monitor patients safety for 
each age group when all the patients have completed Part 1 of the study in that age group.
Besides, one formal interim efficacy analysis will be conducted for Part 2 when at least 180 
patients (at least 36 patients from each age group) have completed the study (i.e., had a 
positively adjudicated event in Category 1 or completed the double-blind epoch), and at least 
40 patients have had an event in Category 1 or 2. Further details can be found in Section 2.15.
The analyses results for Part 1 and Part 2 will be summarized in the CSR.


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In general, continuous variables will be summarized using number of observations, mean, 
standard deviation, median, quartiles, minimum and maximum. Categorical variables will be 
summarized using frequencies and percentages.
Unless otherwise specified, for Part 2, the analyses will include a summary for all the three 
modified age groups (6 years to < 18 years, 2 years to < 6 years, and 1 month to < 2 years) and 
a summary for overall; the efficacy variables will be analyzed based on the full analysis set 
(FAS), the safety variables will be analyzed based on the Part 2 safety set (SAF2); statistical 
testing for the secondary
variables will be performed at the significance level of 
two-sided 0.05. No multiplicity adjustment will be performed for the secondary 
 
variables.
2.1.1
General definitions
Part 1:
Epochs
The period 1 epoch is defined as the period from the date of Visit 101 to the date of Visit 199.
The period 2 epoch is defined as the period from the date of Visit 201 to the date of Visit 299.
Dose cohorts
Dose cohort 1 is defined as the patients who were prescribed at least one dose of the study drug 
at dose level 0.4 mg/kg or 0.8 mg/kg within period 1.
Dose cohort 2 is defined as the patients who were prescribed at least one dose of the study drug 
at dose level 1.6 mg/kg or 3.1 mg/kg within period 2.
Dose cohort S is defined as patients who were prescribed one dose of study drug at dose level 
3.1 mg/kg at Visit 201 and were prescribed another dose of study drug at a different dose level 
within period 2. This definition comes from the special cases when trial is ongoing.
Of note, it is possible that, a patient is in both dose cohort 1 and dose cohort 2.
Dose associated periods
For dose cohort 1, the dose associated period is defined as date of Visit 101 to the date of Visit 
103 or Visit 199, whichever occurred first.
For dose cohort 2, the dose associated period is defined as date of Visit 201 to the date of Visit 
203 or Visit 299, whichever occurred first.
Baseline assessment and period day
Unless otherwise specified, the baseline assessment for period 1 is defined as the last non-
missing assessment (scheduled or unscheduled) prior to the first dose time of the study drug 
within period 1.
Unless otherwise specified, the baseline assessment for period 2 is defined as the last non-
missing assessment (scheduled or unscheduled) prior to the first dose time of the study drug 
within period 2, if visit 199 and 201 happened on the same day, then the visit 199 is included.


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In the Part 1 listings, the period and the period day will be displayed, the period day is defined 
as the date of assessment (event/visit) minus the date of first dose plus one.
Post-baseline assessment
Unless otherwise specified, the post-baseline assessments during period 1 are defined as those 
assessments taken during period 1 and later than the first dose time of the study drug within 
period 1, if visit 199 and 201 happened on the same day, then the visit 201 is included.
Unless otherwise specified, the post-baseline assessments during period 2 are defined as those 
assessments taken during period 2 and later than the first dose time of the study drug within 
period 2.
Age and Age group
For Part 1, the age at screening will be recorded on the Demography page and the age group (6 
years to < 18 years, 1 year to < 6 years, 1 month to < 1 year) will be calculated based on the age 
at screening (Visit 1).
Unscheduled visit
Safety evaluation for unscheduled measurements will be taken into account as appropriate.
PK/PD evaluation for an unscheduled PK/PD (UNS PK/PD) visit will be mapped into Visit 
101/201 as appropriate.
Unscheduled assessment will be included in the listings.
Dose associated analysis visits
In Part 1, visits in both period 1 and period 2 will be mapped into dose associated analysis visits , 
for example, visit 101 in period 1, visit 201 in period 2, the dose associated analysis visit is visit 
101/201. The dose associated analysis visits will be used in by-visit summaries.
Part 2:
Double-blind Epoch
The double-blind epoch is defined as the period from the date of randomization to the end of 
the study, inclusive.
Baseline assessment and study day
Unless otherwise specified, the baseline assessment is defined as below.

For efficacy variables, if the scheduled assessment at visit 401 is performed and the 
assessment value is non-missing, the baseline assessment is defined as the scheduled 
assessment at visit 401.

For efficacy variables, if the scheduled assessment at visit 401 is not performed or the 
assessment value is missing, the baseline assessment is defined as the last non-missing 
assessment (scheduled or unscheduled) prior to or on the visit 401 date and after last part 1 
dose date plus five days.


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
For safety variables, the baseline assessment is defined as the last non-missing assessment 
(scheduled or unscheduled) prior to or at the time of the first dose of double-blind study 
drug (i.e., study drug within the double-blind epoch) and after last part 1 dose date plus 
five days. When the dose and the assessment are on the same date, and the dosing time or 
the assessment time is missing, the assessment is considered as pre-dose.
For efficacy variables, the study day is defined as the date of assessment (event/visit) minus the 
date of randomization plus one, i.e., Visit 401 is Day 1.
For safety variables, the study day will be defined as the date of assessment (event/visit) minus 
the date of first dose of double-blind study medication plus one day, i.e., date of first dose of 
double-blind study medication is double-blind day 1.
Post-baseline assessment
Unless otherwise specified, for efficacy variables, the post-baseline assessments during the 
double-blind epoch are defined as those assessments taken during the double-blind epoch and 
later than the date of randomization; for safety variables, the post-baseline assessments during 
the double-blind epoch are defined as those assessments taken during the double-blind epoch 
and later than the first dose time of the study drug within the double-blind epoch.
Age, age group, modified age group and NYHA/ROSS class group at 
randomization
The study is randomized stratifying by age group (6 years to < 18 years, 1 year to < 6 years, 1 
month to < 1 year) and NYHA/ROSS class group (Class I/II, Class III/IV) at randomization. 
The age and NYHA/ROSS class at randomization will be recorded on the case report form 
(CRF) page. The age “Subject’s Age at Randomization” will be used to calculate the age group 
(6 years to < 18 years, 1 year to < 6 years, 1 month to < 1 year) and modified age group (6 years 
to < 18 years, 2 years to < 6 years, 1 month to < 2 years).
If the information is missing on CRF page, stratification data for age group (6 years to < 18 
years, 1 year to < 6 years, 1 month to < 1 year) and NYHA/ROSS class group (Class I/II, Class 
III/IV) at randomization will be loaded from the randomization data (Interactive Response 
Technology (IRT) system) to impute the age, age group, modified age group and NYHA/ROSS 
class. Week, Month and Year
In general, 1 week = 7 days, 1 month = 30.4375 days and 1 year = 365.25 days.
Visit 499 mapping
For patients who completed the double-blind epoch, Visit 499 will be Week 52.
For patients who discontinued from the study during the double-blind epoch, Visit 499 will be 
mapped according to Table 2-1.


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Table 2-1
Visit 499 mapping crietria
Double-Blind Epoch
Patient Status
Last Attended Scheduled
Visit Prior to Visit 499
Country
Mapped Visit for Visit 499
Visit Number
Visit Name
Visit Number
Visit Name
Discontinued
401
Randomization
Japan
401.1
Week 1
Other
402
Week 2
Discontinued
401.1
Week 1
Japan
402
Week 2
Discontinued
402
Week 2
All
403
Week 4
Discontinued
403
Week 4
All
404
Week 6
Discontinued
404
Week 6
All
405
Week 8
Discontinued
405
Week 8
All
406
Week 12
Discontinued
406
Week 12
All
407
Week 16
Discontinued
407
Week 16
All
408
Week 20
Discontinued
408
Week 20
All
409
Week 24
Discontinued
409
Week 24
All
410
Week 28
Discontinued
410
Week 28
All
411
Week 32
Discontinued
411
Week 32
All
412
Week 36
Discontinued
412
Week 36
All
413
Week 40
Discontinued
413
Week 40
All
414
Week 44
Discontinued
414
Week 44
All
415
Week 48
Discontinued
415
Week 48
All
416
Week 52
Completed
---
---
All
416
Week 52
- For each patient, the last attended scheduled visit prior to Visit 499 is defined as the visit with 
maximal visit number among all scheduled visits (Visit 401 to Visit 415) in the visit panel.
Unscheduled assessments
Data collected at Visit 499 will be included in by-visit summaries, if an assessment were 
scheduled at the mapped visit for Visit 499.
Unscheduled assessments will be included in over period minimum/maximum, and in over 
period shift table.
Unless otherwise specified, in by-visit summaries, the unscheduled assessments will be used as 
below.

For efficacy variables, if a post-randomization scheduled assessment is not performed or 
the assessment value is missing, the last non-missing associated unscheduled assessment 
prior to the next scheduled visit and within 14 days of the target date could be used to 
impute the scheduled assessment.

For safety variables, if a post-randomization scheduled assessment is not performed or the 
assessment value is missing, the last non-missing associated unscheduled assessment prior 
to the next scheduled visit could be used to impute the scheduled assessment.
An unscheduled assessment is considered to be associated with a scheduled assessment if the 
unscheduled visit number and the scheduled visit number are equal up to the first digit, e.g., 
visit 40x.00y is associated with visit 40x, and visit 401.10x is associated with visit 401.1.


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Region
Region will be derived from country. The mapping criteria are specified below.
Table 2-2
Region mapping criteria
Region
Countries
America
Argentina, Canada, USA
Europe
Austria, Bulgaria, Croatia, Czech Republic, Finland, France, Germany, 
Hungary, Italy, Poland, Portugal, Romania, Russia, Spain, Sweden, 
Switzerland, Turkey
Asia/Pacific and other
China, India, Israel, Japan, Jordan, Lebanon, Rep. of Korea, Saudi 
Arabia, Singapore, South Africa, Taiwan, Thailand
2.2
Analysis sets
The following analysis sets will be defined for statistical analysis for Part 1 and Part 2.

Part 1 screened set (SCR1) – All patients who signed the informed consent for Part 1. 
The SCR1 includes only unique screened patients, i.e., in the case of re-screened patients
only the chronologically last screening data is counted.

Part 1 eligible set (ELG1) – All patients who completed the Part 1 screening phase.

Part 1 PK set (PK1) – All ELG1 patients with at least one dose of study drug during Part 
1 of the study, at least one available valid (i.e., not flagged for exclusion) PK 
concentration measurement during Part 1 of the study, and with no protocol deviations 
with relevant impact on PK data during Part 1 of the study. Patients will be analyzed 
according to treatment received.

Part 1 PD set (PD1) – All ELG1 patients with at least one dose of study drug during Part 
1 of the study, at least one available PD measurements during Part 1 of the study and with 
no protocol deviations with relevant impact on PD data. Patients will be analyzed 
according to treatment received.

Part 1 safety set (SAF1) – All ELG1 patients who received at least one dose of study
drug during the Part 1 of the study. Patients will be analyzed according to treatment 
received.

Part 2 screened set (SCR2) – All patients who signed the informed consent for Part 2. The 
SCR2 includes only unique screened patients, i.e., in the case of re-screened patients only 
the chronologically last screening data is counted.

Randomized set (RAN) – All patients who received a randomization number, regardless 
of receiving study drug.

Full analysis set (FAS) – All randomized patients with the exception of those patients who 
have not been qualified for randomization and have not received study drug, but have been 
inadvertently randomized into the study. Following the intent-to-treat principle, for the 
efficacy analysis, patients will be analyzed according to the treatment assigned at 
randomization. Efficacy variables will be analyzed based on the FAS as the primary set.

Per protocol set (PPS) – A subset of the FAS which consists of the patients who do not 
have major deviations from the protocol procedures in the double-blind study stage. Major 
protocol deviations will be pre-specified prior to unblinding treatment codes for analyses. 
This supplemental efficacy set will be used to support the primary analysis results.


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
Part 2 safety set (SAF2) – All randomized patients who received at least one dose of study
drug. For the safety analysis, patients will be analyzed according to the treatment actually 
received. The treatment actually received will be considered identical to the randomized 
treatment if the patient has received at least one dose of the randomized treatment. The 
SAF2 will be used for the safety analyses for Part 2.
Rules leading to exclusion from analysis sets are given in Appendix 5.3.
2.2.1
Subgroup of interest
Table 2-3 specifies the subgroups to be used in subgroup analyses for Part 2.
Table 2-4 summarizes the subgroup analyses for Part 2.
Table 2-3
Subgroup specifications
Subgroups
Source
Data Source
Variable
Visit/Time
Point
Modified age group at 
randomization

6 years to < 18 years;

2 years to < 6 years;

1 month to < 2 years;
CRF Page:
Subject’s Age at
Randomization
Age
Randomization
NYHA/ROSS class groupat 
baseline

NYHA/ROSS Class I/II;

NYHA/ROSS Class III/IV;
CRF Page:
Signs and Symptoms of 
Heart Failure including 
New York Heart Association 
Classification;
Modified ROSS 
HF Classification
NYHA/R
OSS
class 
group
Randomization
NYHA/ROSS class group
at randomization

NYHA/ROSS Class I/II;

NYHA/ROSS Class III/IV;
IRT:
Randomization stratification
NYHA/R
OSS
class 
group
Randomization
Gender

Female;

Male;
CRF Page:
Demography
Sex
Screening or 
Pre-
Randomization
Region

America;

Europe;

Asia/Pacific and other;
CRF Page:
Demography
Country
Screening or 
Pre-
Randomization
COVID-19 period

Pre-pandemic: 
EOS prior to 1-Mar-2020

Pre and during pandemic: 
CRF page:
Disposition;
YR domain
date
Randomization
date
End of study
date


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Subgroups
Source
Data Source
Variable
Visit/Time
Point
Randomization date prior to 
1-Mar-2020 and 
EOS after 1-Mar-2020

During pandemic: 
Randomization date on or 
after 1-Mar-2020
Race

Caucasian: White.

Black: Black or African 
American.

Asian: Asian.

Other: American Indian or 
Alaska Native; Unknown;
Other.
CRF Page:
Demography
Race
Screening or 
Pre-
Randomization
Prior ACEI/ARB use

ACEI only

ARB only

ACEI and ARB both

No

Unknown
CRF Page:
Prior Cardiovascular 
Medications-ACEI
Prior Cardiovascular 
Medications-ARB
medicatio
n
Screening or 
Pre-
Randomization
Table 2-4
Subgroup analyses
Subgroup Variable
Primary/Secondary
Efficacy
Selected
Safety
Modified age group at randomization
X
X
NYHA/ROSS class group at randomization
X
NYHA/ROSS class group at baseline
X
Gender
X
X
Region
X
X
COVID-19 impacted period
X
Race
X
X
Prior ACEI/ARB use
X
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Part 1:
The number and percentage of patients who completed the Part 1 screening phase will be 
provided by age group. In addition, the primary reason for not completing the Part 1 screening 
phase will be summarized by age group using the numbers and percentages of patients not 


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qualifying for such reasons. For patient who was screened more than once, the information 
from the last screen will be used in the summary. These summaries will be performed for the 
SCR1.
The patient status for the dose associated period will be summarized by age group and dose 
cohort, using the numbers and percentages of patients who took at least one dose during the 
period, who completed the period, and who discontinued from study during the period; the 
primary reason for discontinuation will be summarized by age group, using the numbers and 
percentages of patients discontinued for such reasons. These summaries will be performed 
based on the ELG1.
The inclusion status for the analysis sets will be summarized by age group and dose cohort 
using the numbers and percentages of patients included in different analysis sets. These 
summaries will be performed based on the ELG1.
The protocol deviations will be summarized by age group and dose cohort using the numbers 
and percentages of patients with the protocol deviation. These summaries will be performed 
based on the ELG1.
In addition, the number and percentage of patients satisfying each criteria leading to exclusion 
from analysis sets will be provided by age group and dose cohort. These summaries will be 
performed based on the ELG1.
Part 2:
The number and percentage of patients who completed the pre-randomization epoch will be 
provided. In addition, the primary reason for not completing the pre-randomization epoch will 
be summarized by age group and modified age group using the numbers and percentages of 
patients not qualifying for such reasons. For patient who was screened more than once, the 
information from the last screen will be used in the summary. These summaries will be 
performed for the SCR2.
The patient status for the double-blind epoch will be summarized by age group/modified age 
group and treatment group, using the numbers of patients who were randomized, the numbers 
and percentages of patients who completed the double-blind epoch, who discontinued from the 
study during the double-blind epoch; the primary reason for discontinuation from the study will 
be summarized by age group/modified age group and treatment group, using the numbers and 
percentages of patients discontinued for such reasons. These summaries will be performed 
based on the RAN.
The numbers and percentages of patients who took at least one dose of the study drug during 
the double-blind epoch, who completed the study drug during the double-blind epoch and who 
permanently discontinued from the study drug during the double-blind epoch will be 
summarized by age group/modified age group and treatment group; the primary reason for 
permanent discontinuation from the study drug will be summarized by age group/modified age 
group and treatment group, using the numbers and percentages of patients discontinued for such 
reasons. These summaries will be performed based on the RAN.
The disposition will also be summarized by COVID-19 periods.


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The inclusion status for the analysis sets (section 2.2) will be summarized by age 
group/modified age group and treatment group using the numbers and percentages of patients 
included in different analysis sets. These summaries will be performed based on the RAN.
The protocol deviations will be summarized by age group/modified age group and treatment 
group using the numbers and percentages of patients with the protocol deviation. This summary 
will also be summarized by COVID-19 periods. These summaries will be performed based on 
the RAN.
The COVID-19 related PD will also be summarized separately.
In addition, the number and percentage of patients satisfying each criteria leading to exclusion 
from analysis sets will be provided by age group/modified age group and treatment group. 
These summaries will be performed based on the RAN.
Furthermore, the numbers and percentages of patients in each country and in each region will 
be provided by age group/modified age group and treatment group. These summaries will be 
performed based on the RAN.
2.3.2
Background and demographic characteristics
Continuous variables will be summarized using number of observations, mean, standard 
deviation, median, minimum, the first quartile (Q1), the third quartile (Q3), and maximum. For 
in-text tables, minimum and maximum will not be presented. Categorical variables will be 
summarized using frequencies and percentages.
Part 1:
Summary statistics will be provided by age group and dose cohort for demographics and 
baseline characteristics including age, age group (not for within age group summary), sex, race, 
ethnicity, (age adjusted percentile) weight, height, body mass index (BMI), head circumference, 
category of prior HF medication (ARB, ACEI), HF etiology, prior HF hospitalization, vital 
signs, and biochemical characteristics, NYHA/Ross classification. BMI will be calculated as 
weight (kg) / height2 (m2) from the collected height and weight at screening (Visit 1).
The SAF1 will be used for the above Part 1 analyses. Baseline assessment will be the one for 
each period (and then each age group).
Part 2:
Summary statistics will be provided by age group/modified age group and treatment group for 
demographics and baseline characteristics including age, age group/modified age group (not for 
within age group/modified age group summary), sex, race, ethnicity, (age adjusted percentile) 
weight, height, body mass index (BMI), head circumference, category of prior HF medication
(ARB, ACEI), HF etiology, prior HF hospitalization, vital signs, and biochemical 
characteristics, NYHA/ROSS classification,. BMI will be calculated as weight (kg) / height2
(m2) from the collected height and weight at Visit 301.
The FAS will be used for the above Part 2 analyses.


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2.3.3
Medical history
Any condition entered on the relevant medical history/current medical conditions CRF will be 
coded using the MedDRA dictionary. Medical history includes heart failure history and other 
medical history in this study, which are collected at Visit 1 or Visit 301. The number and 
percentage of patients with each medical condition will be provided by age group/modified age 
group, treatment group, system organ class (SOC), and preferred term (PT).
For above analyses, the SAF1 will be used for Part 1, and FAS will be used for Part 2.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Part 1:
The total actual dose of the study drug during a given period is defined as the sum of all doses 
of the study drug actually administered (recorded on the DAR-PK page, in unit mg) from the 
start date of the period to the end date of the period.
The planned dose of the study drug at a given visit is defined as the product of the dose 
prescribed of the study drug (recorded on the DAR-PK page, in unit mg/kg) at the visit and 
the weight (recorded on the Vital Signs page, in unit kg) at the visit.
The total planned dose of the study drug during a given period is defined as the sum of all 
planned doses of the study drug from the start date of the period to the end date of the period.
The compliance of the study drug during a given period is defined as the total actual dose of the 
study drug during the period divided by the total planned dose of the study drug during the 
period. 
The total actual dose, the total planned dose and the compliance during the dose associated 
period and at the last visit will be summarized by age group and dose cohort using number of 
observations, mean, standard deviation, median, minimum, Q1, Q3, and maximum.
In addition, the compliance during the dose associated period will be summarized by age group 
and dose cohort using the numbers and percentages of patients with compliance < 80%, 80% to 
< 120%, >120% and < 90%, 90% to < 110%, >110%.
The SAF1 will be used for the above analyses.
The study drug administration and prescription will be listed based on SAF1.
Part 2:
The study drug administration will be recorded on the CRF page: “Dosage Administration 
Record – Double-Blind Study Medication” using start date-time, end date-time and dispensing 
level of the study drug. Each pair of start date and end date will be considered as a dosing 
interval.
For each patient, the dosing intervals will be sorted according to the start date and the end date 
from the earliest to the latest. It is expected that, for each patient, there should be no gaps and 


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overlaps among dosing intervals, with the exception that the end date of a dosing interval can 
be the same as the start date of the next dosing interval, when the patient may take the previous 
dispensing level in the morning and start a different dispensing level in the evening.
In the presence of gaps or overlaps, a data conventional imputation algorithm will be applied to 
the start date and end date. The detailed algorithm will be provided in the study programming 
datasets specifications (PDS).
For patients who permanently discontinue study treatment, there should be a dosing interval 
with its start date equal to the date of the permanent discontinuation of the study drug, its end 
date equal to the study completion/discontinuation date, and its dispensing level equal to “No 
treatment”.
For patients who complete the treatment and study, the dose level for the end of study visit will 
be the dose level for the end of treatment in the dose level by visit report.
The dose level is defined based on the dispensing level according to Table 2-5 and Table 2-6 if 
the dispensing level is a pediatric dose level or an adult dose level. If the dispensing level is no 
treatment, the dose level is defined as 0.
For a dosing interval with a pediatric dose level, the daily dose (mg/day) during the interval is 
defined as the product of the weight based daily dose (mg/day/kg) during the interval and the 
weight during the interval, where the weight based daily dose (mg/day/kg) during the interval 
is defined in Table 2-5 and the weight during the interval is defined as the weight from the last 
non-missing assessment (scheduled or unscheduled) prior to or equal to the start dose time of 
the study drug of the interval.
Table 2-5
Pediatric dose levels and corresponding doses of the study drug
Dispensing 
Level
Dose
Level
Weight Based Dose
Weight Based Daily Dose
LCZ696
Enalapril
LCZ696
Enalapril
Age group 1 and 2
Dose level 1
1
0.8 mg/kg bid.
0.05 mg/kg bid.
1.6 mg/day/kg
0.1 mg/day/kg
Dose level 2
2
1.6 mg/kg bid.
0.10 mg/kg bid.
3.2 mg/day/kg
0.2 mg/day/kg
Dose level 3
3
2.3 mg/kg bid.
0.15 mg/kg bid.
4.6 mg/day/kg
0.3 mg/day/kg
Dose level 4
4
3.1 mg/kg bid.
0.20 mg/kg bid.
6.2 mg/day/kg
0.4 mg/day/kg
Age group 3
Dose level 1x
1
0.8 mg/kg bid.
0.05 mg/kg bid.
1.6 mg/day/kg
0.1 mg/day/kg
Dose level 2x
1.5
1.2 mg/kg bid.
0.075 mg/kg bid.
2.4 mg/day/kg
0.15 mg/day/kg
Dose level 3x
2
1.6 mg/kg bid.
0.1 mg/kg bid.
3.2 mg/day/kg
0.2 mg/day/kg
Dose level 4x
3
2.3 mg/kg bid.
0.15 mg/kg bid.
4.6 mg/day/kg
0.3 mg/day/kg
Dose level 5x
4
3.1 mg/kg bid
0.20 mg/kg bid.
6.2 mg/day/kg
0.4 mg/day/kg
Table 2-6 provides the weight based daily dose (mg/day/kg) for dosing intervals with adult dose 
levels.


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Table 2-6
Adult (≥ 57 kg) dose levels and corresponding doses of the study drug
Dispensing Level
Dose
Level
Dose
Weight Based Daily Dose
LCZ696
Enalapril
LCZ696
Enalapril
Adult dose level 1
1
50 mg bid.
2.5 mg bid.
1.6 mg/kg/day
0.1 
mg/kg/day
Adult dose level 2
2
100 mg bid.
5.0 mg bid.
3.2 mg/kg/day
0.2 
mg/kg/day
Adult dose level 3
3
150 mg bid.
7.5 mg bid.
4.6 mg/kg/day
0.3 
mg/kg/day
Adult dose level 4
4
200 mg bid.
10.0 mg bid.
6.2 mg/kg/day
0.4 
mg/kg/day
The weight based daily dose (mg/kg/day) is defined as 0 mg/kg/day for dosing intervals with 
no treatment.
Dispensing level, dose level and daily dose at each visit
For a given visit, the visit associated dosing interval is defined as the dosing interval with its 
start date prior to or equal to the date of visit AND its end date later than or equal to the date of 
visit; the dispensing level, dose level and weight based daily dose (mg/day/kg) at the visit are 
defined as the dispensing level, dose level and weight based daily dose (mg/day/kg) for the visit 
associated dosing interval. In the case that, the visit date is equal to the end date of an earlier 
dosing interval as well as the start date of a later dosing interval, the later dosing interval will 
be taken as the visit associated dosing interval.
The dispensing level and the dose level will be summarized by treatment group and visit, for 
overall and for each modified age group, using the number and percentage of patients on each 
level; the dose level will be summarized by treatment group and visit, for overall and for each 
age group and modified age group, using number of observations, mean, standard deviation, 
median, minimum, Q1, Q3, and maximum; the weight based daily dose (mg/day/kg) will be 
summarized by treatment group and visit, for overall and for each age group and modified age 
group, using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum.
The summary will include all scheduled visits in the double-blind epoch.
The SAF2 will be used for the above analyses.
Duration of treatment exposure
The duration (day) of treatment exposure during the double-blind epoch is defined as the date 
of the last dose of the study drug during the double-blind epoch minus the date of the first dose 
of the study drug during the double-blind epoch plus one day, regardless of the temporary 
treatment interruption.
The duration (month) of treatment exposure during the double-blind epoch will be converted 
from the duration (day) of treatment exposure during the double-blind epoch to months using a 
factor of 30.4375 day/month. The duration (year) of treatment exposure during the double-blind 
epoch will be converted from the duration (day) of treatment exposure during the double-blind 
epoch to years using a factor of 365.25 day/year. The duration (day) of treatment exposure 


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during the double-blind epoch will be categorized into the following categories, where 1 week 
= 7 days.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 6 months

>= 6 months
The categorized duration of treatment exposure during the double-blind epoch will be 
summarized by age group and modified age group and treatment group using the numbers and 
percentages of patients within each category.
The duration (month) of treatment exposure during the double-blind epoch will be summarized 
by age group and modified age group and treatment group using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum.
Besides, the overall patient-years on-treatment will be provided by age group and modified age 
group and treatment group, where the overall patient-years on-treatment is defined as the sum 
of duration (year) of treatment exposure among the corresponding the age group and modified 
age group and/or the treatment group.
The SAF2 will be used for the above analyses.
Duration on each dose level
For a given dose level, the duration (day) on this dose level is defined as the number of days on 
this dose level during the period from the date of the first dose of the study drug to the date of 
the last dose of the study drug. In the case that, the end date of an earlier dosing interval is the 
same as the start date of a later dosing interval, the day will be counted as 0.5 day on both the 
earlier dose level and the later dose level. In the case that, the date of permanent discontinuation 
of the study drug is the same as the date of the last dose the study drug, the day will be counted 
as 0.5 day on the dose level of the last dose but not counted on dose level 0.
The duration (month) on each dose level during the double-blind epoch will be derived from 
the duration (day) on this dose level during the double-blind epoch using a factor of 30.4375 
day/month, and will be summarized by age group and modified age group and treatment group 
using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum.
The duration (day) on each dose level during the double-blind epoch will be categorized into 
the following categories, where 1 week = 7 days and 1 month = 30.4375 days.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 6 months

>= 6 months
The categorized duration on each dose level during the double-blind epoch will be summarized 
by age group and modified age group and treatment group using the numbers and percentages 
of patients within each category.


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The SAF2 will be used for the above analyses.
Duration of study drug exposure
The duration (day) of study drug exposure during the double-blind epoch is defined as the sum 
of the duration (day) on dose level 1 to 4 during the double-blind epoch.
The duration (month) of study drug exposure during the double-blind epoch will be derived 
from the duration (day) of study drug exposure during the double-blind epoch using a factor of 
30.4375 day/month, and will be summarized by age group and modified age group and 
treatment group using number of observations, mean, standard deviation, median, minimum, 
Q1, Q3, and maximum.
The duration (day) of study drug exposure during the double-blind epoch will be categorized 
into the following categories, where 1 week = 7 days and 1 month = 30.4375 days.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 6 months

>= 6 months
The categorized duration of study drug exposure during the double-blind epoch will be 
summarized by age group and modified age group and treatment group using the numbers and 
percentages of patients within each category.
The SAF2 will be used for the above analyses.
Percentage of study drug exposure
For each patient, the percentage of study drug exposure during the double-blind epoch is defined 
as the percentage of the duration (day) of study drug exposure during the double-blind epoch 
out of the duration (day) of treatment exposure during the double-blind epoch.
The percentage of study drug exposure during the double-blind epoch will be summarized by 
age group and modified age group and treatment group using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum.
The SAF2 will be used for the above analyses.
Time to first dose of each dose level
For a given dose level, the time (day) to first dose on this dose level during the double-blind 
epoch is defined as the date of the first dose on this dose level during the double-blind epoch 
minus the date of the first dose of the study drug plus one day. If there is no dosing interval on 
this dose level during the double-blind epoch, the time (day) to first dose on this dose level 
during the double-blind epoch will be censored on the date of last visit during the double-blind 
epoch for this patient.
For each dose level, the time (day) to first dose on the dose level during the double-blind epoch 
will be summarized using the Kaplan-Meier curve for each treatment group within each age 
group and modified age group.


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The SAF2 will be used for the above analyses.
Time to permanent discontinuation of the study drug
The time (day) to permanent discontinuation of the study drug during the double-blind epoch is 
defined as the date of the permanent discontinuation of the study drug minus the date of the first 
dose of the study drug plus one day. If the study drug is not permanently discontinued during 
the double-blind epoch, the time (day) to permanent discontinuation of the study drug during 
the double-blind epoch will be censored on the date of last visit during the double-blind epoch 
for this patient.
The time (day) to permanent discontinuation of the study drug during the double-blind epoch 
(excluding death) will be summarized for each treatment group within each age group and 
modified age group using the Kaplan-Meier curves.
The SAF2 will be used for the above analyses.
Mean weight based daily dose and mean dose level
For a given dose level, the duration (day) on this dose level is defined as the number of days on 
this dose level during the period from the date of the first dose of the double-blind study drug 
to the date of the last dose of the double-blind study drug. In the case that, the end date of an 
earlier dosing interval is the same as the start date of a later dosing interval, the day will be 
counted as 0.5 day on both the earlier dose level and the later dose level. In the case that, the 
date of permanent discontinuation of the study drug is the same as the date of the last dose the 
study drug, the day will be counted as 0.5 day on the dose level of the last dose but not counted 
on dose level 0.
For each patient, the mean weight based daily dose (mg/kg/day) during the double-blind epoch 
is defined as the weighted mean of the weight based daily dose (mg/kg/day) among dose level 
0 to 4 using the duration (day) on each dose level during the double-blind epoch as the weight, 
i.e.
the mean dose level during the double-blind epoch is defined as the weighted mean of the dose 
level among dose level 0 to 4 using the duration (day) on each dose level during the double-
blind epoch as the weight, i.e.,
The mean weight based daily dose (mg/day/kg) during the double-blind epoch and the mean 
dose level during the double-blind epoch will be summarized by treatment group, for each age 
group and modified age group, using number of observations, mean, standard deviation, median, 
minimum, Q1, Q3, and maximum.
The SAF2 will be used for the above analyses.
∑
Weight Based Daily Dose (mg/kg/day) for Dose Level  × Duration (day) on Dose Level 
4
=0
∑
Duration (day) on Dose Level 
4
=0
∑
 × Duration (day) on Dose Level 
4
=0
∑
Duration (day) on Dose Level 
4
=0
.


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Duration of study exposure
The duration (day) of study exposure during the double-bind epoch is defined as the date of last 
visit (Visit 416/499) minus the date of randomization plus one day.
The duration (month) of study exposure during the double-blind epoch will be derived from the 
duration (day) of study exposure during the double-blind epoch using a factor of 30.4375 
day/month, and will be summarized by age group and modified age group and treatment group 
using number of observations, mean, standard deviation, median, minimum, Q1, Q3, and 
maximum.
The duration (day) of study exposure during the double-blind epoch will be categorized into the 
following categories, where 1 week = 7 days and 1 month = 30.4375 days.

< 2 weeks

2 weeks to < 8 weeks

8 weeks to < 6 months

>= 6 months
The categorized duration of study exposure during the double-blind epoch will be summarized 
by age group and modified age group and treatment group using the numbers and percentages 
of patients within each category.
The SAF2 will be used for the above analyses.
Last recorded dose level
The last recorded dose level during the double-blind epoch is defined as the dose level for the 
last dosing interval during the double-blind epoch.
The last recorded dose level during the double-blind epoch will be summarized by age group 
and modified age group and treatment group using the numbers and percentages of patients on 
each dose level.
The same summary will be performed for patients who permanently discontinued from the 
study treatment and for patients who completed the study treatment.
The SAF2 will be used for the above analyses.
Dose down titration
A down-titration dosing interval is defined as a dosing interval whose dose level is changed to 
a lower dose level from its previous dosing interval.
The dose down titration during the double-blind epoch will be summarized by age group and 
modified age group and treatment group using the numbers and percentages of patients with at 
least one down-titration dosing interval during the double-blind epoch.
The SAF2 will be used for the above analyses.
Dose interruption
A dose-interruption dosing interval is defined as a dosing interval with “NO TREATMENT”.


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The numbers and percentages of patients with at least one dose-interruption dosing interval 
during the double-blind epoch will be provided by age group and modified age group and 
treatment group.
For each patient and each given dose-interruption dosing interval, the duration (day) of dose-
interruption is defined as the number of days temporarily off-study drug in this dosing interval. 
In the case that the start date of a latter dosing interval is the same as the end date of this dosing 
interval, the end date will be counted as 0.5 day. In the case that, the end date of an earlier 
dosing interval is the same as the start date of this dosing interval, the start date will be counted 
as 0.5 day.
The numbers and percentages of patients having at least one dose-interruption dosing interval
with duration (day) of dose-interruption larger than 14 days will be provided by age group and 
modified age group and treatment group.
The SAF2 will be used for the above analyses.
2.4.2
Prior, concomitant and post therapies
Heart failure and cardiovascular medications (prior and concomitant) will be recorded on the 
CRF pages: “Prior Cardiovascular Medications-ARB”, and “Prior Cardiovascular Medications-
ACEI”. Other general prior and concomitant medications will be recorded on the page: “Prior 
and Concomitant Medications”. Procedures and significant non-drug therapies (prior and 
concomitant) will be recorded on the CRF page “Surgical and Medical Procedures”.
The missing or partially missing start/end date for prior/concomitant therapies will be imputed 
using the Novartis ADaM Governance Board (AGB) global standard approach.
Prior and concomitant medications/non-drug therapies will be identified based on recorded or 
imputed start and end dates. Details will be provided in the study programming datasets 
specifications (PDS).
‘Prior medications’ are defined as drugs taken prior to first dose of double-blind study 
medication. Any medication which has been started during the double-blind treatment epoch 
including medications started prior to randomization but continued in the double-blind 
treatment epoch are identified as ‘Concomitant medications’.
Prior and concomitant medications will be summarized separately by modified age group, 
treatment group, anatomical therapeutic classification (ATC) and PT. Prior and concomitant 
non-drug therapies will be summarized separately by modified age group, treatment group, 
SOC and PT.
In addition, for each of the following classes, prior medications and concomitant medications 
during the  dose associated period will be summarized by age group and dose cohort for Part 1, 
and also summarized by modified age group and treatment group for Part 2.
Table 2-7
Cardiovascular and heart failure medications 
Medication
ATC code
Angiotensin converting enzyme inhibitor (ACEI)
C09A, C09B
Angiotensin receptor blocker (ARB)
C09C, C09D


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Beta blockers
C07
Diuretics
C03
Aldosterone antagonists (including spironolactone)
C03DA
Calcium antagonists
C08
Nitrates
C01DA
Other vasodilators
C01DX
Cardiac glycocytes (Digoxin/digitalis glycoside)
C01A
Antiarrhythmic agents
C01B
Aspirin
B01AC with preferred term of 
(ACETYLSALICYLIC ACID and/or 
ACETYLSALICYLATE LYSINE)
Other antiplatelet agents
B01AC except preferred term of 
(ACETYLSALICYLIC ACID and/or 
ACETYLSALICYLATE LYSINE)
Oral anticoagulants
B01AA, B01AE, B01AF, B01AX
Sodium-dependent glucose transporters 2 (SGLT2i)
A10BK
The use of prohibited medication during the study, if any, will also be summarized.
The SAF1 will be used for the Part 1 analyses and the SAF2 will be used for the Part 2 analyses.
2.5
Analysis of the primary objective for Part 1
2.5.1
Analysis of the PK parameters
The PK parameters will include for all LCZ696 analytes (Sacubitril, LBQ657 [also known as 
sacubitrilat] and Valsartan)

Cmax

Tmax

AUClast

AUCinf

Clearance (Cl/F)

T1/2
In Part 1, PK samples (as blood volume will allow) will be taken at Visit 101 and 201 PK/PD 
at the following intervals for the various age groups:
1. Patients > 6 years of age: Blood samples are collected at pre-dose (pre-dose sample for all 
patients) 0.5, 1, 2, 4, 8, 10, and optional 24 hours post dosing
2. Patients < 6 years of age: Blood samples are collected at pre-dose (pre-dose sample only 
from those patients who are on valsartan) 1, 2, 4, 10, and at an optional 24 hours post 
dosing
The PK parameters will be determined using non-compartmental method(s) with Phoenix v6.4, 
including clearance (Cl/F), T1/2, Cmax, Tmax, AUClast, AUCinf based on Part 1 scheduled or 
unscheduled PK samples.


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For each of the LCZ696 analytes (Sacubitril, LBQ657 and Valsartan), if data available, the PK 
parameters will be summarized by PK parameter, dose cohort within each age group using 
number of observations, mean, standard deviation, coefficient of variation (CV), geometric 
mean, geometric standard deviation, geometric CV, median, minimum, and maximum, where 
the geometric mean is the exponential transformation of the mean of the log transformed data, 
the geometric standard deviation is the exponential transformation of the standard deviation of 
the log transformed data, the geometric CV is the square root of (the exponential transformed 
variance of the log transformed data minus one).
These summaries will only include scheduled assessments within the dose associated period.
For each of the LCZ696 analytes (Sacubitril, LBQ657 and Valsartan), if data available, the 
individual LCZ696 concentration-time profiles within the dose day to the dose day plus 5 days 
will be plotted at patient level, by dose cohort within each age group.
The PK1 will be used for the above analyses. Listing will be provided.
2.5.2
Analysis of the PD parameters
The  following PD parameters (biomarkers) will be included.

plasma cGMP

plasma NTproBNP

plasma BNP

urine cGMP
The blood samples will be collected at pre-dose, 4, 8 and optional 24 hours post dosing. The 
urine samples will be collected at pre-dose and once between 4 to 8 hours post dosing.
For each PD parameter, the test values and the ratios to baseline in the PD parameter will be 
summarized by time point, dose cohort within each age group using number of observations, 
geometric mean, geometric standard deviation, median, minimum, Q1, Q3, and maximum.
These summaries will only include scheduled assessments within the dose associated period.
The following analyses will not be included in the CSR but in separate report.
A population PK model will be developed to describe incoming data from pediatric patients 
based on an established model developed for the adult HF population. 
Pharmacodynamic evaluations will include analysis of change in plasma cGMP, plasma BNP, 
plasma NTproBNP and urine cGMP. Dose and exposure-response relationship will be 
evaluated based on changes in plasma cGMP levels (and also plasma NTproBNP, plasma BNP, 
urine cGMP).
PKPD modeling of Part 1 data may be carried out, depending on the robustness of both the PK 
and biomarkers to be used to inform the dose justification for Part 2. The PD1 will be used for 
the above analyses. Listing will be provided.


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2.5.3
Handling of missing values/censoring/discontinuations
All concentrations below the lowest limit of quantitation (LLOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LLOQ will be treated as 
zero in summary statistics and for the calculation of PK parameters.
An UNS PK/PD assessment will be mapped into Visit 101/201 if all the following criteria are 
satisfied.

The UNS PK/PD assessment is post-baseline.

The UNS PK/PD assessment is valid (i.e., not flagged for exclusion).

There is no valid (i.e., not flagged for exclusion) PK/PD assessment on Visit 101/201.

The dose level prescribed on Visit 101/201 and on the UNS PK/PD visit are the same.
2.6
Analysis of the primary objective for Part 2
2.6.1
Primary endpoint
Patient strata will be defined based on the combination of the modified age group (6 years to < 
18 years, 2 years to < 6 years, 1 month to < 2 years) at randomization and NYHA/ROSS class 
group (Class I/II, Class III/IV) at randomization. There will be six patient strata listed as 
following.
1. Age Group 1 (6 years to < 18 years) and NYHA/ROSS Class I/II
2. Age Group 1 (6 years to < 18 years) and NYHA/ROSS Class III/IV
3. Age Group 2a (2 years to < 6 years) and NYHA/ROSS Class I/II
4. Age Group 2a (2 years to < 6 years) and NYHA/ROSS Class III/IV
5. Age Group 3a (1 month to < 2 years) and NYHA/ROSS Class I/II
6. Age Group 3a (1 month to < 2 years) and NYHA/ROSS Class III/IV
The primary endpoint is the global rank endpoint through 52 weeks of treatment (analysis cutoff 
date will be set to 58 weeks, i.e. 406 days), which will be constructed through two steps within 
each of the six strata.

Step 1: Patients are classified into five ordinal categories based on the logic described 
below in Table 2-8.

Step 2: Within each category, patients are ranked from worst to best based first on the 
subcategory if applicable, and then the ranking algorithm as explained in Table 2-8.
Table 2-8
Primary endpoint algorithm using ranked analysis
Categor
y
Sub-
categor
y
Description
Ranking algorithm
1
Death; UNOS status 1A listing for heart transplant or equivalent; VAD/ECMO/mechanical 
ventilation/intra-aortic ballon pump requirement for life support at end of study.
A
Death;
UNOS status 1A listing for heart 
transplant or equivalent;
Rank within this category by time to 
first event. All Category 1 events are 
considered equal.


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Categor
y
Sub-
categor
y
Description
Ranking algorithm
VAD/ECMO/mechanical 
ventilation/intra-aortic balloon pump 
requirement for life support at end of 
study.
2
Worsening HF (WHF); defined by signs and symptoms of WHF that requires an 
intensification of HF therapy.
B
Worsening heart failure hospitalization 
with intensive care unit stay.
Within Category 2, the patients will be 
ranked first by event subcategory, and 
then by number of events within each 
subcategory. Further ranking by time 
to first event in the worst subcategory.
C
Worsening heart failure hospitalization 
without intensive care unit stay.
D
Worsening heart failure without 
hospitalization.
3
Worsened; worse NYHA/ROSS or worse PGIS; and further ranking by PedsQL physical 
functioning domain.
E
NYHA/ROSS or PGIS worsened 
based on last available assessment 
compared to baseline.
Rank by combination of NYHA/ROSS
and PGIS degree of change. Within a 
group of the same degree of 
NYHA/ROSS and PGIS change, 
further rank by PedsQL (physical 
functioning domain) change from 
baseline.
4
Unchanged; unchanged NYHA/ROSS and unchanged PGIS; and further ranking by 
PedsQL physical functioning domain.
F
NYHA/ROSS and PGIS unchanged 
based on last available assessment 
compared to baseline.
Worst baseline combination of 
NYHA/ROSS functional class and 
PGIS without change is ranked worse 
than a better baseline NYHA/ROSS
functional class and PGIS. Within a 
group of the same baseline 
NYHA/ROSS and PGIS, further rank 
by PedsQL (physical functioning 
domain) change from baseline.
5
Improved; improved NYHA/ROSS or improved PGIS (neither can be worse); and further 
ranking by PedsQL physical functioning domain).
G
NYHA/ROSS or PGIS improved 
(neither worsened) based on last 
available assessment compared to 
baseline
Rank by combination of NYHA/ROSS
and PGIS degree of change. Within a 
group of the same degree of 
NYHA/ROSS and PGIS change, 
further rank by PedsQL (physical 
functioning domain) change from 
baseline.

PedsQL physical functioning will only be used for the global rank endpoint for Age Group 1.
Patient classification for global rank endpoint
Category 1 events include the following three events, and will be reported by the investigator 
and adjudicated by the adjudication committee.


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
Death;

UNOS status 1A listing for heart transplant or equivalent;

VAD/ECMO/mechanical ventilation/intra-aortic balloon pump requirement for life 
support.
The investigator reported events will be recorded on the CRF pages: “Death (Endpoint)”, “Heart 
Transplant Listing Endpoint” and “Circulatory or Respiratory Mechanical Assistance Endpoint” 
together with the reported date of event; the adjudicated events will be recorded on the CRF 
pages: “Death (Adjudication)”, “Heart Transplant Listing Adjudication” and “Circulatory or 
Respiratory Mechanical Assistance Adjudication” together with the adjudicated date of event.
A patient will be classified into Category 1 if at least one positively adjudicated Category 1 
event occurred during the double-blind epoch.
Within Category 1, patients will be ranked by the time to first positively adjudicated Category 
1 event, which is defined as the date of first positively adjudicated Category 1 event minus the 
date of randomization plus one day.
Category 2 event is the worsening heart failure (WHF), which is further categorized into three 
sub-categories as following.

Category 2-B: Worsening heart failure hospitalization with intensive care unit stay.

Category 2-C: Worsening heart failure hospitalization without intensive care unit stay.

Category 2-D: Worsening heart failure without hospitalization.
The WHF will be reported by the investigator and adjudicated by the adjudication committee.
The investigator reported events will be recorded on the CRF pages: “Clinical Worsening of 
Heart Failure Endpoint”; the adjudicated events will be recorded on the CRF page: “Clinical 
Worsening of Heart Failure Endpoint (Adjudication)” together with the date of event and event 
sub-category.
A patient will be classified into Category 2 if at least one positively adjudicated Category 2 
event occurred during the double-blind epoch AND the patient is not in Category 1.
Category 2 patients will be classified into three sub-categories (2-B, 2-C and 2-D), using the 
following criteria. 

A patient will be classified into Category 2-B if the patient has at least one positively 
adjudicated Category 2-B event during the double-blind epoch.

A patient will be classified into Category 2-C if the patient has at least one positively 
adjudicated Category 2-C event during the double-blind epoch, and is not in Category 2-B.

A patient will be classified into Category 2-D if the patient has at least one positively 
adjudicated Category 2-D event during the double-blind epoch, and is not in Category 2-B 
or 2-C.
Within Category 2, patients will be first ranked by the patient-sub-category (2-B < 2-C < 2-D). 
Within each patient-sub-category, patients will be ranked first by the number of positively 
adjudicated events in the corresponding sub-category (taking into consideration worsening 
hierarchy of 2-B < 2-C < 2-D), and then by the time to first positively adjudicated event in the


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sub-category, which is defined as the date of the first positively adjudicated event in the sub-
category minus the date of randomization plus one day.
Patients not in Category 1 and 2 will be classified into Category 3 to 5 based on NYHA/ROSS 
class and PGIS at Week 52.
The NYHA/ROSS class is defined based on the age at randomization.

For patients with age at randomization from 1 month to < 6 years, the NYHA/ROSS class 
will be the ROSS class recorded on the CRF page: “Modified ROSS HF Classification”.

For patients with age at randomization from 6 years to < 18 years, the NYHA/ROSS class
will be the NYHA class recorded on the CRF page: “Signs and symptoms of Heart Failure 
including NYHA Classification”.
The PGIS score is also based on the age at randomization.

For patients with age at randomization < 5 years, the PGIS will be a five-point scale 
(None / Mild / Moderate / Severe / Very severe) recorded on the CRF page: “Patient 
Global Impression of Severity – Heart Failure Symptoms – Parent/Caregiver (For patient 
< 5 years of age)”.

For patients with age at randomization from 5 years to < 7 years, the PGIS will be a three-
point scale (Good / Neither good nor bad / Bad) recorded on the CRF page: “Patient 
Global Impression of Severity – Heart Failure Symptoms (Patients 5 to <7 years old)”.

For patients with age at randomization from 7 years to < 18 years, the PGIS will be a five-
point scale (None / Mild / Moderate / Severe / Very severe) recorded on the CRF page: 
“Patient Global Impression of Severity – Heart Failure Symptoms (Patients 7 to <18 years 
old)”.
Table 2-9 and Table 2-10 define the degree of change from baseline in NYHA/ROSS class and 
in PGIS at each post-baseline visit.
Table 2-9
Degree of change from baseline in NYHA/ROSS class
Degree of Change from Baseline
Post-Baseline Visit
Class I
Class II
Class III
Class IV
Baseline
Class I
0
-1
-2
-3
Class II
+1
0
-1
-2
Class III
+2
+1
0
-1
Class IV
+3
+2
+1
0
Table 2-10
Degree of change from baseline in PGIS
Degree of Change from Baseline
Post-Baseline Visit
None
(Good)
Mild
Moderate
(NGNB)
Severe
Very severe
(Bad)
Baseline
None (Good)
0
-1
-2
-3
-4
Mild
+1
0
-1
-2
-3
Moderate (NGNB)
+2
+1
0
-1
-2
Severe
+3
+2
+1
0
-1
Very severe (Bad)
+4
+3
+2
+1
0


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Degree of Change from Baseline
Post-Baseline Visit
None
(Good)
Mild
Moderate
(NGNB)
Severe
Very severe
(Bad)

NGNB = neither good nor bad
Based on the degree of change defined above in Table 2-9 and Table 2-10, Table 2-11 defines 
an initial ranking score. For patients in Category 3 to 5, patients with lower initial ranking score 
are considered worse than those with higher score.
A patient not in Category 1 and 2 will be classified into Category 3, if the initial ranking score 
at Week 52 is lower than 30; into Category 4, if the initial ranking score at Week 52 is equal to 
30, into Category 5, if the initial ranking score at Week 52 is higher than 30.
Table 2-11
Initial ranking score based on degree of change from baseline in 
NYHA/ROSS class and PGIS at Week 52
Initial Ranking Score
Degree of Change from baseline in PGIS at Week 52
-4
-3
-2
-1
0
+1
+2
+3
+4
Degree of Change from Baseline
in NHYA/ROSS Class at Week 52
-3
1
2
4
7
10
14
18
22
26
-2
3
4
6
9
13
17
21
25
28
-1
5
7
9
12
16
20
24
27
29
0
8
10
13
16
30
31
32
34
36
+1
11
14
17
20
31
33
35
37
39
+2
15
18
21
24
32
35
38
40
41
+3
19
22
25
27
34
37
40
42
43
A subset of the physical functioning domain based on patient reported PedsQL will be used to 
rank patients with age at randomization from 6 years to < 18 years.
The PedsQL is an age based questionnaire. For patients with age at randomization from 6 years 
to < 18 years, the patient reported PedsQL will be recorded on the following CRF pages.

“PEDsQL Pediatric Quality of Life Inventory Acute Version Teen Report (Ages 13-18)”

“PEDsQL Pediatric Quality of Life Inventory Acute Version Child Report (Ages 8-12)”

“PEDsQL Pediatric Quality of Life Inventory Acute Version Young Child Report (Ages 
5-7)”
Table 2-12 and Table 2-13 present the items in PedsQL functioning domain used for ranking 
and the mapped score for the observed values at Week 52.
Table 2-12
PedsQL Ranking Items (Age at Randomization: 8 years to < 18 years)
Item
ID
Item
Never
Almost
Never
Some-
times
Often
Almost
Always
1
It is hard for me to walk more than one block
100
75
50
25
0
2
It is hard for me to run
100
75
50
25
0
3
It is hard for me to do sports activity or 
exercise
100
75
50
25
0
4
It is hard for me to lift something heavy
100
75
50
25
0


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Item
ID
Item
Never
Almost
Never
Some-
times
Often
Almost
Always
6
It is hard for me to do chores around the 
house
100
75
50
25
0
Table 2-13
PedsQL Ranking Items (Age at Randomization: 6 years to 7 years)
Item ID
Item
Not at All
Sometimes
A Lot
1
It is hard for you to walk 
100
50
0
2
It is hard for you to run
100
50
0
3
It is hard for you to play sports activity or exercise
100
50
0
4
It is hard for you to pick up big things
100
50
0
6
It is hard for me to do chores (like pick up your toys)
100
50
0
For each post-baseline visit, if there are three or more non-missing items, the PedsQL ranking 
score will be defined as the mean of the non-missing mapped values; if there are three or more 
missing items, the PedsQL ranking score will be considered as missing.
Within Category 3 to 5, patients with age at randomization from 6 years to < 18 years will be 
ranked by the initial ranking score (Table 2-11) at Week 52 and the change from baseline in the 
PedsQL ranking score at Week 52, while patients with age at randomization from 1 month to < 
6 years will be ranked only by the initial ranking score at Week 52 but not by the PedsQL 
ranking score.
The response category is defined as the category which the patient is classified into.
Due to unresolvable technical reasons in study drug supply, the study treatment of all patients 
remaining in the study will be discontinued by the end of October 2021, two months prior to 
the scheduled study end. This early study drug discontinuation is not expected to compromise 
the scientific integrity of the study. The early study drug discontinuation affects a maximum of 
31 patients, who are still on-treatment with current follow-up between 297 days to 395 days. 
The total on-treatment follow-up time lost is expected to be <1% (2.26 patient-years of the 
anticipated 375 patient-years; assuming immediate study drug discontinuation on 31-Oct-2021).
The reason for treatment discontinuation will be documented as ‘Technical problems’. In case 
of patient withdrawal from further study participation after study drug discontinuation due to 
the USM, the reason for study phase discontinuation will also be documented as ‘technical 
problems’. 
The unforeseen intercurrent events of USM based study treatment discontinuations are not 
related to disease progression or to the assigned study treatment and not reflecting a real world 
setting, and the exposure to the study treatment and follow-up is reasonably long. Hence, an on-
treatment approach is considered to be more appropriate for the handling of USM-impacted 
patients in the primary analysis, utilizing the relevant components of the global rank endpoint 
including Category 1 and Category 2 status at the unscheduled assessment at the time of 
treatment discontinuation.


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2.6.2
Statistical hypothesis, model, and method of analysis
Within each stratum, the Mann-Whitney (MW) probability is defined as the probability of the 
patient from the LCZ696 group having better outcome than the patient from the Enalapril group 
plus half of the probability of the patient from the LCZ696 group having equal outcome to the 
one from the Enalapril group, when the two patients are independently sampled from the 
LCZ696 group and the Enalapril group. Correspondingly, the MW odds is defined as (one 
minus the MW probability) divided by the MW probability.
The null hypothesis is that, the MW odds in all strata are equal to one, while the alternative 
hypothesis is that, the MW odds is not equal to one in at least one stratum.
The hypothesis will be tested by the stratified Wilcoxon rank-sum test with modified age group 
(6 years to < 18 years, 2 years to < 6 years, 1 month to < 2 years) and baseline NYHA/ROSS 
class group (Class I/II, III/IV) as stratification factors. The testing statistic will be based on the 
weighted sum of the within-stratum rank-sum statistics, in which, the weight for stratum will 
be the reciprocal of (one plus the total sample size of the stratum), the mean and the variance 
will be estimated under the null hypothesis as outlined in Appendix 5.2.1. The test will be 
performed at an overall significance level of two-sided 0.05.
Note that the expected value of the stratified Wilcoxon rank-sum statistics is proportional to the 
overall MW probability (defined as weighted mean of the MW probabilities, with weights 
depending only on the sizes of each stratified stratum as specified in Appendix 5.2.1), with 
modified age group (6 years to < 18 years, 2 years to < 6 years, 1 month to < 2 years) and 
baseline NYHA/ROSS class group (Class I/II, III/IV) as stratification factors. The treatment 
effect size will be defined by the overall MW probability, which can be estimated using the 
stratified Wilcoxon rank-sum statistic, see Appendix 5.2.1. The corresponding confidence 
interval will also be provided for overall MW probability using the approach in Appendix 5.2.1, 
or see Kawaguchi et.al. 2011.
Correspondingly, the overall MW odds is defined as (one minus the overall MW probability) 
divided by the overall MW probability. The estimate and the corresponding 95% confidence 
interval for the overall MW odds will also be provided (Appendix 5.2.1).
The superiority of LCZ696 to Enalapril in the global rank endpoint will be claimed if the test is 
significant and the point estimate of the overall MW probability is greater than 0.5.
Besides, the response category will be summarized by modified age group, baseline 
NYHA/ROSS class group, and treatment group, using the numbers and percentages of patients 
in each category.
The FAS will be used for the above analyses.
2.6.3
Handling of missing values/censoring/discontinuations
For Category 1 and Category 2, patients will be classified into the worst possible category.

A patient will be classified into Category 1 with event date imputed by the last known 
alive date (recorded on CRF page: “Survival Information”), or the date of last visit, 
whichever occurred later but earlier than the analysis cutoff date, if the patient 
discontinues from the study during the double-blind epoch without any positively 


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adjudicated Category 1 event and with no available clinical endpoint information to refute 
classification into Category 1.

A patient will be classified into Category 2 with event date imputed by the last known 
alive date (recorded on CRF page: “Survival Information”), or the date of last visit, 
whichever occurred later but earlier than the analysis cutoff date, if the patient discontinue 
from the study during the double-blind epoch without any positively adjudicated Category 
1 and there is available and retrievable information for the patient that refutes 
classification into Category 1.

Any positively adjudicated Category 2 event with its adjudicated sub-category missing 
will be classified into Category 2-B (Category 2-B: Worsening heart failure 
hospitalization with intensive care unit stay).

If the event date of a positively adjudicated Category 1 event is missing, the event date 
will be imputed by the last known alive date (recorded on CRF page: “Survival 
Information”), or the date of last visit, whichever occurred later but earlier than the 
analysis cutoff date.

If the event date of a positively adjudicated Category 2 event is missing, the event date 
will be imputed by the date of last visit but earlier than the analysis cutoff date.
For patients in Category 3 to 5, if the 52 weeks measurements of NYHA/Ross, PGIS or PedsQL 
score are missing then the last-observation-carried-forward (LOCF) technique will be used to 
impute the missing post-randomization values (for patients who do not experience any events 
in Category 1 or 2). While ranking, if the baseline is missing, then the baseline will be imputed 
using the median assessment within each stratum. If all the post-randomization assessments is 
missing, then the post randomization assessment will be imputed to the worst case at week 52.
2.6.4
Supportive and sensitivity analyses
PPS analysis
As a sensitivity analysis, the primary analysis approach will also be performed on the PPS.
Response category analysis
The primary analysis approach (Section 2.6.2) will be performed for the response category 
(Category 1 to Category 5) at Week 52 based on the ranking algorithm (Section 2.6.1) for the 
primary endpoint.
MI analysis
A multiple imputation approach will be applied, whereby all missing data for degree of change 
in NYHA/ROSS class, degree of change in PGIS, and change from baseline in PedsQL ranking 
score, will be considered as missing at random within each arm, within Category 3 to Category 
5 and will be imputed as described below.

Missing data of degree of change from baseline in NYHA/ROSS class and degree of 
change from baseline in PGIS will be imputed based on cumulative proportional odds 
models using fully conditional specifications. For each post-baseline scheduled visit
(Week 4, Week 12, Week 24, Week 36, Week 52), the imputation model will include 
region, modified age group (6 years to < 18 years, 2 years to < 6 years, 1 month to < 2 
years) at randomization, NYHA/ROSS class group (Class I/II, Class III/IV) at 


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randomization, baseline value, and value at the immediately previous scheduled visit (Not 
applicable for Week 4, Week 4 for Week12, Week 12 for Week 24, Week 24 for Week 36, 
Week 36 for Week 52) as fixed-effect factors.

Missing data of change from baseline in PedsQL ranking score will be imputed based on 
linear regression models (for continuous variables) via fully conditional specifications. For 
each post-baseline scheduled visit (Week 12, Week 24, Week 36 and Week 52), the 
imputation model will include region, modified age group (6 years to < 18 years, 2 years 
to < 6 years, 1 month to < 2 years) at randomization, NYHA/ROSS class group (Class I/II, 
Class III/IV) at randomization as fixed-effect factor; baseline value, and value at the 
immediately previous scheduled visit (Not applicable for Week 12, Week 12 for Week 24, 
Week 24 for Week 36, Week 36 for Week 52) as covariates.

The imputation will be performed within each arm for degree of change from baseline in 
NYHA/ROSS, degree of change from baseline in PGIS, and change from baseline in 
PedsQL ranking score within Category 3 to Category 5.
The stratified estimation for the MW probability and the MW odds will be estimated from 
each imputed datasets, and then be combined using Rubin’s rules to get the final stratified 
estimations. (Appendix 5.2.1)
Tipping point analysis
A tipping point analysis will be performed for the primary analysis on the FAS. In the primary 
analysis, patients who discontinued from the study without Category 1 event will be classified 
(with probability 1) to the worst possible category. Alternatively, responses after 
discontinuation can be imputed assuming censoring at random, by combining the observed 
data prior to discontinuation with data of a sampled patient among those patients who are still 
in the study at that time. If combined data has Category 1 or 2 events, then, the discontinued 
patient will be classified based on the events information. If combined data has no Category 1 
or 2 event, then the discontinued patient will be classified using the ranking score of the 
sampled patient.
The imputation/sampling will be performed within each treatment arm. The probability to 
utilize worst category imputation for a discontinued patient (p) will be varied from 1 to 0 in 
steps of 0.1 and accordingly the probability to utilize MAR imputation (1-p) will be varied 
from 0 to 1 in steps of 0.1. For each p, multiple imputed datasets will be produced and for 
each dataset, the stratified MW probability and MW odds will be estimated. The results will 
then be combined across datasets using Rubin’s rules to get the final stratified estimations. 
After such tipping point is determined, clinical judgement can be applied as to the plausibility 
of the assumptions underlying this tipping point. This methodology will provide a good 
picture of what it would take to overturn study conclusions on the basis of varying 
assumptions about patients discontinued from the study.
Pooled strata analysis
When there is no patient or only 1 patient in any treatment group within any of the stratum, a 
supportive analysis will be added using the four pooled strata, listed below:
1. Age Group 1 (6 years to < 18 years) and NYHA/ROSS Class I/II
2. Age Group 1 (6 years to < 18 years) and NYHA/ROSS Class III/IV
3. Age Group 2a and 3a (1 month to < 6 years) and NYHA/ROSS Class I/II


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4. Age Group 2a and 3a (1 month to < 6 years) and NYHA/ROSS Class III/IV
USM-impacted off treatment analysis
For the USM-impacted patients, the full data, including the off-treatment part, from the 
impacted patients will be included as a sensitivity analyses.
Without cutoff analysis
The primary analysis approach will also be performed on the nominal week 52 assessment, i.e. 
without considering analysis cutoff date for NYHA/ROSS, PGIS, and PedsQL.
Supportive analysis
If possible, primary analysis will be done excluding patients who received expired drug.
The FAS will be used for above analysis.
2.6.5
Subgroup analyses
The subgroup variables in Table 2-6 will be used for subgroup analyses.
The primary analysis approach (Section 2.6.2) will be performed within each subgroup.
The FAS will be used for the subgroup analyses.
2.7
Analysis of the secondary objectives for Part 2
For the USM-impacted patients, the relevant assessments at the unscheduled visit at the time of 
treatment discontinuation will be utilized in the secondary analyses (on-treatment approach).
For the USM-impacted patients, the full data, including the off-treatment part, from the 
impacted patients will be included as a sensitivity analyses.
2.7.1
Time to first adjudicated Category 1 or 2 event
Adjudicated Category 1 or 2 events include all positively adjudicated Category 1 events and 
positively adjudicated Category 2 events (Section 2.6.1).
The time to first adjudicated Category 1 or 2 event is defined as the date of first occurrence of 
adjudicated Category 1 or 2 events minus the date of randomization plus one day.
The censoring will occur at minimum [date of death, date of withdrawal of consent, maximum
(date of last visit, last known alive date)].
The time to first adjudicated Category 1 or 2 event will be analyzed using a Cox proportional 
hazard model, stratified by modified age group and NYHA/ROSS class group (Class I/II, Class 
III/IV) at randomization with treatment (LCZ696, Enalapril) included as a fixed-effect factor.
Based on the above model, the estimate and the 95% confidence interval will be provided for 
the adjusted hazard ratio (LCZ696 over Enalapril), the corresponding two-sided p-value will 
also be provided.
Besides, the time to first adjudicated Category 1 or 2 event will be summarized by modified age 
group and treatment group, using Kaplan-Meier curves.


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For the first adjudicated Category 1 or 2 event, the annualized event rate will be presented by 
modified age group and treatment group.
The investigator reported Category 1 or 2 event will also be analyzed by the above method.
The FAS will be used for the above analyses.
2.7.2
NYHA/ROSS class change
The NYHA/ROSS class is an age based four-point scale (Section 2.6.1).
Table 2-14 defines the NYHA/ROSS class change at each post-baseline visit.
Table 2-14
NYHA/ROSS class change
NYHA/ROSS Class Change
Post-Baseline Visit
Class I
Class II
Class III
Class IV
Baseline
Class I
unchanged
worsened
worsened
worsened
Class II
improved
unchanged
worsened
worsened
Class III
improved
improved
unchanged
worsened
Class IV
improved
improved
improved
unchanged
The NYHA/ROSS class change will be analyzed using a by-visit proportional cumulative odds
model. For each visit (Week 4, Week 12, Week 24, Week 36 and Week 52), the proportional 
cumulative odds model uses NYHA/ROSS class change (order specified as “improved” < 
“unchanged” < “worsened”) at the visit as response, and include treatment (LCZ696, Enalapril), 
baseline NYHA/ROSS class (Class I to Class IV), modified age group(6 years to < 18 years, 2
years to < 6 years, 1 month to < 2 years) as fixed effect. The analysis cutoff date will be 
considered.
Based on the above model, the estimate and the 95% confidence interval will be provided for 
the adjusted odds ratios (LCZ696 over Enalapril) at each post-baseline scheduled visit (Week 
4, Week 12, Week 24, Week 36 and Week 52), the corresponding two-sided p-values will also 
be provided.
Besides, the NYHA/ROSS class and the NYHA/ROSS class change will both be summarized 
by modified age group, treatment group, and visit, using the numbers and percentages of 
patients in each category.
A sensitivity analysis will be also included without considering analysis cutoff date.
The FAS will be used for the above analyses.
2.7.3
PGIS change
The PGIS score is an age based five-point or three-point scale (Section 2.6.1).
Table 2-15 defines the PGIS change at each post-baseline visit.


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Table 2-15
PGIS change
PGIS Change
Post-Baseline Visit
None
(Good)
Mild
Moderate
(NGNB)
Severe
Very severe
(Bad)
Baseline
None (Good)
unchanged
worsened
worsened
worsened
worsened
Mild
improved
unchanged
worsened
worsened
worsened
Moderate (NGNB)
improved
improved
unchanged
worsened
worsened
Severe
improved
improved
improved
unchanged
worsened
Very severe (Bad)
improved
improved
improved
improved
unchanged

NGNB = neither good nor bad
The PGIS change will be analyzed using a by-visit proportional cumulative odds model. For 
each visit(Week 4, Week 12, Week 24, Week 36 and Week 52), the proportional cumulative 
odds model uses PGIS change (order specified as “improved” < “unchanged” < “worsened”) at 
the visit as response, and include treatment (LCZ696, Enalapril), baseline PGIS (None [Good], 
Mild, Moderate [Neither good nor bad], Severe, Very severe [Bad]), modified age group(6 years 
to < 18 years, 2 years to < 6 years, 1 month to < 2 years), NYHA/ROSS class group (Class I/II, 
Class III/IV) at randomization as fixed effect. The analysis cutoff date will be considered.
Based on the above model, the estimate and the 95% confidence interval will be provided for 
the adjusted odds ratios (LCZ696 over Enalapril) at each post-baseline scheduled visit (Week 
4, Week 12, Week 24, Week 36 and Week 52), the corresponding two-sided p-values will also
be provided.
Besides, the PGIS and the PGIS change will be summarized by modified age group, treatment 
group, and visit, using the numbers and percentages of patients in each category.
A sensitivity analysis will also be included without considering analysis cutoff date.
The FAS will be used for the above analyses.
2.7.4
Handling of missing values/censoring/discontinuations
In the analyses described in the above sections (Section 2.7.2 to 2.7.3), Category 1 event is 
considered the worst possible outcome and hence scheduled visits after Category 1 event will 
be imputed to be the worst case accordingly. For others, the missing data will not be imputed.
As a sensitivity analysis, a multiple imputation approach will be applied. Responses at 
scheduled visits after Category 1 event will be imputed to be the worst case. And all the other 
missing data for change in NYHA/ROSS class and change in PGIS will be considered as 
missing at random within each arm, and will be imputed as described below.

Missing change from baseline in NYHA/ROSS class and change from baseline in PGIS 
will be imputed based on cumulative proportional odds models using fully conditional 
specifications. For each post-baseline scheduled visit (Week 4, Week 12, Week 24, Week 
36, Week 52), the imputation model will include region, modified age group (6 years to < 
18 years, 2 years to < 6 years, 1 month to < 2 years) at randomization, NYHA/ROSS class 
group (Class I/II, Class III/IV) at randomization, baseline value, and value at the 
immediately previous scheduled visit (Not applicable for Week 4, Week 4 for Week12, 


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Week 12 for Week 24, Week 24 for Week 36, Week 36 for Week 52) as fixed-effect 
factors.
The FAS will be used for the above sensitivity analyses.
2.7.5
Subgroup analysis for secondary endpoints
Subgroup analyses will be performed for secondary endpoints (Section 0 to 2.7.3) based on the 
subgroup variables in Table 2-6 without multiplicity adjustment.
Time to first adjudicated Category 1 or 2 event
For time to first adjudicated Category 1 or 2 event (Section 0), the subgroup analyses will be 
performed utilizing a Cox proportional hazard model, stratified by modified age group, with
subgroup, treatment (LCZ696, Enalapril) and subgroup-by-treatment interaction included as 
fixed-effect factors.
Based on the Cox proportional hazard model, the two-sided p-value for the interaction will be 
provided, the estimate and the corresponding 95% confidence interval will be provided for the 
adjusted hazard ratio (LCZ696 over Enalapril) within each subgroup.
The estimates and the corresponding 95% confidence intervals for the adjusted hazard ratios 
within subgroups and for the overall adjusted hazard ratio will be presented graphically using a 
forest plot.
The FAS will be used for the subgroup analyses.
NYHA/ROSS class change and PGIS change
For NYHA/ROSS class change (Section 2.7.2) and PGIS change (Section 2.7.3), the subgroup 
analyses will be performed using a by-visit proportional cumulative odds model. For each visit
(Week 4, Week 12, Week 24, Week 36 and Week 52), the proportional cumulative odds model 
uses corresponding NYHA/ROSS or PGIS change at the visit as response, and include treatment 
(LCZ696, Enalapril), corresponding baseline value (baseline NYHA/ROSS class or baseline 
PGIS), subgroup, subgroup by treatment, modified age group (6 years to < 18 years, 2 years to 
< 6 years, 1 month to < 2 years) as fixed effect.
Based on the above model, the estimate and the 95% confidence interval will be provided for 
the adjusted odds ratios (LCZ696 over Enalapril) at each post-baseline scheduled visit (Week 
4, Week 12, Week 24, Week 36 and Week 52) within each subgroup, and the p-values for the 
subgroup-by-treatment interactions at all post-baseline scheduled visits will be also provided.
In addition, the estimates and the corresponding 95% confidence intervals for the adjusted odds 
ratios at Week 52 within subgroups and the overall adjusted odds ratio at Week 52 will be 
presented graphically using a forest plot.
The FAS will be used for the subgroup analyses.
 


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2.9
Safety analyses
For Part 1, the SAF1 will be used for all safety analyses.
For Part 2, the SAF2 will be used for all safety analyses.
In addition, selected safety analysis will be done for patients who received expired drug.
2.9.1
Adverse events (AEs)
All AEs will be recorded on the CRF page “Adverse Events” and be identified using Medical 
Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for reporting the 
study will be described in a footnote.
An AE with its severity increased should be considered and recorded as a new AE.
Part 1:
Treatment emergent adverse events (TEAEs) during the dose associated period are defined as 
any recorded AE with its start date (recorded or imputed) later than or equal to the date of the 
first dose of the study drug within the dose associated period AND its start date prior to or equal 
to the end date of the dose associated period.
TEAEs during the dose associated period will be summarized separately by age group, dose 
cohort, SOC, PT and maximum severity.
The following rules are applicable to the summaries.

If a subject reported more than one adverse event with the same preferred term, the 
adverse event with the maximum severity will be presented. 

If a subject reported more than one adverse event within the same primary system organ 
class, the subject will be counted only once with the maximum severity at the system 
organ class level, where applicable. 
Study drug related AEs are defined as any recorded AE with “Reasonable possibility that AE 
is related to study treatment” answered as “YES”. Study drug related TEAEs during the dose 
associated period will be summarized by age group, dose cohort, SOC and PT.
Serious adverse events (SAEs) are defined as any recorded AE with “Does AE meet the 
definition of an SAE” answered as “Yes”.
Treatment emergent SAEs during the dose associated period will be summarized by age group, 
dose cohort, SOC and PT.
TEAEs leading to death during the dose associated period will be summarized by age group, 
dose cohort, SOC and PT.
The SAF1 will be used for the above analyses for Part 1.


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Part 2:
Treatment emergent adverse events (new or worsened) during the double-blind epoch are 
defined as any recorded AE with its start date (recorded or imputed) later than or equal to the 
date of the first dose of the study drug within the double-blind epoch.
TEAEs during the double-blind epoch will be summarized by:
1. modified age group, treatment group, SOC and PT, 
2. modified age group, treatment group, SOC, PT and maximum severity.
3. modified age group, treatment group, Standard Medical Queries (SMQs) and PT.
The following rules are applicable to the summaries.

If a patient reported more than one AE with the same PT during the double-blind epoch, 
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 during the double-blind 
epoch, the patient will be counted only once with the greatest severity at the SOC level, 
where applicable.
Study drug-related AEs are defined as any recorded AE with “Reasonable possibility that AE 
is related to study treatment” answered as “YES”. 
Study drug-related TEAEs during the double-blind epoch will be summarized by modified age 
group, treatment group, SOC and PT.
Serious adverse events (SAEs) are defined as any recorded AE with “Does AE meet the 
definition of an SAE” answered as “Yes”.
Treatment emergent SAEs during the double-blind epoch will be summarized by modified age 
group, treatment group, SOC and PT.
AEs leading to permanent discontinuation of study treatment are defined as any recorded AE 
with “Action taken with study treatment” answered as “DRUG WITHDRAWN”.
TEAEs leading to permanent discontinuation of study treatment during the double-blind epoch 
will be summarized by modified age group, treatment group, SOC and PT.
AEs leading to dose adjustment or temporarily interruption of study treatment are defined as 
any recorded AE with “Action taken with study treatment” answered as “DOSE REDUCED”, 
“DOSE INCREASED” or “DRUG INTERRUPTED”.
TEAEs leading to dose adjustment or temporarily interruption of study treatment during the 
double-blind epoch will be summarized by modified age group, treatment group, SOC and PT.
The most common TEAEs are defined as any recorded TEAE corresponding to a PT with at 
least 1% of patients in either treatment group having at least one TEAE of this PT during the 
double-blind epoch.
Most common TEAEs during the double-blind epoch will be summarized by modified age 
group, treatment group, SOC and PT, and will be presented in descending frequency according 
to the incidence in the LCZ696 group starting from the most common event.


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Incidence of AEs will also be listed at a patient level by treatment group and modified age group
including outcome, severity and action taken with the AE. 
The SAF2 will be used for the above analyses for Part 2.
2.9.1.1
Adverse events of special interest / grouping of AEs
Specific AEs of interest will be summarized separately in addition to the above analysis: 

Anaphylaxis 

Angioedema 

Change in bone growth and density

Cognitive impairment (Narrow SMQ) 

Embryo-fetal toxicity or lethality 

Hepatotoxicity 8 Hyperkalaemia 

Hypersensitivity (Narrow SMQ) 

Hypotension 

Malignancy 

Neonatal or infantile toxicity through exposure from breast milk 

Renal impairment (Narrow SMQ) 

Statin drug drug interaction.
Besides providing the crude percentages, exposure adjusted incidence rates per 100 patient-
years will also be provided by treatment group. 
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for these risks 
are stored (or alternatively "summarized") in the latest version of LCZ696 Case Retrieval 
Strategy.
In addition to above standard analyses, for part 2, analysis for time-to-first selected AEs
(Hypotension and Angioedema) by treatment group will be performed using Kaplan-Meier 
estimate. 
The following subgroup analysis will be performed based on selected subgroups for Part 2
(gender, race, ACEI/ARB and region).

Treatment emergent AEs during the double-blind epoch will be summarized within each 
subgroup, by treatment group, SOC and PT.
The renal 
The SAF2 will be used for the above analyses for Part 2.


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2.9.2
Death
In Part 1, the death and the investigator reported primary cause of death will be recorded on the 
CRF page “Death (End Point)”. The death and primary cause of death will be listed based on 
SAF1.
In Part 2, death and primary cause of death will be reported by the investigator and adjudicated 
by the adjudication committee. 
The investigator reported death and primary cause of death will be recorded on the CRF page: 
“Death (Endpoint)”. The adjudicated death and primary cause of death will be recorded on the 
CRF page: “Death (Adjudication)”.
The investigator reported death and primary cause of death will be summarized by modified 
age group and treatment group using the number and percentage of patients who died during 
the double-blind epoch (investigator reported), as well as the numbers and percentages of 
patients whose primary cause of death (investigator reported) is in each category and each sub-
category.
Similarly, the adjudicated death and primary cause of death will be summarized by modified 
age group and treatment group using the number and percentage of patients who died during 
the double-blind epoch (adjudicated), as well as the numbers and percentages of patients whose 
primary cause of death (adjudicated) is in each category and each sub-category.
The SAF2 will be used for the above analyses for Part 2.
2.9.3
Laboratory data 
2.9.3.1
General laboratory data
Complete laboratory evaluations (hematology, blood chemistry, and urine) as outlined in Table 
2-17 will be performed in Part 1 at Visit 1 (screening), Visit 199 and/or 299, and/or Visit 301. 
Local laboratory will be used for Visit 1, 199, 299 and 301 for complete laboratory evaluations.
Central laboratory should only be used for Visit 301, as unscheduled assessment, if local lab is 
unavailable.
Besides, it will also be performed in Part 2 at Visit 301, Visit 401, Visit 409 and Visit 416/499.
Local laboratory should be used for Visit 301 for complete laboratory evaluations. Central 
laboratory should only be used for Visit 301, if local lab is unavailable using unscheduled visit. 
Central laboratory must be used for Visit 401, 409 and 416/499 for complete laboratory 
evaluations for all patients.
Table 2-17
Laboratory examinations
Hematology
Biochemistry
Urine measurements**
Hematocrit 
Alanine aminotransferase (ALT)
Specific gravity
Hemoglobin
Albumin (Alb)
pH
Platelet count
Alkaline phosphatase (ALP)
Glucose
Red blood cell count (RBC)
Aspartate aminotransferase 
(AST)
Protein (Total)
White blood cell count (WBC)
Blood urea nitrogen (BUN)
Ketones


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Hematology
Biochemistry
Urine measurements**
WBC differential
Calcium
Bilirubin
Magnesium
Urobilinogen
Phosphate
Hemoglobin (blood)
Red blood cell distribution width 
(RDW)
Chloride
Leukocyte esterase
Mean corpuscular volume 
(MCV)
Creatinine*
Nitrite
Mean corpuscular hemoglobin 
concentration (MCHC)
Glucose
WBC
Potassium*
RBC sediments
Sodium*
Hyaline casts
Bicarbonate
Granular casts
Total bilirubin (TBL)
Waxy casts
Fractionated bilirubin (if total 
bilirubin >2x ULN)
WBC casts
Total protein
RBC casts
Uric acid
eGFR*
*Abbreviated laboratory evaluations must include these parameters
**Urinalysis with dipstick includes specific gravity, pH, glucose, total protein, bilirubin, ketones, 
urobilinogen, nitrite, leukocytes esterase and hemoglobin (blood). Other urine measurements listed are 
not required. If a urine dipstick is positive, other urine measurements such as a qualitative microscopic 
determination of WBC, RBC sediments (and casts) will also be measured.
Abbreviated safety laboratory evaluation consists of serum sodium, potassium, creatinine, and 
eGFR. Abbreviated safety laboratories will be performed locally. If the local laboratory is 
unavailable (either for abbreviated or complete labs), the central laboratory will be used as an 
unscheduled visit.
Abbreviated laboratory evaluations are to be performed at Part 1 PK/PD Visits 101 (post-dose), 
201 (post-dose), 103 to 120 (when patient comes to the site for a visit about every three months), 
203 to 220 (when patient comes to the site for a visit about every three months), UNS PK/PD;
and also performed in Part 2 at Visit 402, Visit 403, Visit 404 (optional visit), Visit 405, Visit 
406, Visit 412, Visit 415 and as an optional assessment at unscheduled study treatment 
discontinuation (UNS TD), and unscheduled (UNS) visit.
For those patients who have Visits 299 and 301 on the same day (for second PK dose patient) 
or Visits 199 and 301 on the same day (for the first PK dose only patient), laboratories will be 
performed only once.
Local laboratory results will allow investigators to proceed with study visit procedures without 
the need to wait for central laboratory results. The local laboratory results must be recorded on 
the appropriate CRF.
Both complete laboratory evaluations and abbreviated laboratory evaluations will be included 
in the summaries for laboratory data. In general, local lab and central lab data will be analyzed 
separately. For event summary, local lab and central lab will be summarized together.


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Test values based on the local laboratory assessments and the central laboratory assessments 
will be summarized separately by laboratory parameter, modified age group, treatment group 
and visit, using number of observations, mean, standard deviation, median, minimum, Q1, Q3, 
and maximum; 
The change from baseline in test values based on the local laboratory assessments and the 
central laboratory assessments will also be summarized separately by laboratory parameter, 
modified age group, treatment group and visit, using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum. The baseline values for local laboratory 
and central laboratory should be computed separately.
For each laboratory parameter and each specific assessment, the test value will be categorized 
into normal, low, or high, according to the corresponding normal range.
For each laboratory parameter and each specific post-baseline visit, the shift from baseline to 
the visit is defined as the shift from the baseline category to the categorized post-baseline test 
value (low to low, low to normal, low to high, normal to low, normal to normal, normal to high, 
high to low, high to normal, high to high).
The shift from baseline will be summarized by laboratory parameter, modified age group, 
treatment group and visit, using the numbers and percentages of patients in each category. By-
visit summary will include scheduled (central or local) assessments.
For each laboratory parameter, the minimum and maximum post-baseline category during the 
double-blind epoch are defined based on the categorized post-baseline test values according to 
Table 2-18. All scheduled or unscheduled, central or local assessments will be included.
Table 2-18
Minimum and maximum post-baseline category
Range of Categorized
Post-Baseline Test Values
Minimum post-baseline
category
Maximum post-baseline
category
Low, Normal, High, Missing
Low
High
Low, Normal, High
Low
High
Low, Normal, Missing
Low
Normal
Low, Normal
Low
Normal
Low, High, Missing
Low
High
Low, High
Low
High
Low, Missing
Low
Low
Low
Low
Low
Normal, High, Missing
Normal
High
Normal, High
Normal
High
Normal, Missing
Normal
Normal
Normal
Normal
Normal
High, Missing
High
High
High
High
High
Missing
Missing
Missing


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The shift from baseline to minimum and maximum post-baseline category during the double-
blind epoch will be summarized separately by laboratory parameter, modified age group and 
treatment group, using the numbers and percentages of patients in each category.
Table 2-19 provides criteria for clinically notable laboratory abnormality.
The shift from baseline in laboratory parameters will be summarized by laboratory parameter, 
age group, dose cohort, dose associated analysis visit, using the numbers and percentages of 
patients in each category. By-visit summary will only include scheduled assessments in the dose 
associated periods. Unscheduled assessments may be used for imputation if needed.
In Part 1, the clinically notable laboratory abnormality will be calculated based on the local 
laboratory assessments.
The clinically notable laboratory abnormality during the dose associated period will be 
summarized by criteria, age group and dose cohort, using the numbers and percentages of 
patients satisfying such criteria.
Table 2-19
Clinical notable criteria for laboratory values
Parameter
Conventional
Units
SI Alert
Value
SI
Units
Hematology
Red Blood Cell 
Count 
x10E6/uL
>50% increase and >ULN;
>30% decrease and <LLN.
x10E12/L
Hemoglobin
g/dL
>50% increase and >ULN;
(>30% decrease and <LLN) or any value <70.
g/L
Hematocrit
%
>50% increase and >ULN;
>30% decrease and <LLN.
L/L
White Blood Cell 
Count 
x10E3/uL
>50% increase and >ULN;
>50% decrease and <LLN.
x10E9/L
Platelet Count
x10E3/uL
>75% increase and >ULN;
>50% decrease and <LLN.
x10E9/L
Chemistry
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


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Parameter
Conventional
Units
SI Alert
Value
SI
Units
Calcium
mg/dL
>10% increase and >ULN;
>10% decrease and <LLN.
mmol/L
Uric Acid
mg/dL
>50% increase and >ULN
mmol/L
In the above table, increase and decrease are defined as compared to the baseline value.
The clinically notable laboratory abnormality during the double-blind epoch based on the local 
laboratory assessments and the central laboratory assessments will be summarized by criteria, 
modified age group and treatment group, using the numbers and percentages of patients 
satisfying such criteria.
The SAF2 will be used for the above analyses. Listing will be provided.
2.9.3.2
Special laboratory data
Liver events
Table 2-20 provides criteria for liver laboratory triggers and liver events.
The liver laboratory triggers and liver events during the double-blind epoch based on the local 
laboratory assessments and the central laboratory assessments will be summarized by criteria, 
modified age group and treatment group, using the numbers and percentages of patients 
satisfying such criteria.
Table 2-20
Liver event and laboratory trigger definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert 
syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × 
ULN and TBL > 2 × ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or 
rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
The SAF2 will be used for the above analyses.


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Renal events
The renal events during the double-blind epoch based on the local laboratory assessments and 
the central laboratory assessments will be summarized by criteria, modified age group and 
treatment group, using the numbers and percentages of patients satisfying such criteria.
The renal imparment related events during the double-blind epoch will be summarized for age 
group 1 and 2 for baseline eGFR≤170 mL/min/1.73 m2 and baseline eGFR >170 mL/min/1.73 
m2 separately. And additional output for age group 3 will be presented. Normal ranges for eGFR 
will be provided in the reference (Heilbron 1991).
The SAF2 will be used for the above analyses.
2.9.4
Vital signs
In Part 1, the test values and the changes from baseline in vital signs (pulse rate, sitting/supine 
systolic blood pressure, sitting/supine diastolic blood pressure, height, head circumference and 
body weight) will be summarized by vital sign parameter, age group, dose cohort, dose 
associated analysis visit, and time point (if applicable), using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum. By-visit summary will only 
include scheduled visits in the dose associated periods. Unscheduled assessments may be used 
for imputation if needed.
In Part 2, the test values and the changes from baseline in vital signs (sitting/supine pulse rate, 
sitting/supine systolic blood pressure, sitting/supine diastolic blood pressure, height, head 
circumference and body weight) will be summarized by vital sign parameter, modified age 
group, treatment group, visit, and time point (if applicable), using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum. By-visit summary will only 
include scheduled assessments. Unscheduled assessments may be used for imputation if needed.
Table 2-21 provides criteria for clinically notable vital sign.
In Part 1, the clinically notable vital signs during the dose associated period will be summarized 
by criteria, age group and dose cohort, using the numbers and percentages of patients with at 
least one post-baseline assessment during the corresponding period satisfying such criteria, and 
the numbers and percentages of patients with baseline assessment not satisfying such criteria 
and at least one post-baseline assessment during the corresponding period satisfying such 
criteria.
In Part 2, the clinically notable vital signs during the double-blind epoch will be summarized 
by criteria, modified age group and treatment group, using the numbers and percentages of 
patients with at least one post-baseline assessment during the double-blind epoch satisfying 
such criteria, and the numbers and percentages of patients with baseline assessment not 
satisfying such criteria and at least one post-baseline assessment during the double-blind epoch 
satisfying such criteria.
Table 2-21
Criteria for clinically notable vital signs
Age
HR [min-1]
SBP [mmHg]
DBP [mmHg]
1-3 months
<90, >160
<60, >95
<40, >50
3-6 months
<80, >130
<60, >100
<40, >60


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Age
HR [min-1]
SBP [mmHg]
DBP [mmHg]
6-12 months
<70, >130
<60, >110
<45, >70
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
The change from baseline in height and height Z-score at end of study will be provided by 
treatment group and modified age group, using number of observations, mean, standard 
deviation, median, minimum, Q1, Q3, and maximum.
The SAF1 will be used for the Part 1 analyses, and the SAF2 will be used for the Part 2 analyses.
2.9.5
Electrocardiogram (ECG)
For each ECG parameter (QTcF, heart rate, PR duration, QT duration, QRS duration), the test 
value and the change from baseline will be summarized using number of observations, mean, 
standard deviation, median, minimum, Q1, Q3, and maximum, by ECG parameter, age group, 
dose cohort and dose associated analysis visit for Part 1, and also by ECG parameter, modified 
age group, treatment group and visit for Part 2.
For each ECG assessment, a clinically significant abnormality is defined as an answer of “Yes” 
to the question “any new clinically significant abnormalities” on the CRF page “12-Lead ECG 
Evaluation – Local Analysis”.
For each specific post-baseline visit, a new onset clinically significant abnormality is defined 
as a clinically significant abnormality at the visit while no clinically significant abnormality at 
baseline.
The number and percentage of patients with new onset clinically significant abnormality will 
be provided by age group, dose cohort and dose associated analysis visit for Part 1, and also by 
modified age group, treatment group and visit for Part 2.
The number and percentage of patients with at least one post-baseline new onset clinically 
significant abnormality during the dose associated period will be provided for Part 1, and also 
will be provided for Part 2 during the double-blind epoch.
The SAF1 will be used for the Part 1 analyses, and the SAF2 will be used for the Part 2 analyses.
2.10
Pharmacokinetic (PK) endpoints
See section 2.5.1.
The population PK Model will be updated with sparse PK data from a subset of Part 2 Group 2 
patients for the purpose of further confirming the target dose for Age Group 2. This will be 
performed prior to database lock and requires unblinding, and as such will be done by an 
unblinded team who is not involved in the conduct of the study.  
2.11
Pharmacodynamics (PD) and PK/PD analyses
See section 2.5.2 for Part 1.


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In Part 2, pre-dose PK blood sample will be collected at Visit 402, Visit 406, and Visit 416/499 
for population PK analysis. If a PK sample is not obtained at Visit 402 or 406, the PK sample 
can be collected at a subsequent scheduled visit.
 
The population PK/PD analysis will be in a separate report.
2.12
Patient-reported outcomes
See Section 2.7 and 2.8.
2.13
Biomarkers
See section 2.5 for Part 1.
 
 
 
2.15
Interim analysis
Safety monitoring
An external DMC will monitor patient safety data during the course of the study. For this study, 
the DMC will review safety data on a regular frequency of every six months. DMC may request 
additional safety data review. Such safety analyses do not inflate the type I error for the primary 
efficacy hypothesis testing and thus require no multiplicity adjustments.
Besides, the safety, tolerability, pharmacokinetic, and pharmacodynamic data from open label 
use of LCZ696 will be evaluated by Novartis and the DMC to advance patients safely for each 
age group when all the patients have completed Part 1 of the study in that age group. Details 
will be included in a separate interim statistical analysis plan.
Interim efficacy analysis
It is planned to have one formal interim efficacy analysis, when at least 180 patients (at least 36 
patients from each modified age group) have completed the study (i.e., had a positively
adjudicated Category 1 event or completed the double-blind epoch), and at least 40 patients 
have had a positively adjudicated event in Category 1 or Category 2. Some adjustment to the 
time of interim analysis may be made to coincide with the regular DMC meetings.


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For the planned interim analysis, the primary test will be performed at a nominal significance 
level of one-sided 0.00153 (calculated based on the O’Brien-Fleming boundary with a sample 
size fraction of 0.5). The above interim analysis or the analysis set will comprise all patients 
who have completed the study (i.e., had a positively adjudicated Category 1 event or completed 
the double-blind epoch) or discontinued from the study by the cutoff date.
For the final analysis, appropriate adjustment will be made according to the actual sample size 
fraction to control the overall Type I error rate at two-sided 0.05.
Table 2-22 provides several examples for nominal significance levels based on actual sample 
size fractions.
Table 2-22
Nominal significance levels and actual sample size fraction
Actual Sample Size Fraction
at the Interim Analysis
Nominal Significance Level
Interim Analysis
(One-sided)
Final Analysis
(One-sided)
Final Analysis
(Two-sided)
0.20
0.00153
0.02390
0.04780
0.30
0.00153
0.02410
0.04819
0.40
0.00153
0.02430
0.04860
0.50
0.00153
0.02450
0.04900
0.60
0.00153
0.02469
0.04938
0.70
0.00153
0.02485
0.04970
0.80
0.00153
0.02496
0.04992
The trial may only be concluded early for efficacy, if the primary test is significant at level of 
one-sided 0.00153 (pre-specified boundary at the interim analysis) and the overall risk/benefit 
profile is considered positive.
Besides, a futility analysis will also be incorporated, whereby the study may be stopped if the 
conditional power for having a significant positive result at the final analysis, based on a 
standardized effect size which will produce a power of at least 80% at the final analysis for the 
sample size of 360 (or re-estimated sample size), is less than 10%. Here the standardized effect 
size is chosen to be 0.147 corresponding to a MW probability of 0.585 for continuous 
distributions, which mimics the case that we have broken all ties. See Appendix 5.2.2 for 
derivation details.
The interim analysis will be performed by an external independent statistician at an external 
data analysis center, who will not be involved in the study conduct. The results will be reviewed 
by the independent DMC. Investigators and others who are involved in the conduct of the trial 
and in the analysis of the final trial results, or who have contact with study centers, will remain 
blinded to the treatment codes and interim analysis results until all monitoring decisions have 
been made and the database has been unblinded for final analysis.
If the study is stopped early at the interim analysis due to overwhelming efficacy, the patients 
used in the interim analysis will be used for the CSR. In this case, at Day 30 (Week 4), Day 90 
(Week 12) and Day 180 (Week 24), the global rank endpoints (as well as their components)
will be defined similarly as Section 2.6.1 and will be analyzed using the same approach in 
Section 2.6.2. This sensitivity analysis will include all patients randomized by the cutoff date


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with a positively adjudicated Category 1 event occurred or the corresponding visit [Week 4, 
Week 12, Week 24] completed.
The FAS will be used for this supportive analyses.
3
Sample size calculation
3.1
Sample size for Part 1
From a prior clinical study in adult HF patients, the observed CV% for body-weight normalized 
LBQ657 exposure was 37.1%, and the observed CV% for body-weight normalized clearance 
and volume of distribution of valsartan was 39.4% and 49.6%, respectively (Study 
CLCZ696A2117). Therefore, 49.6% of CV% was assumed for sample size estimations. A 
sample size of 12 observations (except Group 3 where N=6 observations) is expected to have 
80% probability that the 95% CI of the point estimate for the geometric mean estimates of 
clearance and volume of distribution will be between 60% and 140% range (95% CI: 71 –
141%).
3.2
Sample size for the primary analysis for Part 2
In the sample size evaluation for Part 2, the stratification factors will be ignored.
The planned sample size of 360 is to provide adequate power for the primary test.
The power calculation is based on the data from the Carvedilol pediatric heart failure (CPHF) 
study (Shaddy et al. 2007) within the subgroup of patients with heart failure due to systemic 
left ventricle systolic dysfunction.
Table 3-1 presents the assumed underlying probabilities for Category 1 to 5 in the global rank 
endpoint (Section 2.6.1) at Month 8, based on data from the CPHF study (Shaddy et al. 2007).

The percentages of Category 1 patients at Month 8 in the LCZ696 group and in the 
Enalapril are assumed to be the observed percentages of dead patients in the Carvedilol 
group and in the placebo group in the CPHF study (Figure 2 in Shaddy et al. 2007).

The percentages of Category 2 patients at Month 8 in the LCZ696 group and in the 
Enalapril are assumed to be the observed percentages of alive patients with heart failure 
hospitalization in the Carvedilol group and in the placebo group in the CPHF study 
(Figure 2 in Shaddy et al. 2007).

The percentages of patients in Category 5 for the LCZ696 group and for the Enalapril are 
assumed to be the observed percentages of patients who were categorized as “improved” 
for the primary endpoint in the Carvedilol group and in the placebo group in the CPHF 
study (Table 2 in Shaddy et al. 2007) within the subgroup of patients with systemic left 
ventricle.

The percentages of patients in Category 3 and 4 are formed by splitting the remaining 
percentages approximately equally for these two categories.
Table 3-1 also presents the assumed underlying probabilities for Category 1 to 5 in the global 
rank endpoint (Section 2.6.1) at Week 52, whereby, the percentages for Category 1 and 2 are 
calculated based on an assumption of the exponential distribution, extending from Month 8 to 
Month 12; the remaining percentages within treatment group are distributed to Categories 3 to 


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5 according to the percentages at Month 8 (i.e., 9 : 11 : 64 for the LCZ696 group, and 14 : 13 : 
51 for the enalapril group).
Table 3-1
Assumed percentage of each category in the global rank endpoint at 
Month 8 (Week 32) and Month 12 (Week 52)
Category
Month 8 (Week 32)
Month 12 (Week 52)
LCZ696 (%)
Enalapril (%)
LCZ696 (%)
Enalapril (%)
1
6
9
9
13
2
10
13
15
19
3
9
14
8.1
12.2
4
11
13
10.0
11.3
5
64
51
57.9
44.5
Assuming the percentages in Table 3-1, for the response category (Category 1 to Category 5) 
based on the ranking algorithm (Section 2.6.1), the MW probability is approximately 0.570, 
which leads to a MW odds of approximately 0.753; for a MW analysis on the response category, 
the power is approximately 70% with a significance level of two-sided 0.05 and a sample size 
of 354 (177 patients for each treatment group). Using a global ranked endpoint, the power under 
the same assumptions is expected to increase. While the exact increase in power is dependent 
on the distribution of the ranking within each category, simulation studies have demonstrated 
that the power for the global rank endpoint increases 10-20% more than with the ordered 
categorical analysis when the power of the ordered categorical endpoint is more than 50% (Sun 
et al. 2012). Based on the assumptions stated, the power is estimated to be at least 80% for this 
study. 
The sample size is further increased to 360 (180 patients for each treatment group) to account 
for the alpha adjustment for the interim analysis.
Assuming the same percentages and response categories in Table 3-1, the following arguments 
illustrate how the analysis power will be increased by the effective tie breaking based on the 
global rank endpoint within each of the 5 response categories.
The MW probability based on the global rank endpoint can be decomposed into
where ψ0 is the conditional probability of the patient from the LCZ696 group having a better 
response category than the patient from the Enalapril group given that they are not in the same 
response category, ψ is the conditional probability of the patient from the LCZ696 group being 
better response (with global rank endpoint) than the patient from the Enalapril group given that 
they are in the same response category, ω is the conditional probability of the two patients 
having the same response given that the two patients are in the same response category, ϱ is the 
probability of the patient from the LCZ696 group and the patient from the Enalapril group 
sharing the same response category, when the two patients are independently sampled from the 
LCZ696 group and the Enalapril group.
The parameter, ψ, characterizes the effect of the tie breaker, while the parameter, ψ0, can be 
considered as the effect of the response category (original 5 categories in Table 3-1), 1 – ω can 
MW probability = (1 −))*0 + )(1 −ω)* + ) 1
2 ω,


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be considered as the proportion of between-treatment-group ties being broken within each 
category (assumed to be the same across all the categories).
Assuming the same percentages in Table 3-1, we have ϱ = 0.319, ψ0 ≈0.604, and
Hence, the MW probability can be viewed as a function of (ψ, ω). 
Assuming that a tie-breaker has the tie-breaking effect of ψ = ψ0 ≈0.604, Table 3-2 presents 
the powers for a total sample size of 360 and the sample sizes for a power of 80% for this tie 
breaker with different proportions (1 – ω) of ties being broken, where the upper bound of the 
variance parameter (Appendix 5.2.3) is used in the calculation (which may lead to the presented 
powers slightly under-estimated and the sample sizes slightly over-estimated).
According to Table 3-2, with 50% between-treatment-group ties resolved, the power for the
primary test would be at least 80%.
Table 3-2
Power and sample size based on within-category proportions of 
between-treatment-group ties resolved (1 – ω) when ψ = ψ0 ≈0.604
Within-Category Proportion of 
Between-Treatment-Group Ties Resolved
(1 – ω)
MW
Probability
Power for a Total
Sample Size of 360
Sample Size for
a Power of 80%
10%
0.574
68%
450*
20%
0.577
72%
436
30%
0.581
76%
401
40%
0.584
79%
370
50%
0.587
82%
342
60%
0.591
85%
318
70%
0.594
87%
296
80%
0.597
89%
276
90%
0.601
91%
258
100%
0.604
93%
242
Note *: Since the upper bound of the variance parameter (Appendix 5.2.3) is used in the calculation, 
the presented powers may be under-estimated and the sample sizes may be over-estimated. The 
sample size corresponding to 1 – ω = 10% is 476 with this upper bound of the variance, which has 
been truncated to 450 in the Table since the note below.
Note that, assuming the percentages in Table 3-1, without breaking any tie, a total sample size 
of 450 will provide approximately 80% power for the primary test.
3.3
Sample size re-estimation for Part 2
In the sample size evaluation and sample size re-estimation for Part 2, the stratification factors 
will be ignored.
As discussed in the Section 3.2, assuming the percentages in Table 3-1, the effect size of the 
primary analysis depends on the percentage (1 – ω) of between-treatment ties resolved within 
each category, given the effectiveness (ψ) of ties breaker.
MW probability ≈(1 −0.319) × 0.604 + 0.319 × (1 −ω) × * + 0.319 × 1
2 ω.


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The value of ω is usually unknown and requires an assessment during the study to ensure the 
power for the primary test close to the designed power of 80%.
A blinded sample size re-estimation will be performed to avoid a penalty from unblinding the 
treatment codes in the middle course of the study. It will be performed, when it is about six 
months prior to the predicted end of patient enrollment, or when at least 180 patients have 
completed the study and at least 40 patients have had a positively adjudicated event in Category 
1 or Category 2, whichever occurs the first.
When treatment codes are blinded, ω will not be identifiable itself. We will use the pooled 
probability of observing any tie for the global rank endpoint within any response category
(Category 1 to Category 5) regardless of the treatment group (Appendix 5.2.3), noted as λ, to 
replace it, which can be considered as a reasonable “estimate” of ω. In our sample size re-
estimation, we will assume the percentages in Table 3-1 and effectiveness of tie breaker ψ = ψ0
≈0.604. With these assumptions, the MW probability is bounded below by
The parameter, λ, will be estimated using the pooled data available at the time for the sample 
size re-estimation (Appendix 5.2.3), denoted as λ4. Consequently, the MWP will be estimated 
using
In addition, the variance parameter will be estimated by ΩM, using the pooled data (Appendix 
5.2.3). The sample size re-estimation for 80% power will be based on the following formula:
On the other hand, we also require 80 events in Categories 1 and 2, the final re-estimated sample 
size will be
where N(80) = 80/(PN,1 + PN,2) is the sample size needed for obtaining 80 adjudicated Category 
1 or 2 events; PN,1 and PN,2 are the estimated proportions of patients in Categories 1 and 
Categories 2 based on the pooled data, respectively. The number of 450 is used as a sample size 
cap under the assumption that our study would have an event distribution outlined in Table 3-1
as the worst scenario.
Detailed formula for the sample size re-estimation are provided in Appendix 5.2.3.
4
Change to protocol specified analyses
Above efficacy analysis also considers NYHA/ROSS class group (Class I/II, Class III/IV) at 
randomization, i.e. the randomization stratification.
MW probability ≥Ψ = (1 −)) ∙*0 + ) ∙(1 −8) ∙* + ) ∙1
2 ∙8 ≈0.604 −0.033 × 8.
ΨM = 0.604 −0.033 × λM.
NM = 4 × ΩM × ;Ψ−1(0.975) + Ψ−1(0.8)
ΨM −0.5
?
2
.
maxAmin{NM, 450} , N(80)D,


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5
Appendix
5.1
Imputation rules
5.1.1
Missing or partially missing AE or concomitant medication start/end 
date
The missing or partially missing start/end date for AEs and prior/concomitant therapies will be 
imputed using the Novartis AGB global standard approach. Details will be provided in the study 
PDS.
5.1.2
Missing visit date
If the visit date is missing, the scheduled date (per protocol) of the visit will be used.
5.1.3
Event date missing or partially missing
If the date of an event is not known or is incomplete, the imputation rules are:
a) If the day of the event is unknown, then the 15th day of this month will be imputed for a 
missing day;
b) If only the month is unknown, then July will be used for imputation of the missing;
c) If only the year of the event is known, then the 1st of July will be imputed for a missing day 
and month;
d) The above rules are only for general case. If there is additional information available for the 
missing date, then the information should be used and the imputation of missing date should 
be treated differently. For example, if an event occurs between two visits and its date is 
missing, then the date in the middle of these visits may be used.
5.2
Statistical models
5.2.1
Primary analysis
Notations
Suppose that there are totally K strata.
Let Nk,0 and Nk,1 be the number of patients in the Enalapril group and in the LCZ696 group in 
stratum k, Nk = Nk,0 + Nk,1 be the total number of patients in stratum k, k = 1, … , K.
Let FN,k,0 and FN,k,1 be the empirical cumulative distribution function for the response variable 
in the Enalapril group and in the LCZ696 group in stratum k, FN,k = (Nk,0/Nk) × FN,k,0 + (Nk,1/Nk) 
× FN,k,1 be the pooled empirical cumulative distribution function, k = 1, …,K.


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Stratified Wilcoxon rank-sum test
For stratum k, the Wilcoxon rank-sum statistic is
whose mean and variance under the null hypothesis will be estimated by
where
The stratified Wilcoxon rank-sum statistic is
whose mean and variance under the null hypothesis will be estimated by
The testing statistic for the stratified Wilcoxon rank-sum statistic is
which leads to a one-sided p-value (right-side) of
and a two-sided p-value of
where Φ is the cumulative distribution function for the standard Gaussian distribution.
Stratified estimation for the MW probability and the MW odds
For stratum k, the MW probability within stratum k will be estimated by
whose variance will be estimated by
where
WRSN, = 1
2 N,1 + 1
2 N,1
2
+ N,1N,0 G 1
2 HFN,,0(J) + FN,,0(J −)K LFN,,1(J)
MWRSN, = 1
2 N,1 + 1
2 N,1
2
+ 1
2 N,1N,0, VWRSN, = NN,1N,0O
2 ;VN,,0
NULL
N,0
+ VN,,1
NULL
N,1
?,
VN,,0
NULL = G Q1
2 HFN,,1(J) + FN,,1(J −)K −1
2R
2
LFN,,0(J),
VN,,1
NULL = G Q1
2 HFN,,0(J) + FN,,0(J −)K −1
2R
2
LFN,,1(J).
WRSN = S WRSN,
N + 1
K
=1
,
MWRSN = S MWRSN,
N + 1
K
=1
= 1
2 S N,1
K
=1
,
VWRSN = S VWRSN,
(N + 1)2
K
=1
= S QN,1N,0
N + 1 R
2
;VN,,0
NULL
N,0
+ VN,,1
NULL
N,1
?
K
=1
.
TWRSN = VWRSN
−1 2
⁄ (WRSN −MWRSN),
PVRSN = 1 −Φ(TWRSN),
PVTSN = 2N1 −Φ(|TWRSN|)O,
MWPN, = WRSN, −N,1NN,1 + 1O 2
⁄
N,1N,0
= G 1
2 HFN,,0(J) + FN,,0(J −)K LFN,,1(J),
VMWPN, = VN,,0
N,0
+ VN,,1
N,1
,


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The overall MW probability is defined as
where MWPk denotes the MW probability in stratum k.
The overall MW probability will be estimated by
whose variance will be estimated by
The 1-α confidence interval for the overall MW probability will be given as
where
with Φ-1 being the quantile function for the standard Gaussian distribution.
The overall MW odds will then be estimated by
the 1-α confidence interval for the overall MW odds will be given as
5.2.2
Futility analysis
Suppose there are M patients for the planned efficacy interim analysis.
Conditioning on the testing statistic for the interim analysis, the conditional power for the test 
at the final analysis is approximately
VN,,0 = G ;1
2 HFN,,1(J) + FN,,1(J −)K −N1 −MWPN,O?
2
LFN,,0(J),
VN,,1 = G Q1
2 HFN,,0(J) + FN,,0(J −)K −MWPN,R
2
LFN,,1(J).
MWP = S N,0N,1
N + 1 MWP
K
=1
S N,0N,1
N + 1
K
=1
Z
,
MWPN = S N,1N,0
N + 1 MWPN,
K
=1
S N,1N,0
N + 1
K
=1
Z
,
VMWPN = [S QN,0N,1
N + 1 R
2
VMWPN,
K
=1
\
[S N,0N,1
N + 1
K
=1
\
2
Z
.
;
1
1 + exp{]N
U} ,
1
1 + exp{]N
L}?,
]N
L = log 1 −MWPN
MWPN
−Φ−1(1 −^ 2
⁄ )VMWPN
1 2
⁄
MWPN(1 −MWPN)
,
]N
U = log 1 −MWPN
MWPN
+ Φ−1(1 −^ 2
⁄ )VMWPN
1 2
⁄
MWPN(1 −MWPN)
,
MWON = 1 −MWPN
MWPN
,
NexpA]N
LD , expA]N
UDO
CPN,M = 1 −Φ ab
N
N −M Φ−1 H1 −^
2K −b
M
N −M Φ−1(1 −PVRSM) −√N −M ∙de,


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where PVRSM is the one-sided (right-side) p-value for the primary test at the interim analysis,
N is the sample size at the final analysis, α is the two-sided nominal significance level for the 
final analysis based on the sample size fraction M/N, and δ is an assumed standardized effect 
size:
with 
in which, the sum in the last term is over the mass point.
5.2.3
Sample size calculation and blinded re-estimation
Notations
Let Yi be the global rank endpoint for patient i, Gi be the group indicator for patient i (Gi = 1 if 
patient i is in the LCZ696 group, Gi = 0 if patient i is in the Enalapril group), C(Yi) be the 
response category (Category 1 to Category 5) for patient i.
Let patient i and patient j be two independent patients.
Let ϱ be the probability of a patient from the LCZ696 group and a patient from the Enalapril 
group sharing one category, i.e., ϱ = P(C(Yi)= C(Yj)|Gi = 1, Gj = 0).
Effect size decomposition
Note that, the MW probability (MWP) is
where ψ is defined as
ψ0 is defined as
and ω is defined as
Assuming the percentages in Table 3-1, and that ψ = ψ0, we have ϱ ≈ 0.319 and ψ = ψ0≈ 0.604, 
which leads to a MWP of
Power and sample size under the contiguous alternative
For a two-sided test of α = 0.05, under the contiguous alternative, the power for a sample size 
of n is approximately
d = MWP −0.5
2√Ω
Ω = fgh ;iNYk < YmnYmO + 1
2 iNYk = YmnYmO? = 1
12 [1 −SNi(Yk = J)O
3
J
\,
MWP = iNYk > YmnGk = 1, Gm = 0O + 1
2 iNYk = YmnGk = 1, Gm = 0O
= (1 −)) ∙*0 + ) ∙(1 −q) ∙* + ) ∙1
2 ∙q,
* = iNYk > YmnYk ≠Ym , C(Yk) = CNYmO, Gk = 1, Gm = 0O,
*0 = iNC(Yk) > CNYmOnC(Yk) ≠CNYmO, Gk = 1, Gm = 0O.
ω = iNYk = YmnC(Yk) = CNYmO, Gk = 1, Gm = 0O.
MWP ≈0.604 × (1 −0.319) + 0.319 × 0.604 × (1 −ω) + 0.319 × 1
2 × ω.


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and the sample size for a power of 1 – β = 0.8, is approximately
where Ω is the variance parameter defined as
in which, the sum in the last term is over the mass point.
Note that the variance parameter, Ω, is bounded above by
Thus, the power for a sample size of n has a lower bound of approximately
and the sample size for a power of 1 – β = 0.8 has an upper bound of approximately
Blinded sample size re-estimation
The probability, ω, is non-identifiable in the blinded analysis and is bounded above by
which is the pooled probability of observing ties within any response category, regardless of 
the treatment group. Hence, under the previous assumptions, the MW probability is bounded 
below by
the power for a sample size of n is approximately bounded below by
and the sample size for a power of 1 – β = 0.8, is approximately bounded above by
Suppose there are M patients available for the blinded sample size re-estimation.
At the blinded interim analysis for sample size re-estimation, the within-category probability of 
observing ties, λ, will be estimated by
Φ s1
2 tu
Ω QMWP −1
2R −Φ−1 H1 −^
2Kv,
4 ∙Ω ∙;Φ−1(1 −^ 2
⁄ ) + Φ−1(1 −w)
MWP −0.5
?
2
,
Ω = fgh ;iNYk < YmnYmO + 1
2 iNYk = YmnYmO? = 1
12 [1 −SNi(Yk = J)O
3
J
\,
Ω = 1
12 [1 −SNi(Yk = J)O
3
J
\ ≤1
12.
Φ H√3u(MWP −0.5) −Φ−1(1 −^ 2
⁄ )K,
1
3 ∙;Φ−1(1 −^ 2
⁄ ) + Φ−1(1 −w)
MWP −0.5
?
2
.
8 = i HYk = YmyC(Yk) = CNYmOK,
MW probability ≥Ψ = (1 −)) ∙*0 + ) ∙(1 −8) ∙* + ) ∙1
2 ∙8 ≈0.604 −0.033 × 8,
Φ s1
2 ∙tu
Ω ∙QΨ −1
2R −Φ−1 H1 −^
2Kv,
4 ∙Ω ∙;Φ−1(1 −^ 2
⁄ ) + Φ−1(1 −w)
Ψ −0.5
?
2
.
8M =
∑
∑
IAYk = Ym, m ≠kD
M
m=1
M
k=1
∑
∑
IAC(Yk) = CNYmO, m ≠kD
M
m=1
M
k=1


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the lower bound for the MW probability, Ψ, will be estimated by
and the variance parameter, Ω, will be estimated by
the power for a sample size of n = 360 is approximately bounded below by
and the sample size for a power of 1 – β = 0.8, is approximately bounded above by
5.3
Rule of exclusion criteria of analysis sets 
Criteria defining protocol deviations are referenced in the “Protocol Deviations’ tab of the Data 
Review Plan document. Protocol deviations will be classified into 4 categories as appropriate:

Selection criteria not met

Treatment deviation

Prohibited concomitant medication

Other
The protocol deviation criteria are listed in the sheet “Protocol Deviations” in the data review 
plan. The protocol deviation criteria leading to exclusion from the analysis sets are provided 
below.
Table 5-1
Protocol deviations leading to exclusion of patients from from 
analysis sets for Part 1
ID
Description of Protocol Deviation
Excluding from analysis set
SCR1
ELG1
PK1
PD1
SAF1
INCL01
Informed consent missing
x
x
x
x
x
Table 5-2
Non-protocol deviation criteria leading to exclusion of patients from 
analysis sets for Part 1
Criterion
Excluding from analysis set
SCR1
ELG1
PK1
PD1
SAF1
Screen failure
x
x
x
x
No available valid (i.e., not flagged for exclusion)
PK concentration measurement 
x
No available PD measurements
x
Patient not receiving any dose of open-label study drug
x
x
x
ΨM = 0.604 −0.033 × 8M,
ΩM =
1
M −1 S a1
M S 1
2 NIAYm < YkD + IAYm ≤YkDO
M
m=1
−1
2e
2
M
k=1
,
Φ {1
2 ∙b360
ΩM
∙QΨM −1
2R −Φ−1(0.975)|,
4 ∙ΩM ∙;Φ−1(0.975) + Φ−1(0.8)
ΨM −0.5
?
2
.


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Table 5-3
Protocol deviation criteria leading to exclusion from the analysis sets
for Part 2
Protocol Deviation
Excluding from Analysis Set
ID
Description
SCR2
RAN
FAS
PPS
SAF2
INCL01
Informed consent missing
X
X
X
X
X
INCL04
At Screening NYHA/ROSS Class 1 then 
NYHA/ROSS Class 2 to 4 in MH
X
INCL05a
Systemic left ventricular EF <=45% or fractional 
shortening <=22.5% (assessed by 
echocardiogram, MRI, MUGA or left ventricular 
angiogram)
X
INCL05b
Systemic left ventricular EF <=45% or fractional 
shortening <=22.5% (assessed by 
echocardiogram, MRI, MUGA or left ventricular 
angiogram) within 1 month before patient begins 
Part 2
X
EXCL01
Patients with single ventricle or systemic right 
ventricle
X
WITH01
Blind was broken
X
WITH02
Withdrawal of informed consent and patient 
continued in the trial
X
OTH13
Blind was broken in error.
X
TRT01
Overall drug Compliance rate < 80%
X
TRT03
Incorrect treatment taken during double-blind
epoch
X
TRT04
Patients that were randomized in error and did not 
ingest study medication during the Randomized 
treatment.
X
X
X
Table 5-4
Patient classification for Part 2
Analysis Set
Protocol Deviation ID leading
to exclusion of patients
Non-protocol deviation criteria leading
to exclusion from analysis sets
SCR2
INCL01
Not applicable
RAN
INCL01

Patient without a randomization number
FAS
INCL01, TRT04

Patient without a randomization number

GCP issue present at site
PPS
INCL01, INCL04, EXCL01
INCL05a, INCL05b
WITH01, WITH02, OTH13,
TRT01, TRT03, TRT04

Patient without a randomization number

Patient randomized but not receiving any
study drug during the double-blind epoch

GCP issue present at site
SAF2
INCL01, TRT04

Patient without a randomization number

Patient randomized but not receiving any
study drug during the double-blind epoch


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6
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estimators for the comparison of two treatments with randomization based covariance 
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points in phase II acute heart failure clinical trials: Analyzing data using a global method. 
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