Clinical trial NCT04491136
Conditions: Heart Failure
Keywords: LCZ696 sacubitril/valsartan Heart Failure Heart failure with reduced ejection fraction HFrEF Ventricular arrhythmias Implanted Device Healthcare resource utilization
Sponsor: Novartis Pharmaceuticals
Start date: 2020-11-11; Completion date: 2023-06-08
Enrollment: 201 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to generate effectiveness data of Angiotensin receptor neprilysin inhibitor (ARNI), in the Chinese Heart failure with reduced ejection fraction (HFrEF) patients with implantable cardioverted defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D).

Detailed description:
The rationale of this study was to compare the effect of angiotensin-converting enzyme inhibitor (ACEI) / Angiotensin receptor blockers (ARB) with the effect of ARNI on ventricular arrhythmia (VA) events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional, open-label, and prospective single-arm study was considered.

ACEI/ARB was given to the patient for 6 months. After 6 months, patients using ACEI needed to undergo a 36-hr washout period (36-hr washout period was not needed for patients using ARB at month 6). Patients then received ARNI (sponsored by Novartis only for this study).

Arms: arm 1: Patients received angiotensin-converting enzyme inhibitor/angiotensin receptor blockers treatment the first 6 months. The following 6 months patients received angiotensin receptor neprilysin inhibitor treatment.
Interventions: intervention 1: ACEI/ARB intervention 2: ARNI
Intervention descriptions: intervention 1: Oral ACE/ARB drug according to the investigator's discretion for the first 6 months in this study intervention 2: Oral sacubitril/valsartan at the dosage of investigators discretion, whit a target dose of 200mg bid for the next 6 months of this study

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
LCZ696
Clinical Trial Protocol CLCZ696BCN04 / NCT04491136
A multicenter, interventional, open-label and single-arm 
study to investigate the effect of ARNI on ventricular 
arrhythmia in HFrEF patients with ICD or CRT-D
Document type:
Amended Protocol Version
EUDRACT number:
Not applicable
Version number:
02 (Tracked changes Version)
Clinical Trial Phase:
IV
Release date:
15-Mar-2022 (content final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020)


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 2 (Feb 2022)..................................................................................................10
Amendment 1 (May 2020) ................................................................................................14
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................20
2
Objectives and endpoints...................................................................................................20
2.1
Primary estimands .................................................................................................21
2.2
Secondary estimands .............................................................................................22
3
Study design ......................................................................................................................22
4
Rationale............................................................................................................................23
4.1
Rationale for study design .....................................................................................23
4.2
Rationale for dose/regimen and duration of treatment ..........................................23
4.3
Rationale for choice of control drugs (comparator) or combination drugs ...........24
4.4
Rationale for public health emergency mitigation procedures..............................24
4.5
Purpose and timing of interim analyses/design adaptations..................................24
4.6
Risks and benefits..................................................................................................24
5
Study Population ...............................................................................................................24
5.1
Inclusion criteria ....................................................................................................24
5.2
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................25
6.1
Study treatment......................................................................................................25
6.1.1
Investigational and control drugs..........................................................25
6.1.2
Additional study treatments ..................................................................26
6.1.3
Supply of study treatment .....................................................................26
6.1.4
Treatment arms/group ...........................................................................26
6.1.5
Treatment duration................................................................................27
6.2
Other treatments.....................................................................................................27
6.2.1
Concomitant therapy.............................................................................27
6.2.2
Prohibited medication ...........................................................................28
6.2.3
Rescue medication ................................................................................28


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Protocol No. CLCZ696BCN04
6.3
Patient numbering, treatment assignment, randomization.....................................29
6.3.1
Patient numbering .................................................................................29
6.3.2
Treatment assignment, randomization ..................................................29
6.4
Treatment blinding.................................................................................................29
6.5
Dose escalation and dose modification..................................................................29
6.5.1
Dose escalation guidelines....................................................................29
6.5.2
Definitions of dose limiting toxicities...................................................30
6.5.3
Dose modifications................................................................................30
6.5.4
Follow-up for toxicities.........................................................................30
6.6
Additional treatment guidance...............................................................................30
6.6.1
Treatment compliance...........................................................................30
6.6.2
Recommended treatment of adverse events..........................................31
6.6.3
Emergency breaking of assigned treatment code..................................31
6.7
Preparation and dispensation.................................................................................31
6.8
Handling of study treatment and additional treatment ..........................................31
6.8.1
Handling of study treatment..................................................................31
6.8.2
Handling of additional treatment ..........................................................31
6.8.3
Instruction for prescribing and taking study treatment .........................32
6.9
Treatment of overdose ...........................................................................................32
6.9.1
Reporting of study treatment errors including misuse/abuse ...............32
7
Informed consent procedures ...........................................................................................32
8
Visit schedule and assessments .........................................................................................33
8.1
Screening ...............................................................................................................38
8.1.1
Information to be collected on screening failures.................................38
8.2
Patient demographics/other baseline characteristics .............................................38
8.3
Efficacy assessments .............................................................................................38
8.3.1
Primary efficacy endpoint.....................................................................38
8.3.2
Secondary efficacy endpoints ...............................................................39
39
8.3.4
Appropriateness of efficacy assessments..............................................40
8.4
Safety assessments.................................................................................................40
8.4.1
Laboratory evaluations..........................................................................40
8.4.2
Electrocardiogram (ECG) .....................................................................41
8.4.3
Pregnancy and assessments of fertility .................................................42
8.4.4
Appropriateness of safety measurements..............................................42
8.5
External central review committee........................................................................42
8.6
Additional assessments..........................................................................................43


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Protocol No. CLCZ696BCN04
8.6.1
Clinical outcome assessments...............................................................43
9
Study discontinuation and completion ..............................................................................43
9.1
Discontinuation and completion............................................................................43
9.1.1
Study treatment discontinuation and study discontinuation..................43
9.2
Withdrawal of informed consent and exercise of participant’s data privacy 
rights ......................................................................................................................44
9.2.1
Lost to follow-up...................................................................................45
9.2.2
Early study termination by the sponsor.................................................45
9.3
Study completion and post-study treatment ..........................................................45
10 Safety monitoring and reporting........................................................................................46
10.1
Definition of adverse events and reporting requirements......................................46
10.1.1
Adverse events ......................................................................................46
10.1.2
Serious adverse events ..........................................................................47
10.1.3
SAE reporting........................................................................................48
10.1.4
Pregnancy reporting ..............................................................................49
10.1.5
Reporting of study treatment errors including 
misuse/abuse/overdose..........................................................................49
10.1.6
Reporting of Non-serious Adverse Drug Reactions..............................50
10.2
Additional safety monitoring.................................................................................50
11 Data collection and database management........................................................................51
11.1
Data collection.......................................................................................................51
11.2
Database management and quality control............................................................51
11.3
Site monitoring ......................................................................................................51
12 Data analysis and statistical methods ................................................................................52
12.1
Analysis sets ..........................................................................................................52
12.2
Patient demographics and other baseline characteristics.......................................52
12.3
Treatments .............................................................................................................53
12.4
Analysis of the primary endpoint ..........................................................................53
12.4.1
Definition of primary endpoint .............................................................53
12.4.2
Statistical model, hypothesis, and method of analysis..........................54
12.4.3
Handling of remaining intercurrent events of primary estimand..........54
12.4.4
Handling of missing values not related to intercurrent event ...............54
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................54
12.4.6
Supplementary analysis.........................................................................54
12.4.7
Supportive analyses...............................................................................55
12.5
Analysis of secondary endpoints ...........................................................................55
12.5.1
Efficacy endpoints.................................................................................55


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12.5.2
Statistical model, hypothesis, and method of analysis..........................55
12.5.3
Safety endpoints....................................................................................56
57
57
12.7
Interim analyses.....................................................................................................58
12.8
Sample size calculation..........................................................................................58
12.8.1
Primary endpoint...................................................................................58
12.8.2
Power for analysis of selected secondary variables ..............................58
13 Ethical considerations and administrative procedures ......................................................59
13.1
Regulatory and ethical compliance........................................................................59
13.2
Responsibilities of the investigator and IRB/IEC..................................................59
13.3
Publication of study protocol and results...............................................................59
13.4
Quality control and quality assurance....................................................................59
14 Protocol adherence ............................................................................................................60
14.1
Protocol amendments.............................................................................................60
15 References .........................................................................................................................61
16 Appendices ........................................................................................................................63
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................63
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 6-1
Investigational and control drug............................................................25
Table 6-2
Recommended dosage...........................................................................29
Table 6-3
Recommended starting dose of ARNI ..................................................30
Table 8-1
Assessment schedule.............................................................................35
Table 8-2
Assessment & specifications.................................................................40
Table 8-3
Laboratory Assessments........................................................................41
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................50
Table 12-1
Matched pairs 2 x 2 contingency table..................................................54
List of figures
Figure 3-1
Study design..........................................................................................22


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Amended Protocol Version 02 (Track changes)
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List of abbreviations
ACEI
Angiotensin-converting enzyme inhibitor
AE
Adverse Event
ALT
Alanine Aminotransferase
ARB
Angiotensin receptor blockers
ARNI
Angiotensin receptor neprilysin inhibitor
AST
Aspartate Aminotransferase
AT1
Angiotensin II type 1
ATC
Anatomical Therapeutic Chemical
ATP
Anti-tachycardia pacing
b.i.d.
bis in die/twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CMO & PS 
Chief Medical Office and Patient Safety
CO
Country Organization
CPK
Creatinine phosphokinase
CRO
Contract Research Organization
CRT-D
Cardiac resynchronization therapy-defibrillator
CTCAE
Common Terminology Criteria for Adverse Events
DLT
Dose limiting toxicity
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EOS
End of study
ePRO
Electronic patient reported outcome
eSource
Electronic Source
FAS
Full Analysis Set
GCP
Good Clinical Practice
HF
Heart failure
HFrEF
Heart failure with reduced ejection fraction
hr
hour
ICD
Implantable cardioverter defibrillator
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
LVEF
Left ventricular ejection fraction
MedDRA
Medical dictionary for regulatory activities 


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Amended Protocol Version 02 (Track changes)
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mg
milligram(s)
mL
milliliter(s)
NEP
Neutral endopeptidase
NSVT
Non-sustained ventricular tachycardia
NT-proBNP
N-Terminal prohormone of Brain Natriuretic Peptide
NYHA
New York Heart Association
PARADIGM-HF
The prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with an 
Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and 
Morbidity in Heart Failure
p.o.
oral(ly)
PVC
Premature ventricular contraction
QD
Once a day
QMS
Quality Management System
QTcF
Fridericia QT correction formula
RBC
Red blood cell(s)
SAE
Serious Adverse Event
SAF
Safety Set
SD
Standard deviation
SOP
Standard Operating Procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
SVT
Sustained ventricular tachycardia
ULN
Upper limit of normal
VA
Ventricular arrhythmia
VT/VF
Ventricular tachycardia/fibrillation
WBC
White blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Amended Protocol Version 02 (Track changes)
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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), urine, 
etc. taken from a patient.
Cohort
A specific group of patients fulfilling certain criteria and generally treated at the 
same time.
Control drug
A study intervention (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug.
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day).
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the 
use of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care.
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last patient or at a 
later point in time as defined by the protocol.
Enrollment
Point/time of patient entry into the study at which informed consent must be 
obtained.
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
Intercurrent 
events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study.
Medication 
number
A unique identifier on the label of medication kits.
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy).
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease.
Patient
An individual with the condition of interest for the study.
Patient number
A unique number assigned to each patient upon signing the informed consent. 
This number is the definitive, unique identifier for the patient and should be 
used to identify the patient throughout the study for all data collected, sample 
labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis.


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
Personal data
Patient information collected by the Investigator that is coded and transferred 
to Novartis for the purpose of the clinical trial. This data includes patient 
identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned.
Randomization 
number
A unique identifier assigned to each randomized patient.
Run-in Failure
A patient who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to patient’s intervention or other 
treatment).
Screen Failure
A patient who did not meet one or more criteria that were required for 
participation in the study.
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first patient.
Study treatment
Any drug or combination of drugs or intervention administered to the patients 
as part of the required study procedures; includes investigational drug(s) or 
control(s).
Study treatment 
discontinuation
When the patient permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may 
not also be the point/time of study discontinuation.
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each patient that is required to 
address the clinical question. The specification of the variable might include 
whether the patient experiences an intercurrent event.
Withdrawal of 
consent 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation.
This request should be distinguished from a request to discontinue the study. 
Other study participant's privacy rights are described in the corresponding 
informed consent form.


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
Amendment 2 (Feb 2022)
Amendment rationale
Study was initiated in 19-Oct-2020. As of 31-Jan-2022, a total of 142 patients have been 
enrolled in the study. The slow enrollment of patients was impacted by the COVID-19 
pandemic. This amendment is aimed to reduce the study sample size by modification of the 
statistical power of sample size calculation.
Changes in the protocol
Chapter 
V01
V02
Reason
Protocol 
summary
(Study 
design), 
Section 3, 
Section 5
275 HFrEF patients
219 HFrEF patients
Sample size is 
updated
Protocol 
summary –
Exclusion 
criteria
2. Patients who received 
ARNI within 6 weeks prior 
to study
2. Patient received target dose 
(≥200 mg/d) of ARNI for 2 weeks 
continuously within the 6-week 
period prior to study enrollment.
Define 6-week 
period
Section 4.4
NA
In the event of a public health 
emergency as declared by local 
or regional authorities (i.e., 
pandemic, epidemic or natural 
disaster), mitigation procedures 
may be required to ensure 
participant safety and trial 
integrity and are listed in relevant 
sections of the study protocol. 
Notification of the public health 
emergency should be discussed 
with Novartis prior to 
implementation of mitigation 
procedures, and 
permitted/approved by local or 
regional health authorities and 
ethics committees as appropriate.
New section: 
COVID-19-
related 
information is 
added
Section 4.5, 
Section 12.7
138 patients
110 patients
Sample size for 
interim analysis 
is updated
Section 4.6
NA
In the context of COVID-19 
pandemic, there is still lack of 
evidence about the risks or 
benefits of ARNI and ACEI/ARB 
in COVID-19 patients.
COVID-19-
related 
information is 
added
Section 5.2
2. Patients who received 
ARNI within 6 weeks prior 
to study
2. Patient received target dose 
(≥200 mg/d) of ARNI for 2 weeks 
continuously within the 6-week 
period prior to study enrollment.
Exclusion 
criterion 2 is 
updated to define 
6-week period


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
Chapter 
V01
V02
Reason
Section 6.5.1 
– Table 6-3
Moderate or high-dose 
ARB (equivalent of 
valsartan 10 mg bid)
Moderate or high-dose ARB 
(equivalent of valsartan ≥80 mg 
bid)
Error
Section 6.7
NA
During the COVID-19 pandemic 
in which on-site study visits may 
be impacted, delivery of study 
treatment directly to a patient’s 
home is generally permitted. If 
delivery is not available, patients 
may purchase the study drugs 
themselves. Patients will be 
reimbursed for the study drug 
cost with drug packaging as proof 
of purchase.
COVID-19-
related 
information is 
added
Section 6.9
NA
In the event of an overdose, the 
Investigator should:

Contact the medical monitor 
immediately.

Evaluate the patient to 
determine, in consultation 
with the medical monitor, 
whether study treatment 
should be interrupted or 
whether the dose should be 
reduced.

Closely monitor the 
participant for any AE/SAE 
and laboratory abnormalities 
for at least 30 days.

Document the quantity of the 
excess dose as well as the 
duration of the overdose.
Information about 
overdose are 
added.
Section 6.9.1
NA
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.
Information about 
misuse/abuse 
are added


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
Chapter 
V01
V02
Reason
Study treatment errors and uses 
outside of what is foreseen in the 
protocol will be recorded on the 
appropriate CRF irrespective of 
whether or not associated with an 
AE/SAE. Misuse or abuse will be 
collected and reported in the 
safety database irrespective of it 
being associated with an AE/SAE 
within 24 hours of Investigator’s 
awareness.
For more information on AE and 
SAE definition and reporting 
requirements, please see the 
respective sections.
Section 7
NA
In the event of recollection of 
informed consent is needed, the 
Investigator may conduct the 
informed consent discussion 
remotely (e.g., telephone or video 
conference). Guidance issued by 
local regulatory bodies, and 
ECs/IRBs on this aspect prevail 
and must be implemented and 
appropriately documented (e.g., 
the presence of an impartial 
witness, sign/dating separate 
ICFs by trial participant and 
person obtaining informed 
consent, etc.).
Remote consent 
for recollection of 
informed consent 
is added.
Section 8.5
every 3-6 month through 
this study
when necessary
No meeting held 
by review 
committee since 
the study initiated
Section 12.8
power of 0.8 and 
significance level of 0.05, 
the sample size required is 
175. Further consider a 
dropout rate of 20%, the 
minimum sample size 
required is 219.
power of 0.8 and significance 
level of 0.05, the sample size 
required is 175. Further consider 
a dropout rate of 20%, the 
minimum sample size required is 
219.
Reduce the study 
sample size by 
reducing the 
statistical power
Minor edits and corrections of typos are also made throughout the protocol. Several updates are 
also made according to the wordings in CTP template V5.0.
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 approval. 


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
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.


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Amended Protocol Version 02 (Track changes)
Protocol No. CLCZ696BCN04
Amendment 1 (May 2020)
Study protocol amendments and updates (from V00 to V01) are based on launch meeting, 
especially inclusion and exclusion criteria, as this is more reasonable and executable in 
investigator practices.
Chapter 
V00
V01
Reason
Protocol summary-
Key Inclusion criteria 
5.1 Inclusion criteria 
2. Implanted with an 
ICD or CRT-D within 1 
week
2. Implanted with an 
ICD or CRT-D within 2
weeks
Reasonable criteria in 
clinical practice
Protocol summary-
Key Exclusion criteria 
5.2 Exclusion criteria 
2. Patients who 
received ARNI within 2 
months prior to study 
enrollment
2. Patients who 
received ARNI within 6 
weeks prior to study 
enrollment
Reasonable criteria in 
clinical practice
Protocol summary-
Key Exclusion criteria 
5.2 Exclusion criteria 
8. Symptomatic 
hypotension < 90/60 
mmHg in anti-
hypotension drug 
treatment at Visit 1 
(screening)
8. Symptomatic 
hypotension < 90/60 
mmHg in anti-
hypertension drug 
treatment at Visit 1 
(screening)
Wording error
 
 
 
 
 
 
 
 
4.2 Rationale for 
dose/regimen and 
duration of treatment 
ACEI is recommended 
by treatment 
guidelines as the 
treatment of choice for 
HFrEF patients
ACEI/ARB is 
recommended by 
treatment guidelines 
as the treatment of 
choice for HFrEF 
patients
Wording error
5.2 Exclusion criteria 
11.Pregnant or nursing 
(lactating) women, 
where pregnancy is 
defined as the state of 
a female after 
conception and until 
the termination of 
gestation, confirmed 
by a positive human 
chorionic gonadotropin 
(hCG) laboratory test 
(> 5 mIU/mL).
11.Pregnant or nursing 
(lactating) women
Delete extra 
description 
6.1.1 Investigational 
and control drugs 
Basically, initiated 
ARNI dosage accord 
to ACEI/ARB 
alternative dosage, but 
investigators have 
discretion to prescribe 
ARNI dosage
Add initial dosage of 
ARNI.


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Amended Protocol Version 02 (Track changes)
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Chapter 
V00
V01
Reason
6.2.1 Concomitant 
therapy 
Amiodarone dosage 
must be consistent for 
patient treatment 
during this study, if
radiofrequency 
ablation is necessary, 
the patient should 
withdraw from the 
study.
Definition the dosage 
of Amiodarone in 
special case.
6.2.3 Rescue 
medication 
Any patient who 
experiences a 
potassium level ≥6.0 
mmol/L confirmed by 
repeated same blood 
sample testing should 
be withdrawn from the 
study treatment.
Any patient who 
experiences a 
potassium level >6.0 
mmol/L confirmed by 
repeated same blood 
sample testing should 
be discontinued from 
the study treatment.
Clarify hyperkalemia is 
not imply the patient 
will quit the study 
forever if effective 
treatment.
9.1.1 Study treatment 
discontinuation and 
study discontinuation 
4. Serum 
potassium >6.0 
mmol/L at follow Visit
“Serum 
potassium >6.0 
mmol/L at follow Visit” 
is moved from “Study 
treatment must be 
discontinued under the 
following 
circumstances” to
“Study medication may 
be discontinued at the 
investigator’s 
discretion if any of the 
following occurs”
Avoid study treatment 
discontinuation result 
of transient 
hyperkalemia


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Protocol summary
Protocol number
CLCZ696BCN04
Full Title
A multicenter, interventional, open-label and single-arm study to investigate 
the effect of ARNI on ventricular arrhythmia in HFrEF patients with ICD or 
CRT-D
Brief title
RHYTHM
Sponsor and 
Clinical Phase
Novartis 
Phase IV
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to generate effectiveness data of ARNI, in the 
Chinese HFrEF patients with implanted ICD or CRT-D.
The rationale of this study is to compare the effect of ACEI/ARB with the 
effect of ARNI on VA events for HFrEF patients with ICD or CRT-D, thus a 
multicenter, interventional, open-label, and prospective single-arm study was 
considered.
Primary 
Objectives
The primary objective of this study is to assess the proportion of patients with 
VA events over 6 months of ACEI/ARB and 6 months of ARNI treatment
Secondary 
Objectives

To assess numbers of occurrences of VA events and ICD or CRT-D 
shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment

To compare the changes in LVEF and NYHA level between ACEI/ARB 
and ARNI treatments

To compare the changes in the NT-proBNP level between ACEI/ARB and 
ARNI treatments

To compare the healthcare resource utilization of HF patients during 
ACEI/ARB and ARNI treatments
 
Study design
This will be a multicenter, interventional, open-label, and prospective single-
arm study to evaluate the effect of ARNI on VAs in approximately 219 HFrEF 
patients receiving ICD or CRT-D in China.
After the patient is informed and asked to sign an informed consent form, 
baseline data will be collected. Device data of patients will be collected for 
12 months. ACEI/ARB will be given to the patient for 6 months. Dosage of 
ACEI/ARB will be based on investigator’s discretion and up titrated after 2-4 
weeks to the maximum dosage the patients can tolerate and according to 
product label.
After 6 months, patients using ACEI need to undergo a 36-hr washout period 
(36-hr washout period is not needed for patients using ARB at month 6). 
Patients will then receive ARNI (sponsored by Novartis only for this study) 
while the dosage of ARNI will be according to investigator’s discretion and up 
titrated to the maximum dosage the patient can tolerate or 200 mg bid as per 
guideline.
All patients will be followed up for 6 months for each treatment. After patients 
finalize the trial, the investigator will evaluate all patients and produce a 
report. 
An interim analysis is planned when half of the required sample size (110
patients) have completed the study. The intent of the interim analysis is to 


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stop for futility or high incidence of safety events and re-evaluate minimum 
sample size required. 
Study population
The study population will consist of approximately 219 patients with HFrEF 
(LVEF ≤40%) in around 25 sites, aged between 18 years and 80 years, 
implanted with ICD/CRT-D devices.
Key Inclusion 
criteria
1.
Male or female patients ≥18 and ≤80 years of age
2.
Implanted with an ICD or CRT-D within 2 weeks
3.
NYHA functional class II – IV
4.
LVEF ≤40% (measured by echocardiography)
5.
Signed informed consent must be obtained prior to participation in the 
study.
Key Exclusion 
criteria
1.
History of hypersensitivity to any of the study treatments or its excipients 
or to drugs of similar chemical classes.
2.
Patient received target dose (≥200 mg/d) of ARNI for 2 weeks 
continuously within the 6-week period prior to study enrollment.
3.
Participation in other clinical studies 3 months prior to participating study
4.
Advanced cancer or other significant comorbidities with life expectancy of 
<1 year
5.
Previous history of angioedema associated with ACEI/ARB treatment, 
hereditary or idiopathic angioedema
6.
Patients with renal artery stenosis history
7.
Current stage D HF patients requiring vasoactive drugs
8.
Symptomatic hypotension < 100/60 mmHg at visit 1 (screening) or 
Symptomatic hypotension < 90/60 mmHg in anti-hypertension drug 
treatment at visit 1 (screening)
9.
Serum potassium >5.4 mmol/L at visit 1 (screening)
10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 as 
measured at visit 1 (screening)
11. Pregnant or nursing (lactating) women
12. Other exclusion depend on investigator’s discretion
Study treatment
Patients will receive ACEI/ARB, where generics are acceptable. Patients will 
receive then ARNI treatment for 6 months.
Treatment of 
interest
Patients will receive ACEI/ARB for 6 months and then ARNI for 6 months. 
Patients will initiate ARNI treatment after a 36-hr washout period after the 
ACEI treatment. 
Efficacy 
assessments
Primary efficacy endpoints
1. The proportion of patients with VA events over 6 months of ACEI/ARB and 
6 months of ARNI treatment will be measured.
2. Proportion of patients had ATP, ICD or CRT-D shocks occurrence over 6 
months of ACEI/ARB and 6 months of ARNI treatment will be measured.
Secondary efficacy endpoints
1. The episodes of VA events over 6 months of ACEI/ARB and 6 months of 
ARNI treatment will be measured.
2. LVEF (%) will be compared at baseline, Month 6 and EOS.
3. NYHA level will be recorded by investigators and compared at baseline, 
Month 6 and EOS.
4. The measurements of NT-proBNP will be obtained from serum or plasma. 
Samples will be obtained before patients take their morning study drug 


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dose. NT-proBNP (pg/mL) will be compared between ACEI/ARB and ARNI 
treatments at baseline, Month 6 and EOS.
5. Number of hospitalizations for arrhythmia or HF related hospitalizations will 
be recorded during ACEI/ARB and ARNI treatments.
 
Key safety 
assessments
Adverse event monitoring, physical examinations, vital signs, height and 
weight, laboratory evaluations, ECG, and pregnancy test.
Data analysis
Enrolled Set: all patients who enrolled into this study.
Full Analysis Set (FAS): all patients to whom study treatment has been 
assigned and who received at least one dose of study treatment. Patients will 
be analyzed according to the treatment they have been assigned to. Efficacy 
variables will be analyzed based on the FAS as the primary population.
Safety Set (SAF): all patients who received at least one dose of study 
treatment. Patients will be analyzed according to the study treatment 
received. The safety population will be used for the analyses of safety 
variables.
Per Protocol Set (PP): all patients in the FAS and have no major protocol 
deviations. PP population will be used for efficacy analysis.
Demographic and other baseline characteristics
Demographic and other baseline data including laboratory test will be listed 
and summarized descriptively for all patients in the FAS. Categorical data will 
be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum will be presented. Relevant medical histories and current medical 
conditions at baseline will be summarized by system organ class and 
preferred term for all patients as well.
Treatments
The overall duration will be summarized by treatment group using mean, 
standard deviation, median, minimum and maximum. The number and 
percentage of patients will be summarized by treatment group for categorized 
duration group.
Concomitant medications and significant non-drug therapies prior to and after 
the start of the study treatment will be listed and summarized according to the 
ATC classification system for the safety population.
McNemar Test and Wilcoxon sign rank test will be used to assess the 
difference in proportions between treatments.
Summary tables will be reported to show the changes from baseline to Month 
3, and 6 post-indexing and changes from Month 6 to Month 9, and 12 post-
indexing date for each variable involved.
Normality will be checked for the changes calculated, if the data is 
parametric, paired t-tests will be performed; else if the data is non-parametric, 
Wilcoxon signed-rank test will be used.
Key words
Ventricular arrhythmias; heart failure reduced ejection fraction; implanted 
device; treatment; healthcare resource utilization


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1
Introduction
1.1
Background
Heart failure (HF) is a public health issue around the world including China. In China, the 
prevalence of HF is estimated approximately 1.3% among Chinese between 35-74 years old. 
HF imposes a significant economic burden and poor quality of life of patient. Sudden cardiac 
death is responsible for half of all heart disease deaths. In Europe, the incidence of sudden 
cardiac death is estimated between 350,000 and 700,000 people annually (Lippert et al 2010). 
The estimated sudden cardiac death cases in China was 544000 deaths in 1.3 billion people 
every year (Hua et al 2009).
Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB) 
antagonize the action of angiotensin II, a known precursor of interstitial fibrosis that is 
associated with ventricular arrhythmia (VA). ACEI has been used in patients with HF with 
reduced ejection fraction (HFrEF) over the past 2 decades. However, despites advances in 
pharmacological and device therapies, 50% of HF patients die within 4 years and 40% of HF 
patients admitted to hospital die or are readmitted within a year (ESC Guidelines 2008).
Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI) that providing 
concomitant neprilysin (neutral endopeptidase 24.11, NEP) inhibition and angiotensin II type 1 
(AT1) receptor blockade. Sacubitril is a neprilysin inhibitor that inhibits the degradation of 
natriuretic peptides. Valsartan is an angiotensin receptor blocker that mediates the deleterious 
effects of angiotensin II on the cardiovascular system. Neprilysin is a ubiquitous 
metallopeptidase with several different substrates that cleaves vasoactive peptides with 
vasodilation effects (including natriuretic peptides, adrenomedullin, bradykinin, and peptides 
with vasoconstrictor effects). As a result of neprilysin inhibition, there are an increase of 
natriuretic peptides in the circulating levels, which then leads to a cardioprotective effect that 
counteract the detrimental effects of renin-angiotensin system and sympathetic nervous system 
activation (Huber and Brown 2016).
There are multiple mechanisms that may be implicated in sudden cardiac death in HFrEF 
patients including VA, asystole, electromechanical dissociation and cardiogenic shock. Sarrias 
and Bayes-Genis (2018) proposed a mechanism whereby ARNI exerts anti-arrhythmic effects 
by reducing myocardial cell death, hypertrophy, fibrosis and inflammation through reducing 
the substrates required for VA. Increase of enkephalins, endorphins, and bradykinin may also 
play a role in the cardioprotective and anti-arrhythmic effects of neprilysin inhibitors. However, 
the precise mechanism still remains unknown (Sarrias and Bayes-Genis 2018).
Results of the completed pivotal study, “The prospective Comparison of Angiotensin Receptor-
Neprilysin Inhibitor with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on 
Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial” found that ARNI was 
superior compared to ACEI in reducing the risks of death in HFrEF patients and reduce the risk 
of sudden death (McMurray et al 2014). In PARADIGM-HF trial, there are fewer patients’ 
experiences serious adverse events (SAE) on ARNI than on ACEI, and fewer patients who 
received ARNI discontinued study due to adverse events (AE) compared to those patients who 
received ACEI. Hypotension was more frequently reported in ARNI patients than ACEI 
patients. Hyperkalemia, cough and renal dysfunction were more commonly reported in ACEI 
patients than ARNI patients.


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Both implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy-
defibrillator (CRT-D) are device-based therapies prescribed for HF patients who are diagnosed 
with arrhythmia or have an increased risk for arrhythmia-related sudden death. The ESC 
guidelines on cardiac pacing and CRT recommend prophylactic ICD or CRT in HF patients 
with an ejection fraction ≤35% (ESC Guidelines 2013). In 2013, approximately 2 ICD or CRT-
D implantation cases were found among every million people in 2013 in China (National Center 
for Cardiovascular Diseases 2014). The placement of ICD and ICD-CRT improves survival and 
reduces sudden death rates in appropriately selected HFrEF patients (Moss et al 2009).
A previous study shown that ARNI significantly decreased sustained ventricular tachycardia 
(SVT), non-sustained ventricular tachycardia (NSVT), and premature ventricular contraction 
(PVC) in 120 patients with ICD or CRT-D (de Diego et al 2018). Nevertheless, de Diego et al 
study had limitation of low sample size and the study was a single-center study. Hence, our 
study will provide additional value to access the VA prevention role of ACEI/ARB and ARNI 
for HF patients receiving ICD or CRT-D.
A more recent retrospective study had studied the VA prevalence in relation to ARNI initiation 
in 151 patients who received ACEI or ARB in a single tertiary HF clinic in Belgium. Significant 
reductions were observed in ventricular tachycardia/fibrillation (VT/VF), occurrence of 
appropriate therapy, NSVT, and PVC. Improvement was observed in anti-tachycardia pacing 
(ATP) in patients with <90% ATP at baseline. The study found out that VA events reduction 
might be related to left ventricular reverse remodeling (Martens et al 2019). However, this study 
did not have measurements on N-Terminal prohormone of Brain Natriuretic Peptide (NT-
proBNP).
To the best of our knowledge, there is a lack of understanding of the relationship between 
treatment (ACEI/ARB and ARNI) and VA in HFrEF patients with ICD or CRT-D in China.
1.2
Purpose
The purpose of this study is to generate effectiveness data of ARNI, in the Chinese HFrEF 
patients with implanted ICD or CRT-D.
2
Objectives and endpoints
This study aims to explore the effect of ARNI on VA and ICD or CRT-D shocks and ATP. The 
objectives and related endpoints are further described in Table 2-1.
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary Objective

To assess the proportion of patients with VA 
events over 6 months of ACEI/ARB and 6 
months of ARNI treatment
Endpoint for primary objective

Proportion of patients with VA events over 
6 months of ACEI/ARB and 6 months of 
ARNI treatment (VA events are defined as 
SVT, NSVT and PVC, ICD shock and ATP, 
the definitions of SVT, NSVT, PVC, ATP are 
as below)


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Objectives
Endpoints
Secondary Objectives

To assess the number of occurrences of VA 
events and ICD or CRT-D shocks over 6 
months of ACEI/ARB and 6 months of ARNI 
treatment 

To compare the changes in LVEF and 
NYHA level between ACEI/ARB and ARNI 
treatments

To compare the changes in the NT-proBNP
level between ACEI/ARB and ARNI 
treatments

To compare the healthcare resource 
utilization of HF patients during ACEI/ARB 
and ARNI treatments
Endpoints for secondary objectives

Numbers of NSVT, SVT, PVC, ICD shock 
and ATP experienced by patients over 6 
months of ACEI/ARB and 6 months of ARNI 
treatment 

LVEF (%) over 6 months of ACEI/ARB and 6 
months of ARNI treatment

NYHA level over 6 months of ACEI/ARB and 
6 months of ARNI treatment

NT-proBNP (pg/mL) level over 6 months of 
ACEI/ARB and 6 months of ARNI treatment

Number of hospitalizations for arrhythmia or 
HF related hospitalizations over 6 months of 
ACEI/ARB and 6 months of ARNI treatment
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; 
 
; ARB = angiotensin receptor blockers; ARNI = angiotensin receptor neprilysin inhibitor; 
ATP = anti-tachycardia pacing; CRT-D = cardiac resynchronization therapy-defibrillator; HF = heart 
failure; ICD = implantable cardioverter defibrillator; LVEF = left ventricular ejection fraction; NSVT = 
non-sustained ventricular tachycardia; NT-proBNP = N-Terminal prohormone of Brain Natriuretic 
Peptide; NYHA = New York Heart Association; PVC = premature ventricular contraction; SVT = 
sustained ventricular tachycardia; VA = ventricular arrhythmias
Note:
Sustained ventricular tachycardia is defined as tachycardia with hemodynamic disorder or lasting for 
≥30 seconds.
Non-sustained ventricular tachycardia is defined by different ICD devices.
Premature ventricular contraction is defined as an early ventricular depolarization as determined by 
the device.
Anti-tachycardia pacing is defined as a low-energy alternative to high-energy biphasic shocks
2.1
Primary estimands
The primary clinical question of interest is: What is the effect of the ARNI versus ACEI/ARB
on change on VA and ICD or CRT-D shocks and ATP in patients with implanted ICD or 
CRT-D?
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of additional medications, mirroring the conditions in clinical practice. Further 
details can be found in Section 12.
The primary estimand is described by the following attributes:


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1. Population: patients defined through appropriate inclusion/exclusion criteria to reflect the 
targeted patient population for approval. Further details about the population are provided 
in Section 5.
2. Variable: VA, ICD and ATP events over 6 months of ACEI/ARB and 6 months of ARNI 
treatment.
3. Treatment of interest: ACEI/ARB for 6 months and ARNI for 6 months. Further details 
about the investigational treatment and control treatment are provided in Section 6.
Handling of remaining intercurrent events:
1. Treatment discontinuations for any reason: ignore (treatment policy strategy).
2. Unforeseen change in the dose of allowed concomitant medications: ignore (treatment 
policy strategy).
3. Unforeseen change in the dose of the investigational treatment or the control treatment due 
to adverse event or other reason: ignore (treatment policy strategy).
The summary measure: Proportion of patients with VA, ICD and ATP events over 6 months of 
ACEI/ARB and 6 months of ARNI treatment
2.2
Secondary estimands
None.
3
Study design
This will be a multicenter, interventional, open-label, and prospective single-arm study to 
evaluate the effect of ARNI on VAs in approximately 219 HFrEF patients receiving ICD or 
CRT-D in China (Figure 3-1).
Figure 3-1
Study design
Abbreviations: ACEI = Angiotensin-converting enzyme inhibitor; ARB = Angiotensin receptor blockers; 
ARNI = Angiotensin receptor neprilysin inhibitor; EOS = End of Study
Note:
- *Data collection at Baseline(0), Month 1, Month 3, Month 6, Month 7, Month 9, and Month 12 
according to the evaluation schedule.
- Dosage and titration plan of ACEI/ARB and ARNI treatments will be according to investigator’s 
discretion and product label (Please refer to Table 6-2 and Table 6-3).
- 36-hr washout period is not needed for patients using ARB.
ARNI treatment
ACEI/ARB treatment
Month 3*
Month 9*
36-hr 
washout 
period for 
patients using 
ACEI
Baseline*
Month 6*
Month 12*
EOS
Month 1*
Month 7*


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Patients will be informed about the study purpose and asked to sign an informed consent form. 
Demographics, etiology of HF, comorbidities, New York Heart Association (NYHA) class, 
baseline laboratory, electrocardiogram, echocardiogram, medical treatment, and implanted 
device (ICD or CRT-D) type and date will be collected at Baseline. Device data of patients will 
be collected for 12 months. Once the device is implanted, ACEI/ARB will be given to the 
patient. Dosage of ACEI/ARB will be based on investigator’s discretion and up-titrated after 
2-4 weeks to the maximum dosage the patients can tolerate and according to product label.
After 6 months, patients using ACEI need to undergo a 36-hr washout period (36-hr washout 
period is not needed for patients using ARB at month 6). Patients will then receive ARNI 
(sponsored by Novartis only for this study) while the dosage of ARNI will be according to 
investigator’s discretion and up titrated to the maximum dosage the patient can tolerate or 
200 mg bid as per guideline. The recommended starting dose of ARNI is presented in Table 6-3.
All patients will be followed up for 6 months for each treatment. After patients finalize the trial, 
the investigator will evaluate all patients and produce a report. 
A Central Review Committee which composed by 2 separated subgroups. Subgroup 1 will be 
formed to confirm the type of events as defined by the device. If there are any discrepancies or 
disagreements in review, the Chairman will provide a final decision. The events that will be 
reviewed periodically include: appropriate shocks, inappropriate shocks, SVT, NSVT, PVC, 
ATP, 
. Subgroup 2 will review SAE reports.
An Academic Committee composed by 11 members of certified electrophysiologists is formed 
to design and revise this study.
4
Rationale
4.1
Rationale for study design
The purpose of this study is to generate effectiveness data of ARNI, in the Chinese HFrEF 
patients with implanted ICD or CRT-D.
The rationale of this study is to compare the effect of ACEI/ARB with the effect of ARNI on 
VA events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional, open-
label, and prospective single-arm study was considered.
4.2
Rationale for dose/regimen and duration of treatment
The dosage of ARNI will be according to investigator’s discretion and up titrate to the 
maximum dosage the patient can tolerate or 200 mg bid. In addition, 6-month is long enough 
to see the VA events changes after switch to ARNI.
Major clinical trials have established ACEI/ARB treatment as the standard of care for RAAS 
blockade and ACEI/ARB is recommended by treatment guidelines as the treatment of choice 
for HFrEF patients. ACEI/ARB has been shown to be superior to placebo in reducing mortality 
in HFrEF and is mostly used as comparator in large randomized controlled trials in HF.


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4.3
Rationale for choice of control drugs (comparator) or 
combination drugs
ACEI/ARB are chosen as the comparator in this study. The ACEI/ARB treatment has been used 
as the standard of care for RAAS blockade and is recommended by treatment guidelines as the 
first-line treatment for HFrEF patients (Yancy et al 2017). 
4.4
Rationale for public health emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities (i.e., 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate.
4.5
Purpose and timing of interim analyses/design adaptations
The study will have one interim analysis (IA) and one final analysis (FA). The intent of the 
interim analysis is to stop for futility or high incidence of safety events and re-evaluate 
minimum sample size required. It is planned once at least 110 patients (half of the required 
sample size) have completed the study. All study endpoints stated in Section 2 will be analyzed.
4.6
Risks and benefits
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol. 
The risk to patients in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.
Women of child-bearing potential must be informed that taking the study treatment may cause 
injury and death to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements. If there is any 
question that the patient will not reliably comply, they should not be entered in the study.
The overall benefit-risk balance of ARNI is positive for the treatment of HF (NYHA class II-IV) 
in patients with systolic dysfunction.
In the context of COVID-19 pandemic, there is still lack of evidence about the risks or benefits
of ARNI and ACEI/ARB in COVID-19 patients.
5
Study Population
The study population will consist of approximately 219 patients with HFrEF (left ventricular 
ejection fraction [LVEF] ≤40%) in 25 sites, aged between 18 years and 80 years, receiving 
ICD/CRT-D devices.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:


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1. Male or female patients ≥18 and ≤80 years of age.
2. Implanted with an ICD or CRT-D within 2 weeks.
3. NYHA functional class II – IV.
4. LVEF ≤40% (measured by echocardiography).
5. Signed informed consent must be obtained prior to participation in the study.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes.
2. Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-
week period prior to study enrollment. 
3. Participation in other clinical studies 3 months prior to participating study.
4. Advanced cancer or other significant comorbidities with life expectancy of <1 year.
5. Previous history of angioedema associated with ACEI/ARB treatment, hereditary or 
idiopathic angioedema.
6. Patients with renal artery stenosis history.
7. Current stage D HF patients requiring vasoactive drugs.
8. Symptomatic hypotension < 100/60 mmHg at visit 1 (screening) or Symptomatic 
hypotension < 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening).
9. Serum potassium >5.4 mmol/L at visit 1 (screening).
10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 as measured at visit 1 
(screening).
11. Pregnant or nursing (lactating) women.
12. Other exclusion depend on investigator’s discretion.
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Investigational and control drugs are summarized in Table 6-1 (no limitation to the list).
Patients will receive ACEI/ARB, where generics are acceptable and listed in Table 6-1. Patients 
will initiate ARNI treatment after a 36-hr washout period after the ACEI treatment. Basically,
initiated ARNI dosage accord to ACEI/ARB alternative dosage, but investigators have 
discretion to prescribe ARNI dosage.
Table 6-1
Investigational and control drug
Drug
(Name)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
(local)
Investigational Drug


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Drug
(Name)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
(local)
Sacubitril/Valsartan, 
50mg
Tablet
Oral use
Open label 
subject packs; 
supply
Control Drug
ACEI
Enalapril
Tablet 
Oral use
Open label 
subject packs; 
No supply
Captopril, 6.25 mg, 
50 mg
Tablet 
Oral use
Open label 
subject packs; 
No supply
Perindopril, 2 mg, 8 
mg
Tablet 
Oral use
Open label 
subject packs; 
No supply
Ramipril, 1.25 mg, 
10 mg
Tablet 
Oral use
Open label 
subject packs; 
No supply
Benazepril, 2.5 mg, 
20 mg
Tablet 
Oral use
Open label 
subject packs; 
No supply
ARB
Candesartan, 4 mg, 
32 mg
Tablet 
Oral use
Open label 
subject packs; 
No supply
Valsartan, 40 mg, 
160 mg
Capsule
Oral use
Open label 
subject packs; 
No supply
Losartan, 25 mg, 
150 mg
Tablet 
Oral use
Open label 
subject packs; 
No supply
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Supply of study treatment
ARNI drugs will be supplied in this study by Novartis. Open drug label should be attached on 
each pack before transport to every site. Every site is responsible for drug storage, drug dispense,
drug recycle and recording by documents.
6.1.4
Treatment arms/group
This is a single-arm study.


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6.1.5
Treatment duration
The planned duration of treatment for ACEI/ARB and ARNI is 6 months each. During the 
ACEI/ARB period, the drug choice and dosage are at the discretion of the physician. The EOS
will occur when the pre-specified number of patients completed the 12 months treatment. 
Patients may be discontinued earlier due to unacceptable toxicity and/or treatment is 
discontinued at the discretion of the investigator or the patient. For patients who in the opinion 
of the investigator are still deriving clinical benefit from ARNI, every effort will be made to 
continue provision of study treatment.
6.2
Other treatments
6.2.1
Concomitant therapy
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 
on the appropriate electronic Case Report Forms (eCRF).
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before allowing a new medication to be started. If the patient is already enrolled, contact 
Novartis to determine if the patient should continue participation in the study.
The concomitant use of other ACEIs or ARBs is strictly prohibited while the patient is receiving 
ARNI. Study medication should be stopped the day prior to addition of other ACEIs or ARBs.
Drugs for arrhythmia include antiarrhythmic drugs (amiodarone), beta-2 blockers (metoprolol 
sustained release tablets), and digitalis drugs (digoxin).Except for titration dose adjustment of 
beta-2 beta blockers, no special dose adjustment for other drugs. Amiodarone dosage must be 
consistent for patient treatment during this study, if radiofrequency ablation is necessary, the 
patient should withdraw from the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
The patient should be on an optimal medical regimen of background HF medications. Use of 
an aldosterone antagonist should be considered in patients eligible for this study. Every effort 
should be made to keep the dose level of disease-modifying HF medications stable throughout 
the entire study. However, if the investigator believes a disease-modifying medication is 
causing an AE or patient’s condition needs a change in any of disease-modifying HF 
medications, it is allowed at the discretion of the investigator. Diuretics may be used and may 
be adjusted throughout the length of the study at the discretion of investigator.
If patients experience any AEs that may be related to the study drug, other HF medications, or 
other cardiovascular medications, the investigator should adjust non-disease-modifying 
medications (e.g. calcium channel blocker, nitrates, α-blockers, and diuretics) first in attempt to 
alleviate the AEs.
Potassium-sparing diuretics
(e.g., spironolactone, triamterene, amiloride), potassium 
supplements, aldosterone antagonists, and any other medications known to raise potassium 
levels should be used with caution. The investigator should assess patient’s potassium levels, 
especially in those who are receiving these medications. 


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Phosphodiesterase-5 inhibitors should be used with caution while the patient is receiving study 
medications due to the increased possibility of occurrence of hypotension.
In case the patient requires the concomitant administration of neseritide and/or intravenous 
nitrates with the study medications, the investigator should consider starting them at a lower 
dose or a slower infusion rate while monitoring the patient’s blood pressure carefully.
Nonsteroidal Anti-Inflammatory Drugs
In patients who are elderly, volume-depleted, or with compromised renal function, concomitant 
use of nonsteroidal anti-inflammatory drugs, including cyclooxygenase-2 (COX-2) inhibitors, 
with sacubitril/valsartan may result in worsening of renal function, including possible acute 
renal failure.
Lithium
Increases in serum lithium concentrations and lithium toxicity have been reported during 
concomitant administration of lithium with angiotensin II receptor antagonists and ARBs. There 
is no data on this interaction as for now. Base on related data, serum lithium concentration 
should be monitored when concomitant sacubitril/valsartan with lithium supplement.
6.2.2
Prohibited medication
Followed by ARNI instructive document. Concomitant use of ARNI with an ACEI/ARB is 
contraindicated because of the increased risk of angioedema. 
Bile acid sequestrants (cholestyramine and colestipol) are also prohibited to avoid disturbing 
effect on the drug absorption of study medication.
6.2.3
Rescue medication
There is no rescue medication, however in the event of hyperkalemia, investigator should 
review the medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Any patient who experiences a potassium level 
> 6.0 mmol/L confirmed by repeated same blood sample testing may be discontinued from the 
study treatment.
If symptomatic hypotension occurs, correct any treatable cause. If hypotension persists, any 
anti-hypertensive drug and non-disease-modifying drugs, such as diuretics, calcium channel 
blockers, nitrates, and α-blockers, should be down-titrated or stopped. If hypotension persists, 
the study drug should be temporarily withdrawn, the re-initiation of ARNI will be at 
Investigator discretion. ARNI is unlikely to be removed by hemodialysis because of high 
protein binding.
If ICD electrical storm occurs, correct the underlying arrhythmia. Differential diagnosis to the 
arrhythmia should be determined, with patient hospitalized and observed by an 
electrophysiologist. Drugs such as amiodarone and anti-arrhythmic agents can be used.


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6.3
Patient numbering, treatment assignment, randomization
6.3.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No. eight-digit code), that 
is assigned when the patient is first enrolled for screening and is retained as the primary 
identifier for the patient throughout his/her entire participation in the trial. The Patient No. 
consists of the Center Number (Center No. four-digit code) (as assigned by Novartis to the 
investigative site) with a sequential patient number suffixed to it, so that each patient is 
numbered uniquely across the entire database. 
6.3.2
Treatment assignment, randomization
This is a single-arm study, no treatment assignment will be involved in this study. No
randomization will be performed in this study.
6.4
Treatment blinding
Treatment will be open to patients, investigator staff, persons performing the assessments, and 
the clinical trial team (CTT).
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are under 
investigator’s discretion and according to product labels. Up-titration of patient’s drug should 
be according to the target dose or to the patient’s maximum tolerance level.
6.5.1
Dose escalation guidelines
The dosage of ACEI/ARB and ARNI are under Investigator’s discretion according to the 
recommended dosage (Yancy et al 2017) (Table 6-2). The recommended starting dose of ARNI 
for different population is presented in (Table 6-3). If the patient is well tolerated, the dose of 
study drug should be up-titrated to next dose level until to target dose. Down-titration of the 
study drug at any time based on the judgment of the Investigator will be allowed with the 
consideration for patient safety and tolerability.
Table 6-2
Recommended dosage
Compound
Initiation dosage
Target dosage
ARNI (Sacubitril/Valsartan)
50 – 100 mg bid
200 mg bid
ACEI
  Enalapril
2.50 mg bid
10 mg bid
  Captopril
6.25 mg tid
50 mg tid
  Perindopril
2.00 mg qd
8 mg qd
  Ramipril
1.25 mg qd
10 mg qd
  Benazepril
2.5 mg qd
20 mg qd
ARB


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Compound
Initiation dosage
Target dosage
  Candesartan
4 mg qd
32 mg qd
  Valsartan
40 mg bid
160 mg bid
  Losartan
25 – 50 mg qd
150 mg qd
Table 6-3
Recommended starting dose of ARNI
Population
Initial dose
Moderate or high-dose ACEI (equivalent of enalapril ≥10 mg bid)
100 mg bid 
Moderate or high-dose ARB (equivalent of valsartan ≥80 mg bid)
100 mg bid
Low dose ACEI (equivalent of enalapril <10 mg bid)
50 mg bid
Low dose ARB (equivalent of valsartan <80 mg bid)
50 mg bid
Severe renal impairment (eGFR <30 mL/min/1.73 m2)
50 mg bid
Moderate hepatic impairment (Child-Pugh Class B)
50 mg bid
Elderly (age ≥75 years)
50 mg bid
6.5.2
Definitions of dose limiting toxicities
A dose limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs when taking study drugs. Dosage of study drugs is according to product 
label. Patients who meet any of the DLTs defined in the product label will be withdrawn from 
this study.
6.5.3
Dose modifications
Dose modifications are according to investigator’s discretions and follow the local product label.
6.5.4
Follow-up for toxicities
Not applicable.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
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. Compliance will be assessed by 
the investigator and/or study personnel at each visit using drug tablet counts and information 
provided by the patient or guardian via a self-administered diary card. Compliance should be 
ensured by the investigator to be > 80%. This information should be captured in the source 
document at each visit. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log.


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6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of AEs.
Medication used to treat AEs must be recorded on the appropriate eCRF.
6.6.3
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with ARNI in packaging as described under investigational 
section. Storage must obey instructional request.
Authorized investigator and drug administrator are responsible for dispensing drug at visit 4, 5, 
6 and recycling at visit 5, 6, 7. The number of ARNI distributed was calculated according to the 
investigator's order and the window period of treatment, and was distributed in the smallest unit, 
namely box. If titration adjustment is happened between two continuous visits, enough ARNI 
dose should take into investigator’s consideration to avoid drug shorting, or investigators are 
responsible for reminding patient to go to site and receipt supplementary ARNI in time.
Patients must take medicine follow by doctor advice, return ARNI pack and the redundant drug. 
After returning back drugs at visits, authorized investigator and drug administrator are needed 
to check the drug tablet accord with their diary card and assess patient compliance.
In case the ARNI dosage is not enough for monthly titration modification, the investigator is 
obligated to remind the patients to return the site and dispense ARNI. 
ACEI/ARB is prescribed by the investigators according to the clinical routine.
During the COVID-19 pandemic in which on-site study visits may be impacted, delivery of 
study treatment directly to a patient’s home is generally permitted. If delivery is not available, 
patients may purchase the study drugs themselves. Patients will be reimbursed for the study 
drug cost with drug packaging as proof of purchase. 
6.8
Handling of study treatment and additional treatment
6.8.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance.
6.8.2
Handling of additional treatment
Not applicable.


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6.8.3
Instruction for prescribing and taking study treatment
The study drug dosage will be under investigator’s discretion according to local guideline and 
product label (Table 6-2). Patients should take their morning study dose at approximately 08:00 
(8 AM) and their evening study dose at approximately 19:00 (7 PM). The study medication 
should be taken with a glass of water with or without food. If the patient misses taking any 
study drug dose, he/she should take it as soon as possible, unless if it is almost time for the 
following scheduled dose. In this case, the patient should skip the missed dose and take the 
regular study drug administration schedule.
All dosages prescribed and dispensed to the patients and all dose changes during the study must 
be recorded in the Dosage Administration Record eCRF.
6.9
Treatment of overdose
In the event of an overdose, the Investigator should:

Contact the medical monitor immediately.

Evaluate the patient to determine, in consultation with the medical monitor, whether study 
treatment should be interrupted or whether the dose should be reduced.

Closely monitor the participant for any AE/SAE and laboratory abnormalities for at least 
30 days.

Document the quantity of the excess dose as well as the duration of the overdose.
6.9.1
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, 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 recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Misuse or abuse 
will be collected and reported in the safety database irrespective of it being associated with an 
AE/SAE within 24 hours of Investigator’s awareness. For more information on AE and SAE 
definition and reporting requirements, please see the respective sections.
7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board/Independent Ethics Committee (IRB/IEC)-
approved informed consent.
If applicable, in cases where the patient’s representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 


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his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH)/ Good Clinical Practice (GCP)
guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the label. 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 investigational drug that is identified between label updates will be 
communicated as appropriate, for example, via an investigator notification (IN) or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the patient. In the event of recollection of informed consent is needed, the 
Investigator may conduct the informed consent discussion remotely (e.g., telephone or video 
conference). Guidance issued by local regulatory bodies, and ECs/IRBs on this aspect prevail 
and must be implemented and appropriately documented (e.g., the presence of an impartial 
witness, sign/dating separate ICFs by trial participant and person obtaining informed consent, 
etc.).
Women of childbearing potential must be informed that taking the study treatment may involve 
risks to the fetus if pregnancy were to occur during the study and agree that in order to 
participate in the study they must adhere to the contraception requirements.
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the patient’s source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. 
Patients who discontinue from the study treatment are to complete the end of treatment visit as 
soon as possible, and attend the follow-up visits as indicated in Table 8-1.
Patients who discontinue from study should be scheduled for a final evaluation visit if they 
agree, 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 events and concomitant medications not previously reported must be recorded on 


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the eCRF. All treated patients should have a safety follow-up call conducted 30 days after last 
administration of study treatment.


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Table 8-1
Assessment schedule 
Period
Screening
ACEI/ARB treatment
ARNI treatment
Visit name
1
2
3
4
5
6
7
Week/Month
0
1m (± 1w)
3m (± 2w)
6m (± 2w)
7m (± 1w)
9m (± 2w)
12m (± 2w)
Obtain informed consent
X
Inclusion/exclusion criteria
X
Demography
  Date of birth
  Age
  Gender
  Race
  Height (cm)
  Weight (kg)
  BMI (kg/m2)
  Source of patient referral
X
Patient HF History
X
Relevant medical history/current medical history
X
Prior HF medications
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
Implanted device
  Date of implantation
  ICD or CRT-D
  Primary prevention or secondary prevention
X
Device data
  VA events (SVT, NSVT, PVC)
  ICD or CRT-D shocks (appropriate shocks and 
inappropriate shocks)
  Anti-tachycardia pacing (%)
X
X
X
X
X
X


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Abbreviations: ACEI = Angiotensin-converting enzyme inhibitor; 
; ARB = Angiotensin receptor blockers; 
ARNI = Angiotensin receptor neprilysin inhibitor; 
; CRT-D = cardiac resynchronization therapy-defibrillator; 
eGFR = estimated glomerular filtration rate; ICD = Implantable Cardioverter Defibrillators; 
Physical examinations
X
X
X
X
X
X
X
Electrocardiogram (ECG) data
X
X
X
X
X
Holter monitor
X
X
X
Echocardiographic data
  LVEF (%)
  LVEDD (mm)
X
X
X
Vital signs
  Systolic blood pressure (mmHg)
  Diastolic blood pressure (mmHg)
  Heart rate average (bpm)
X
X
X
X
X
X
X
Hematology test
  Routine blood test
  Chemistry test
  Serum potassium (mEq/L)
  NT-proBNP (pg/mL)
  eGFR (mL/min/1.73m2)
  blood pregnancy test
X
X
X
Urinary pregnancy test
X
X
X
NYHA class (I-IV)
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
Hospital admission data
X
X
X
X
X
X
X
Study treatment administration
X
X
X
X
X
X
X
Study treatment dispense (ARNI)
X
X
X
Diary card collection
X
X
X
X
X
X
Study patient compliance assessment
X
X
X
X
X
X
Study completion status
X


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LVEF = left ventricular ejection fraction; LVEDD = left ventricular end diastolic diameter; 
NSVT = non-sustained ventricular tachycardia; NT-proBNP = N-Terminal prohormone of Brain Natriuretic Peptide; 
NYHA = New York Heart Association; PVC = premature ventricular contraction; SVT = sustained ventricular tachycardia
X = assessment to be recorded in the clinical database or received electronically from a vendor; all assessments are requested to do after ICF sign, 
unless base on discretion from investigators, blood test and imaging report were done within 2 weeks before ICF could be acceptable.


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8.1
Screening
All patients must provide informed consent before any study-specific procedure is performed. 
At Visit 1, patient’s eligibility for entering the study will be assessed by the investigator. The 
date and type of implant with ICD or CRT-D will be recorded. The LVEF measurements 
required for eligibility will be based on obtained echocardiograms within 2 weeks before this 
study. Screening NT-proBNP, potassium levels, eGFR and serum creatinine and will be 
assessed by local hospital lab and only patients with the required values per the entry criteria 
will be eligible for entering the study.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the eCRF. The 
demographic information, informed consent, and inclusion/exclusion pages must also be 
completed for screen failure patients. No other data will be entered into the clinical database for 
patients who are screen failures, unless the patient experienced a serious adverse event during 
the screening phase (see Section 10.1.3 for reporting details).
Patients who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition eCRF.
8.2
Patient demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF.
Patient demographic and baseline characteristic data to be collected on all patients include: date 
of birth, age, gender, race, and source of patient referral. Relevant medical history/current 
medical history includes data until the start of study drug. Where possible, diagnoses and 
symptoms will be recorded. HF medications other relevant medical history will be recorded on 
eCRFs separately.
8.3
Efficacy assessments
8.3.1
Primary efficacy endpoint
Ventricular arrhythmia events
Cardiac arrhythmia of ≥3 consecutive complexes originating in the ventricles at a rate >100 bpm 
(cycle length: <600 ms). Ventricular arrhythmia events that will be measured through device to 
determine SVT, NSVT and PVC:
1. Sustained ventricular tachycardia (SVT) is defined as tachycardia lasting for ≥30 seconds 
or with hemodynamic disorder as determined by Holter and/or device
2. Non-sustained ventricular tachycardia (NSVT) is defined as recorded by Holter and/or 
device


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3. Premature ventricular contraction is defined as an early ventricular depolarization as 
determined by the device, and/or detected by Holter
The proportion of patients with VA events over 6 months of ACEI/ARB and 6 months of ARNI 
treatment will be measured.
Anti-tachycardia pacing and implantable cardioverter-defibrillator shocks
Once VA are detected, ICD can treat with high-energy shocks or ATP. ATP consists of one or 
more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a 
given RR interval, from the onset of the preceding R wave.
Patients with sustained VA events will receive ICD or CRT-D shock therapy. Inappropriate 
shocks may occur in patients with atrial fibrillation, SVT, or other intracardiac or extra cardiac 
signals. An inappropriate shock is defined as a shock not delivered for VT or VF and ending if 
sinus rhythm was redetected by the ICD. If a subsequent episode started within 5 minutes after 
the previous episode ended, it was not considered as a new episode (van Rees et al 2011).
Proportion of patients had ATP, ICD or CRT-D shocks occurrence over 6 months of ACEI/ARB 
and 6 months of ARNI treatment will be measured.
8.3.2
Secondary efficacy endpoints
Number of occurrences of VA
The episodes of VA events over 6 months of ACEI/ARB and 6 months of ARNI treatment will 
be measured.
Left ventricular ejection fraction
Left ventricular ejection fraction (%) will be compared at baseline, Month 6 and EOS.
NYHA level
NYHA level will be recorded by investigators and compared at baseline, Month 6 and EOS.
NT-proBNP
The measurements of NT-proBNP will be obtained from serum and plasma. Samples will be 
obtained before patients take their morning study drug dose. NT-proBNP (pg/mL) will be 
compared between ACEI/ARB and ARNI treatments at baseline, Month 6 and EOS.
Number of hospitalizations
Number of hospitalizations for arrhythmia or HF related hospitalizations will be recorded 
during ACEI/ARB and ARNI treatments.
 


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8.3.4
Appropriateness of efficacy assessments
The efficacy assessments selected are standard for this indication/participant population.
8.4
Safety assessments
Safety assessments are specified in Table 8-2 with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.
Table 8-2
Assessment & specifications
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed at Visit 1, Month 6 and EOS.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate eCRF that captures 
medical history. Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure and heart rate measurements at every visit. 
After the patient has been sitting for 5 minutes, with back supported and both feet 
placed on the floor, systolic and diastolic blood pressure will be measured 3 times 
using an automated validated device, with an appropriately sized cuff. The repeat 
sitting measurements will be made at 1 – 2-minute intervals and the mean of the 3 
measurements will be used. In case the cuff sizes available are not large enough 
for the patient's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used.
Clinically notable vital signs are defined in Appendix 1.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured as specified in Table 8-1.
8.4.1
Laboratory evaluations
Hematology, chemistry tests, NT-proBNP tests, Pregnancy Test (Table 8-3) will be measured 
by investigators’ hospital lab at baseline, Month 6 and EOS. Clinically significant abnormalities 
must be recorded as either medical history/current medical conditions or AEs as appropriate.
Clinically notable laboratory findings are defined in Appendix 1.
The eGFR to determine eligibility of the patient for screening will be calculated at Visit 1 from 
the serum creatinine concentration by using the following formula (Stevens et al 2006):
eGFR (mL/min/1.73 m2) = 175 x (standardized SCr in mg/dL)-1.154 x (age in years)-0.203 x (0.742 
if female), where SCr is the standardized serum creatinine value
The eGFR will also be measured at Month 6 and EOS in order to guide the investigator to take 
any appropriate action as necessary. Patient will be treatment discontinuation or suspend from 
the study if eGFR decrease > 50% of baseline value according to investigator decision.


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Table 8-3
Laboratory Assessments
Test 
Category
Test Name
Hematology
Red blood cells count, white blood cells count, platelet count, hemoglobin, 
hematocrit, and WBC differential 
Chemistry
Potassium, creatinine, glucose, sodium, chloride, calcium, blood urea nitrogen, total 
bilirubin, fractionated bilirubin (if total bilirubin >2x ULN), aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, total protein, albumin, 
uric acid, lipid profile, hemoglobin A1C
Kidney 
function
serum creatinine
Biomarkers
NT-proBNP 
Pregnancy 
Test
Serum/Urine pregnancy test
8.4.2
Electrocardiogram (ECG)
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline/according to the ECG investigator manual. 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) should be used for clinical 
decisions.
A 12-lead ECG Holter recording will be performed to capture comprehensive ECG. In addition,
12-lead ECGs are collected at the study site using an ECG machine for safety assessment in 
real time by a qualified physician to ensure patient safety. Only clinically significant 
abnormalities must be reported as AE.
In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), and the ECG is repeated to confirm 
the diagnosis. If the patient is hemodynamically compromised, the investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (for example, 
cardioversion).
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or AE as appropriate in related visit.
ECG data will be collected at baseline, Month 3, 6, 9 and EOS.
8.4.2.1
Cardiac imaging
LVEF (%) and left ventricular end diastolic diameter (LVEDD) (mm) will be measured by 
echocardiography at baseline, Month 6 and EOS.
8.4.2.2
Holter
Holter monitoring constantly records heartbeats for 24 hours and can detect arrhythmia events 
that might be missed by using the ECG. Data of Holter monitoring will be collected at baseline, 
Month 6 and EOS.


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8.4.2.3
Cardiac enzymes
Not applicable.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
Pregnancy testing is required for pre-menopause women at baseline, visit 4, visit 7 of the trial. 
At baseline a urinary and a blood pregnancy test should be performed. If positive, the patient 
should be excluded. If the unpredicted pregnancy happens in the study (visit 4, 7), the patient 
must be discontinued from study treatment.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/participant population.
8.5
External central review committee
A central review committee is responsible for periodic study endpoint events adjudication and 
SAE review in Rhythm Study. The central review committee is an independent group consisting
of individuals who have experience and expertise in the management of trial participants within 
heart failure area and in the monitoring of ICD/CRT-D device. The review committee will be 
separated to two subgroups to perform device data adjudication and SAE review respectively.
Device data report will be exported timely into PDF version by doctors at baseline, 1 month, 
3 months, 6 months, 9 months, 12 months when patient visits happen in local sites and all 
uncertain device events will be sent to the subgroup 1 for adjudication (Device Data 
adjudication Boards). 
All aggregated SAE data will be provided to the subgroup 2 for review (Data and Safety 
Monitoring Boards, DSMB).
Then committee will have a meeting held by chairman either in the site or by conference call 
when necessary. Central review committee members will make every attempt to attend the 
meeting in person or by conference call. Total central review committee members will review 
and interpret device data (include VA events, ICD-shock, ATP, etc) and aggregated SAE data.
The central review committee members vote on all decisions. The member must be present in 
the meetings or must have given written recommendation to the chair prior to the meeting. 
Voting is by voice vote, but any members may request a secret written ballot. After decision 
making, the Chairman will provide minutes of the Board discussions to all Board members 
provide a summary (executive) report of each Board meeting to Novartis. A summary statement 
and recommendation from chairman will be provided in writing to the Novartis Medical 
Responsible within three working days of each meeting. The recipients will acknowledge 
receipt and provide a response, if necessary. If an urgent report (defines according to 
investigator discretion) is needed to interpret, at least 3 committee members should response 
and give their consensus decision to the investigator.
Committee Responsibility:
1. Endpoints adjudication use for final study 


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2. Provide clinical suggestion to investigators
3. Make amendment for protocol to NVS, for example patient exclusion and enrollment 
criteria.
8.6
Additional assessments
No additional tests will be performed on participants entered into this study.
8.6.1
Clinical outcome assessments
Not applicable.
8.6.1.1
Additional biomarker assessments
Not applicable.
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the patient or the investigator.
The investigator must discontinue study treatment for a given patient if, he/she believes that 
continuation would negatively impact the patient’s well-being.
Discontinuation from study treatment is required under the following circumstances:
1.
Patient/guardian decision
2.
Pregnancy
3.
Use of prohibited treatment as per recommendations in the prohibited treatment section
4.
ACEI/ARBs daily dosage below guided dosage last for 1 month 
5.
Any situation in which study participation might result in a safety risk to the patient
6.
Withdrawal of informed consent
Study treatment may be discontinued at the investigator’s discretion if any of the following 
occurs:
1. Any severe, or suspected AE, that may jeopardize patient well-being, if the study drug is 
continued
2. Suspected occurrence of angioedema
3. Serum potassium >6.0 mmol/L at follow Visit
4. Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study
If discontinuation of study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the patient’s premature discontinuation of study treatment 
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Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made to 
contact the patient/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule. Patients are to be 
discontinued from the study treatment if patient has not received the study treatment for 
> 14 days. 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact:

New/concomitant treatments

Adverse events/SAE
9.2
Withdrawal of informed consent and exercise of participant’s 
data privacy rights
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent (WoC) occurs only when a patient:

Explicitly requests to stop use of their data,
and

No longer wishes to receive study treatment,
and

Does not want any further visits or assessments (including further study-related contacts)
Withdrawal of consent impacts ability to further contact the patient, collect follow-up data (e.g. 
to respond to data queries) and potentially other restrictions. It is therefore very important to 
ensure accurate recording of withdrawal vs. discontinuation based on the protocol definitions 
of these terms.
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent/exercise 
data privacy rights and record this information. The Investigator shall clearly document if the 
patient has withdrawn his/her consent for the use of data in addition to a study discontinuation.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
If the patient agrees, a final evaluation at the time of the patient’s withdrawal of consent/exercise 
data privacy rights should be made as detailed in the assessment table.


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Further details on withdrawal of consent or the exercise of patients’ data privacy rights are 
included in the corresponding informed consent form.
9.2.1
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits or fail to respond 
to any site attempts to contact them without stating an intention to discontinue from study 
treatment or discontinue from study or withdraw consent (or exercise other participants’ data 
privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
A patient should not be considered as lost to follow-up until due diligence has been completed 
or until the end of the study.
9.2.2
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination (but not limited to):

Unexpected, significant, or unacceptable safety risk to patients enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study treatment development
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients must be seen as soon as possible and treated as 
a prematurely withdrawn patient. The investigator may be informed of additional procedures to 
be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The study is only conducted in China, the Investigator or Novartis depending 
on local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial.
9.3
Study completion and post-study treatment
Study completion is defined as when the last patient finishes their Study Completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g. Each patient will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them).
All treated patients should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the patient should be recorded in the source 
documentation.
Continuing care should be provided by the investigator and/or referring physician based on 
patient availability for follow-up. This care may include:

Enrollment in an extension study, if any


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10
Safety monitoring and reporting
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.1.
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.1.3.
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical investigation 
participant after providing written informed consent for participation in the study. Therefore, 
an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs 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.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient.
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4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met.
5. Action taken regarding with study treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following:

Dose not changed

Dose reduced/increased

Drug interrupted/permanently discontinued
6. Its outcome
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an AE is detected, it must be followed until its resolution or until it is judged to be not 
recovered/not resolved (e.g., continuing at the end of the study), and assessment must be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
product label.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Appendix 1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of an SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).


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
results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
o
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o
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
o
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
o
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
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. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred. 
10.1.3
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 local 
Novartis Patients Safety within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.
Screen failures
A screen failure occurs when a patient who is screened but is not treated or randomized. SAEs 
occurring after the patient has provided informed consent until the time the patient is deemed a 
screen failure must be reported to Novartis.
Treated patients
SAEs collected between time patient signs ICF until 30 days after the patient has discontinued 
or stopped study treatment.


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Package Insert (new occurrence) and is thought 
to be related to the study treatment, a Chief Medical Office and Patient Safety (CMO & PS)
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an IN to inform all investigators involved in any 
study with the same study treatment that this SAE has been reported.
If a SAE is unexpected, i.e., the event an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information and is suspected to be related to the Novartis 
study drug, this event is considered a Suspected Unexpected Serious Adverse Reaction 
(SUSAR). 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 China.
Any SAEs experienced after the 30-day period after the last study visit should only be reported 
to the local Novartis Patient Safety if the Investigator suspects a causal relationship to study 
treatment.
10.1.4
Pregnancy reporting
Pregnancies
In case a female patient becomes pregnant, or plans to become pregnant, the study drug must 
be discontinued (or, from the date the pregnancy becomes known) for the entire duration of the 
pregnancy and lactation period (or, for the entire duration that contraception is discontinued). 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to Novartis 
within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the presence 
or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Patient Safety. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the Novartis 
study drug of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
10.1.5
Reporting of study treatment errors including misuse/abuse/overdose
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) (Table 10-1).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.


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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Overdose is any dose and / or regimen which are over the protocol specified dose/regimen.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
Overdose
Yes
Yes
Only if associated with 
an SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.1.6
Reporting of Non-serious Adverse Drug Reactions
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. An ADR implies at least a reasonable possibility of a causal relationship between 
a medicinal product and an adverse event.
Non-serious ADRs that occurred in patients exposed to the Novartis drug(s) of interest must 
also be recorded in the local Novartis Patient Safety database for local regulatory reporting. 
The Novartis drug(s) of interest evaluated in this study is/are: Sacubitril/Valsartan
The treating physician or other involved HCP must assess the relationship to the Novartis drug, 
complete the AE Report Form and send the completed, signed form by fax/ email within 
10 calendar days to the local Patient Safety department. 
The email address, telephone and telefax number of the contact persons in the local Patient 
Safety department, specific to the site, are listed in the treating physician/HCP folder provided 
to each site. The original copy of the AE Report Form and the fax confirmation sheet or email 
must be kept with the CRF documentation at the study site.
10.2
Additional safety monitoring
An external central review committee for this study will also periodically review aggregated 
SAE data, and make recommendation to sponsor if needed, e.g., protocol amendment on 
inclusion/exclusion criteria. See Section 8.5 in the protocol for details of the external central 
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11
Data collection and database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements, Investigator site staff will not be given access to the Electronic Data 
Capture (EDC) system until they have been trained. Automatic validation programs check for 
data discrepancies in the eCRFs, allow modification and/or verification of the entered data by 
the investigator staff.
The investigator/designee is responsible for assuring that the data (entered into eCRF) is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated contract research organization [CRO]) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel and/or Novartis designated CRO representative will review the protocol and data 
capture requirements (i.e. eSource DDE or eCRFs) with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of patient records, the accuracy of data capture / data entry, 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 Novartis personnel and/or Novartis designated CRO. 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.


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The investigator must maintain source documents for each participant 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 data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Enrolled Set comprises all patients who enrolled into this study.
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received at least one dose of study treatment. Patients will be analyzed according to 
the treatment they have been assigned to. Efficacy variables will be analyzed based on the FAS 
as the primary population.
The Safety Set (SAF) includes all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the study treatment received. The safety population will 
be used for the analyses of safety variables.
The Per Protocol Set (PP) includes all patients in the FAS and have no major protocol deviations. 
PP population will be used for efficacy analysis.
12.2
Patient demographics and other baseline characteristics
Demographic and other baseline data including laboratory test will be listed and summarized 
descriptively for all patients in the FAS, SAF and PP in separate. Baseline data is defined as 
data collected during screening phase.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term for all patients as well.


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12.3
Treatments
Description on how the exposure data for investigational and other treatment medication will 
be collected by the assessments have been given in Section 6.3. The treatment duration of this 
study is 12 months (6 months for each treatment) in total. The overall duration will be 
summarized by treatment group using mean, standard deviation, median, minimum and 
maximum. The number and percentage of patients will be summarized by treatment group for 
categorized duration group.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the ATC classification system for 
the safety population.
12.4
Analysis of the primary endpoint
The purpose of primary objectives are to explore the effect of ARNI and ACEI/ARB in HFrEF 
patients with ICD or CRT-D in terms of VA events and in terms of ICD shocks and ATP using 
primary estimand described in Section 2.1. 
In this study, patients will be observed for 6 months under ACEI/ARB alone. Then, ARNI 
treatment will be initiated (ACEI/ARB stopped, 36-hr washout period applied for patients using 
ACEI only) and patients will be observed for another 6 months under ARNI.
Multiple primary endpoints will be evaluated in this study during 2 different treatment periods, 
that are 6 months of ACEI/ARB treatment and 6 months of ARNI treatment (see detailed 
definitions in Section 12.4.1.)
Since the endpoints are all paired qualitative variable, McNemar Test will be used respectively 
to assess the difference in primary endpoint proportion between treatments.
12.4.1
Definition of primary endpoint
The endpoints of primary objective are as follow:
1. To explore the effect of ARNI in VA events, ICD shocks and ATP.
1. Paired proportion of patients by the occurrence of at least one SVT over 6 months of 
ACEI/ARB and 6 months of ARNI treatment
2. Paired proportion of patients by the occurrence of at least one NSVT over 6 months 
of ACEI/ARB and 6 months of ARNI treatment
3. Paired proportion of patients by the occurrence of at least one PVC over 6 months of 
ACEI/ARB and 6 months of ARNI treatment
4. Paired proportion of patients by the occurrence of at least one ICD shocks over 
6 months of ACEI/ARB and 6 months of ARNI treatment
5. Paired proportion of patients by the occurrence of at least one ATP over 6 months of 
ACEI/ARB and 6 months of ARNI treatment
The VA event, ICD shocks and ATP assessment will be captured by ICD or CRT-D implanted 
into the patients.


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12.4.2
Statistical model, hypothesis, and method of analysis
For all primary endpoints, summaries at baseline, Month 3, 6, 9 and 12 post-indexing date will 
be reported together. Different hypothesis testing will be done on different types of variables as 
follow:
Analysis of paired patient proportions
Occurrence events to be considered SVT, NSVT, PVC, ICD shocks and ATP.
For each of the occurrence event, number of patients with at least one event stratified by 
treatments, will be presented in a 2 x 2 contingency table as follow:
Table 12-1
Matched pairs 2 x 2 contingency table
ARNI (case)
ACEI/ARB (control)
At least one event
No event
Total
At least one event


 + 
No event


 + 
Total 
 + 
 + 
	 =  +  +  + 
The following statistical hypothesis under 95% significance level will be tested to address the 
primary objective:
Null hypothesis:  =  versus alternative hypothesis:  ≠, where  and  is  	

and 
 	

respectively. The test statistic considered is McNemar Test statistic as follow:
 = ( −)
 + 
which has a chi-squared distribution with degree of freedom of one.
However, an exact test (binomial sign test) will be used if the discordant cells have low values 
( +  < 25).
12.4.3
Handling of remaining intercurrent events of primary estimand
The analysis will account for different intercurrent events as explained in Section 2.1.
12.4.4
Handling of missing values not related to intercurrent event
No assumptions on the type of missing data will be made (missing completely at random etc.). 
The comparison using McNemar Test required the proportion observed to be in pair, hence the 
analysis will be done on complete-case basis.
12.4.5
Sensitivity analyses for primary endpoint/estimand
None.
12.4.6
Supplementary analysis
None.


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12.4.7
Supportive analyses
In addition to the primary analysis, all the paired proportion will also be analyzed using the 
Liddell’s exact test (Liddell 1983) as supportive analysis. From Table 12-1, the maximum 
likelihood estimate of relative risk (Mantel and Haenszel 1959),  is given as follow:
 = 
.
Null hypothesis:  = 1 versus alternative hypothesis:  ≠1. The test statistic considered,  is 
given as follow:
 =

 + 1
which has a -distribution with degrees of freedom of 2(c+1) and 2b. Two-sided probability 
and 95% confidence interval of estimated relative risk will be presented as well.
12.5
Analysis of secondary endpoints
12.5.1
Efficacy endpoints
Please refer to Section 2 for the secondary objectives. The corresponding secondary variables 
are listed below:
1. Paired numbers of VA (SVT and NSVT in separate), PVC, ICD and ATP over 6 months 
of ACEI/ARB treatment and 6 months of ARNI treatment
2. Change in LVEF from date of treatment initiation over 6 months of ACEI/ARB treatment 
and 6 months of ARNI treatment
3. Change of NYHA level over 6 months of ACEI/ARB treatment and 6 months of ARNI 
treatment
4. Change proportion of NT-proBNP from date of treatment initiation over 6 months of 
ACEI/ARB treatment and 6 months of ARNI treatment
5. Number of hospitalizations for all causes and HF related hospitalizations during 
ACEI/ARB and ARNI treatments
12.5.2
Statistical model, hypothesis, and method of analysis
All the following analysis will be performed on the FAS and PP.
Analysis of change from date of treatment initiation after 6 months of treatment 
for paired quantitative endpoints
Variables involved are number of SVT experienced, number of NSVT experienced, number of 
hourly PVC experienced, number of ICD shocks experienced, number of ATP experienced and 
time duration of NSVT experienced. 
For each variable, a summary table will be reported to show the changes from baseline to Month 
3, and 6 post-indexing and changes from Month 6 to Month 9, and 12 post-indexing date. The 
changes will be summarized by mean, standard error, median, quartiles, minimum and 
maximum.


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The change from date of treatment in interested endpoint after 6 months of each treatment is 
calculated by taking the difference between value recorded at the date of first treatment intake 
and at the date of last treatment intake.
Normality will be checked for the changes calculated, if the data is parametric, paired t-tests 
will be performed; else if the data is non-parametric, Wilcoxon signed-rank test will be used.
Analysis of change from date of treatment initiation after 6 months of treatment 
for continuous endpoints
Variables involved are LVEF, NYHA and NT-proBNP.
For each variable, a summary table will be reported to show the changes from baseline to 
Month 3, and 6 post-indexing and changes from Month 6 to Month 9, and 12 post-indexing date. 
The changes will be summarized by mean, standard error, median, quartiles, minimum and 
maximum.
The change from date of treatment in interested endpoint after 6 months of each treatment is 
calculated by taking the difference between value recorded at the date of first treatment intake 
and at the date of last treatment intake.
Normality will be checked for the changes calculated, if the data is parametric, paired t-tests 
will be performed; else if the data is non-parametric, Wilcoxon signed-rank test will be used.
Other than that, the variables involved before and after the initiation of ARNI will also be 
analyzed using the same statistical method.
Note that NYHA is a qualitative variable, appropriate data transformation (to be described in 
Statistical Analysis Plan) will be used to convert it into quantitative form. 
12.5.3
Safety endpoints
For all safety analyses, the SAF will be used and there will be no formal statistical inference 
analysis. All listings and tables will be presented by treatment group.
Safety summaries (tables and figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
Adverse events
All information obtained on AE will be displayed by treatment group and patient.
The number (and percentage) of patients with treatment-emergent AE (events started after the 
first dose of study medication or events present prior to start of double-blind treatment but 
increased in severity based on preferred term) will be summarized by treatment, primary system 
organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related AE, death, SAE, other 
significant AE leading to discontinuation and AE leading to dose adjustment.


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The number and proportion of patients with AE as described in Section 10.1 will be summarized 
by treatment.
A patient with multiple AE within a primary system organ class is only counted once toward 
the total of the primary system organ class.
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 
from being not suspected to being suspected of study drug relationship, or developed into SAEs 
after the start of the treatment period.
Vital signs
All vital signs data (see Section 8.4.2) will be listed by treatment group, patient, and visit/time 
and if ranges are available, abnormalities (and relevant orthostatic changes) will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data (see Section 8.4.1) will be listed by treatment group, patient, and visit/time 
and if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided by treatment and visit/time. Shift tables will be used to compare baseline to the worst 
on-treatment value.


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12.7
Interim analyses
An interim analysis will be conducted once half of the enrolled patients have completed the 
study.
12.8
Sample size calculation
12.8.1
Primary endpoint
McNemar Test is used in the primary analysis to test for 2 correlated proportions. Approximate 
formula from Machin et al (1997) is used to calculate the minimum size required.
For the proportion of discordant pairs, the following approximate formula is used:
Proportion Discordant = )*(1 −)+) + )+(1 −)*)
where )* and )+ are proportion of patients experiencing the event of interest during ACEI/ARB 
and ARNI treatment period respectively. Over here, both proportions are assumed to be similar 
to de Diego et al (2018)’s study. According to de Diego et al (2018)’s study, SVT (one of the 
VA event) has the following incidence 8/120 and 1/120 during ACEI/ARB and ARNI treatment 
period respectively. Hence, by substitute both into the equation above, proportion discordant 
calculated is 0.0739 after rounding off.
For the difference, a parameter under effect size is approximated by the following formula:
Effect Size = )*(1 −)+) −)+(1 −)*)
and after substituting )* and )+ defined above, the effect size calculated is -0.0583.
Thus, by considering the parameters defined above, power of 0.8 and significance level of 0.05, 
the sample size required is 175. Further consider a dropout rate of 20%, the minimum sample 
size required is 219.
The above calculation is calculated using PASS 11 software’s Test for Two Correlated 
Proportion (McNemar Test) [Differences] procedure.
For proportion of patients had ICD or CRT-D shocks occurrence over 6 months of ACEI/ARB 
and 6 months of ARNI treatment, the above sample size will provide 95% - 98% power to detect 
a proportion difference of 0.075 at two-sided significance level of 0.05. The proportion 
difference is derived from the published literature (de Diego et al 2018).
12.8.2
Power for analysis of selected secondary variables
The following test of secondary variables are part of the global testing strategy.


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For the paired differences of numbers of NSVT, SVT, ICD shocks and ATP over ACEI/ARB 
and ARNI treatment period, the above sample size will provide >95% power to detect mean of 
paired difference of at least -3 and standard deviation of at most 10. These are under the 
assumption of similar patient experiences as de Diego et al (2018)’s study. 
For the change from date of treatment initiation after 6 months of treatment assessed by LVEF 
and NT-proBNP, the above sample size will provide 84% – 91% power to detect a treatment 
difference of 3 numeric values at the two-sided significance level of 0.05, assuming a standard 
deviation of 15.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US CFR 21), and with the ethical principles laid 
down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
participant recruitment procedures (e.g., advertisements) and any other written information to 
be provided to patients. Prior to study start, the investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov, In 
addition, after study completion (defined as last patient last visit) and finalization of the study 
report the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results.
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality control and quality assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures (SOPs) as well as applicable global/local GCP regulations and ICH 
Guidelines.


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Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
de Diego C, González-Torres L, Núñez JM, et al (2018) Effects of angiotensin-neprilysin 
inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection 
fraction patients under continuous remote monitoring of implantable defibrillator devices. 
Heart Rhythm; 15(3):395-402.
ESC Guidelines (2008) ESC Guidelines for the diagnosis and treatment of acute and chronic 
heart failure 2008. Eur Heart J; 29:2388-442.
ESC Guidelines (2013) 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization 
therapy. Europace; 15:1070-118.
Hua W, Zhang S, Zhang LF, et al (2009) Incidence of sudden cardiac death in China –
analysis of 4 regional populations. J Am Coll Cardiol; 54:1110 –8.
Huang J, Yin H, Zhang M, et al (2017) Understanding the economic burden of heart failure in 
China: impact on disease management and resource utilization. J Med Econ; 20(5):549-53.
Hubers SA, Brown NJ (2016) Combined angiotensin receptor antagonism and neprilysin 
inhibition. Circulation;133:1115–24.
Liddell FDK (1983) Simplified exact analysis of case-reference studies: matched pairs; 
dichotomous exposure. J Epidemiol Commun H; 37: 82-4.
Lippert FK, Raffay V, Georgiou M, et al (2010) European Resuscitation Council Guidelines 
for Resuscitation 2010 Section 10. The ethics of resuscitation and end-of-life decisions. 
Resuscitation; 81:1445 –51.
Machin D, Campbell M, Fayes P, et al (1997) Sample Size Table for Clinical Studies. 
Blackwell Science. Malden, MA.
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective 
studies of disease. J Natl Cancer Inst; 22: 719-48.
Martens P, Nuyens D, Rivero-Ayerza M, et al (2019) Sacubitril/valsartan reduces ventricular 
arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced 
ejection fraction. Clin Res Cardiol; 1-9.
Maxwell AE (1970) Comparing the classification of the subjects by two independent judges. 
British Journal of Psychiatry, 116: 651-655.
McMurray JJV, Packer M, Desai AS, et al (2014) Angiotensin–neprilysin inhibition versus 
enalapril in heart failure. N Engl J Med; 371:993-1004.
Moss AJ, Hall WJ, Cannom DS, et al (2009) Cardiac-resynchronization therapy for the 
prevention. N Engl J Med; 361(14):1329-38.
National Center for Cardiovascular diseases (2014) Report on Cardiovascular diseases in 
China 2014. Encyclopedia of China Publishing House. pp. 133-7.


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Sarrias A, Bayes-Genis A (2018) Is sacubitril/valsartan (also) an antiarrhythmic drug? 
Circulation; 138:551-3.
Stuart AA (1955) A test for homogeneity of the marginal distribution in a two-way 
classification. Biometrika, 42: 412-416.
The SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left 
ventricular ejection fractions and congestive heart failure. N Engl J Med; 325:293-302.
van Rees JB, Borleffs CJW, de Bie MK, et al (2011) Inappropriate Implantable Cardioverter-
Defibrillator Shocks: Incidence, Predictors, and Impact on Mortality. J Am Coll Cardiol; 
57(5): 556-62.
Yancy CW, Januzzi Jr. JL, Allen LA, et al (2017) ACC Expert Consensus Decision Pathway 
for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart 
Failure With Reduced Ejection Fraction. J Am Coll Cardiol; 1-30.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:
Hematology
Red blood cell (RBC) count, hemoglobin and hematocrit: >50% increase, >20% decrease
White blood cell (WBC) count: >50% increase, >50% decrease
Platelet: >75% increase, >50% decrease
Blood chemistry
Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST): >150% increase
Blood Urea Nitrogen (BUN), creatinine and uric acid: >50% increase
Total bilirubin and alkaline phosphatase: >100% increase
Creatinine phosphokinase (CPK): >300% increase
Potassium: >20% increase, >20% decrease
Chloride and calcium: >10% increase, >10% decrease

SAP_001.pdf: 
Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
1 
Beijing Novartis Pharma Ltd. 
A multicenter, interventional, open-label and single-arm study to 
investigate the effect of ARNI on ventricular arrhythmia in HFrEF patients 
with ICD or CRT-D 
CLCZ696BCN04 / NCT04491136
Statistical Analysis Plan 
Version: 1.0 
Date: May 25, 2023 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
2 
Approval Page of the Sponsor 
 
A multicenter, interventional, open-label and single-arm study to 
investigate the effect of ARNI on ventricular arrhythmia in HFrEF patients 
with ICD or CRT-D 
 
CLCZ696BCN04 
 
Statistical Analysis Plan 
 
Version: 1.0 
Prepared by: 
 
 
 
 
 
 
 
Date:  
 
 
Study Statistician 
 
 
 
 
Reviewed by:  
 
 
 
 
 
 
Date:  
 
 
Study Statistician 
 
 
 
 
Approved by:  
 
 
 
 
 
 
Date:  
 
 
 
Beijing Novartis Pharma Ltd. 
 
 
 
 
 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
3 
Records of Modification 
Version 
Version Date 
Author 
Description 
1.0 
May 25, 2023 
 
Final 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
4 
Table of contents 
List of Abbreviations ................................................................................................................. 6 
1. 
Introduction ........................................................................................................................ 8 
2. 
Study Objectives ................................................................................................................ 8 
2.1 Primary Objective .......................................................................................................... 8 
2.2 Secondary Objectives ..................................................................................................... 8 
 
 8 
3. 
Study design ....................................................................................................................... 8 
3.1 Patient numbering, treatment assignment, randomization ............................................. 9 
3.1.1 Patient numbering ...................................................................................................... 9 
3.1.2 Treatment assignment, randomization ....................................................................... 9 
3.1.3 Treatment blinding ..................................................................................................... 9 
3.2 Sample Size Calculation................................................................................................. 9 
3.2.1 Primary endpoint ........................................................................................................ 9 
3.2.2 Power for analysis of selected secondary variables ................................................. 10 
3.3 Dose escalation and dose modification ........................................................................ 10 
3.3.1 Dose escalation guidelines ....................................................................................... 11 
3.3.2 Definitions of dose limiting toxicities ...................................................................... 11 
3.3.3 Dose modifications .................................................................................................. 11 
3.4 Interim analyses............................................................................................................ 12 
4. 
Study Endpoints ............................................................................................................... 12 
4.1 Efficacy Endpoints ....................................................................................................... 12 
4.1.1 Primary endpoints .................................................................................................... 12 
4.1.2 Secondary endpoints ................................................................................................ 13 
 13 
 13 
4.2 Safety Endpoints .......................................................................................................... 13 
4.2.1 Duration of exposure and exposure dose ................................................................. 13 
4.2.2 Adverse Events ........................................................................................................ 14 
4.2.3 Laboratory test ......................................................................................................... 16 
4.2.4 12-lead ECG examination ........................................................................................ 17 
4.2.5 Holter ....................................................................................................................... 17 
4.2.6 Echocardiography .................................................................................................... 17 
4.2.7 Vital signs ................................................................................................................ 17 
4.2.8 Physical examination ............................................................................................... 17 
4.2.9 Pregnancy test (only for women of childbearing) .................................................... 17 
4.3 Demographics and Disease Characteristics.................................................................. 17 
4.4 Past and concomitant medication and concurrent treatment ........................................ 17 
4.5 Protocol Deviation and Medication Compliance ......................................................... 18 
5. 
Statistical Hypotheses ...................................................................................................... 18 
6. 
Analysis Datasets ............................................................................................................. 18 
7. 
Statistical Methods ........................................................................................................... 18 
7.1 Overall Statistical Considerations ................................................................................ 18 
7.2 Methods for Data Processing ....................................................................................... 19 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
5 
7.2.1 Early withdrawal and missing data .......................................................................... 19 
7.2.2 Derived and converted data...................................................................................... 21 
7.3 Study Subjects .............................................................................................................. 21 
7.3.1 Subject disposition ................................................................................................... 21 
7.3.2 Protocol deviations ................................................................................................... 21 
7.3.3 Analysis datasets ...................................................................................................... 22 
7.3.4 Demographics and baseline characteristics .............................................................. 22 
7.3.5 Prior and concomitant medications and therapies.................................................... 22 
7.3.6 Treatment compliance .............................................................................................. 22 
7.4 Efficacy Analysis ......................................................................................................... 23 
7.4.1 Efficacy analysis of primary endpoint ..................................................................... 23 
7.4.2 Efficacy analysis of secondary endpoints ................................................................ 24 
 25 
 26 
7.5 Safety Analysis ............................................................................................................. 26 
7.5.1 Drug exposure .......................................................................................................... 26 
7.5.2 Adverse events ......................................................................................................... 26 
7.5.3 Laboratory test results .............................................................................................. 27 
7.5.4 12-lead ECG ............................................................................................................. 27 
7.5.5 Holter ....................................................................................................................... 28 
7.5.6 Echocardiogram ....................................................................................................... 28 
7.5.7 Vital signs ................................................................................................................ 28 
7.5.8 Physical examination ............................................................................................... 28 
7.5.9 Pregnancy test .......................................................................................................... 28 
8. 
References ........................................................................................................................ 29 
9. 
Templates of Statistical Figures and Tables .................................................................... 29 
 
 
 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
6 
List of Abbreviations 
Abbreviation 
Explanation 
ACEI 
Angiotensin-converting enzyme inhibitor 
AE 
Adverse event 
 
 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin receptor blockers 
ARNI 
Angiotensin receptor neprilysin inhibitor 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATP 
Anti-tachycardia pacing 
BID 
Twice a day 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CPK 
Creatinine phosphokinase 
CRT-D 
Cardiac resynchronization therapy-defibrillator 
DLT 
Dose limiting toxicity 
DMP 
Data management plan 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
GCP 
Good Clinical Practice 
HF 
Heart failure 
HFrEF 
Heart failure with ejection fraction decreased 
ICD 
Implantable cardioverter defibrillator 
ICF 
Informed consent form 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
NSVT 
Non-sustained ventricular tachycardia 
NT-proBNP 
N-Terminal prohormone of Brain Natriuretic Peptide 
NYHA 
New York Heart Association 
PVC 
Premature ventricular contraction 
QD 
Once a day 
QTcF 
Fridericia QT correction formula 
RBC 
Red blood cell(s) 
SAE 
Serious adverse event 
SAF 
Safety set 
SD 
Standard deviation 
SVT 
Sustained ventricular tachycardia 
TID 
Three times a day 
ULN 
Upper limit of normal 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
7 
VA 
Ventricular arrhythmia 
VT/VF 
Ventricular tachycardia/fibrillation 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
 
 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
8 
1. Introduction 
This Statistical Analysis Plan, prepared for “A multicenter, interventional, open-label and 
single-arm study to investigate the effect of ARNI on ventricular arrhythmia in HFrEF patients 
with ICD or CRT-D” (protocol number: CLCZ696BCN04) sponsored by Novartis, describes 
in detail the content and methods of statistical analysis. 
This Statistical Analysis Plan is prepared based on the Study Protocol Version 02 dated March 
15, 2022 and Case Report Form (CRF) Version 2.0 dated June 3, 2021. 
2. Study Objectives 
2.1 
Primary Objective 
The primary objective of this study is to assess the proportion of patients with VA events over 
6 months of ACEI/ARB and 6 months of ARNI treatment. 
2.2 
Secondary Objectives 
• 
To assess numbers of occurrences of VA events and ICD or CRT-D shocks over 6 months 
of ACEI/ARB and 6 months of ARNI treatment. 
• 
To compare the changes in LVEF and NYHA level between ACEI/ARB and ARNI 
treatments 
• 
To compare the changes in the NT-proBNP level between ACEI/ARB and ARNI 
treatments 
• 
To compare the healthcare resource utilization of HF patients during ACEI/ARB and 
ARNI treatments 
 
 
 
3. Study design 
This will be a multicenter, interventional, open-label, and prospective single-arm study to 
evaluate the effect of ARNI on VAs in approximately 219 HFrEF patients receiving ICD or 
CRT-D in China. 
After the informed consent process has been conducted and the patient has signed the informed 
consent form, baseline data will be collected. Implanted device data of patients will be collected 
for 12 months. ACEI/ARB therapy will be given to patients for 6 months. Dosage of 
ACEI/ARB will be based on investigator’s discretion and up titrated after 2-4 weeks to the 
maximum dosage the patients can tolerate and according to product label. 
After 6 months, patients using ACEI need to undergo a 36-hr washout period (36-hr washout 
period is not needed for patients using ARB at month 6). Patients will then receive ARNI 
(sponsored by Novartis only for this study) while the dosage of ARNI will be according to 
investigator’s discretion and up titrated to the maximum dosage the patient can tolerate or 200 


Beijing Novartis Pharma Ltd. 
Statistical Analysis Plan 
CLCZ696BCN04 
Version: 1.0 
9 
mg bid as per guideline. Table 3-2 lists the recommended starting dose of ARNI. 
All patients will be followed up for 6 months for each treatment. After patients finalize the trial, 
the investigator will evaluate all patients and produce a report. 
Study flow chart: 
Figure 3-1  
Study design 
 
Abbreviations: ACEI = Angiotensin-converting enzyme inhibitor; ARB = Angiotensin receptor blockers; 
ARNI = Angiotensin receptor neprilysin inhibitor; EOS = End of Study 
Notes: 
*Data collection at Baseline (0), Month 1, Month 3, Month 6, Month 7, Month 9, and Month 12 according 
to the evaluation schedule. 
-Dosage and titration plan of ACEI/ARB and ARNI treatments will be according to investigator’s discretion 
and product label (Please refer to Table 3-1 and Table 3-2). 
-36-hr washout period is not needed for patients using ARB. 
3.1 
Patient numbering, treatment assignment, randomization 
3.1.1 Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No. eight-digit code), that 
is assigned when the patient is first enrolled for screening and is retained as the primary 
identifier for the patient throughout his/her entire participation in the trial. The Patient No. 
consists of the Center Number (Center No. four-digit code) (as assigned by Novartis to the 
investigative site) with a sequential patient number suffixed to it, so that each patient is 
numbered uniquely across the entire database. 
3.1.2 Treatment assignment, randomization 
This is a single-arm study, no treatment assignment will be involved in this study. No 
randomization will be performed in this study. 
3.1.3 Treatment blinding 
Treatment will be open to patients, investigator staff, persons performing the assessments, and 
the clinical trial team (CTT). 
3.2 
Sample Size Calculation 
3.2.1 Primary endpoint 
Baseli
Month 1* 
Month 3* 
Month 6* 
Month 7* 
Month 9* 
Month 12* 
ARNI 
ACEI/ARB 
36-hr 
washout 
period for 
patients 


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McNemar Test is used in the primary analysis to test for 2 correlated proportions. Approximate 
formula from Machin et al (1997) is used to calculate the minimum size required. 
For the proportion of discordant pairs, the following approximate formula is used: 
Proportion Discordant = Pt (1 - Ps) + Ps (1 - Pt) 
where Pt and Ps are proportion of patients experiencing the event of interest during ACEI/ARB 
and ARNI treatment period respectively. Over here, both proportions are assumed to be similar 
to de Diego et al (2018)’s study. According to de Diego et al (2018)’s study, SVT (one of the 
VA event) has the following incidence 8/120 and 1/120 during ACEI/ARB and ARNI treatment 
period respectively. Hence, by substitute both into the equation above, proportion discordant 
calculated is 0.0739 after rounding off. 
For the difference, a parameter under effect size is approximated by the following formula: 
Effect Size = Pt (1 - Ps) + Ps (1 - Pt) 
Pt and Ps after substituting Pt and Ps defined above, the effect size calculated is 0.0583. 
Thus, by considering the parameters defined above, power of 0.8 and significance level of 0.05, 
the sample size required is 175. Further consider a dropout rate of 20%, the minimum sample 
size required is 219. 
The above calculation is calculated using PASS 11 software’s Test for Two Correlated 
Proportion (McNemar Test) [Differences] procedure. 
For proportion of patients had ICD or CRT-D shocks occurrence over 6 months of ACEI/ARB 
and 6 months of ARNI treatment, the above sample size will provide 95% - 98% power to 
detect a proportion difference of 0.075 at two-sided significance level of 0.05. The proportion 
difference is derived from the published literature (de Diego et al 2018). 
3.2.2 Power for analysis of selected secondary variables 
The following test of secondary variables are part of the global testing strategy. 
For the paired differences of numbers of NSVT, SVT, ICD shocks and ATP over ACEI/ARB 
and ARNI treatment period, the above sample size will provide >95% power to detect mean of 
paired difference of at least -3 and standard deviation of at most 10. These are under the 
assumption of similar patient experiences as de Diego et al (2018)’s study. 
For the change from date of treatment initiation after 6 months of treatment assessed by LVEF 
and NT-proBNP, the above sample size will provide 84% – 91% power to detect a treatment 
difference of 3 numeric values at the two-sided significance level of 0.05, assuming a standard 
deviation of 15. 
3.3 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are under 
investigator’s discretion and according to product labels. Up-titration of patient’s drug should 


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be according to the target dose or to the patient’s maximum tolerance level. 
3.3.1 Dose escalation guidelines 
The dosage of ACEI/ARB and ARNI are under Investigator’s discretion according to the 
recommended dosage (Yancy et al 2017) (Table 3-1). The recommended starting dose of ARNI 
for different population is presented in Table 3-2. If the patient is well tolerated, the dose of 
study drug should be up-titrated to next dose level until to target dose. Down-titration of the 
study drug at any time based on the judgment of the Investigator will be allowed with the 
consideration for patient safety and tolerability. 
Table 3-1 Recommended dosage 
Compound 
Initial dose 
Target dosage 
ARNI (Sacubitril/Valsartan) 
50 – 100 mg bid 
200 mg bid 
ACEI 
Enalapril 
2.50 mg bid 
10 mg bid 
Captopril 
6.25 mg tid 
50 mg tid 
Perindopril 
2.00 mg qd 
8 mg qd 
Ramipril 
1.25 mg qd 
10 mg qd 
Benazepril 
2.5 mg qd 
20 mg qd 
ARB 
Candesartan 
4 mg qd 
32 mg qd 
Valsartan 
40 mg bid 
160 mg bid 
Losartan 
25 – 50 mg qd 
150 mg qd 
Table 3-2 Recommended starting dose of ARNI 
Population 
Initial dose 
Moderate or high-dose ACEI (equivalent of enalapril ≥ 10 
mg bid) 
100 mg bid 
Moderate or high-dose ARB (equivalent of valsartan ≥ 80 
mg bid) 
100 mg bid 
Low dose ACEI (equivalent of enalapril < 10 mg bid) 
50 mg bid 
Low dose ARB (equivalent of valsartan < 80 mg bid) 
50 mg bid 
Severe renal impairment (eGFR < 30 mL/min/1.73 m2) 
50 mg bid 
Moderate hepatic impairment (Child-Pugh Class B) 
50 mg bid 
Elderly (age ≥ 75 years) 
50 mg bid 
3.3.2 Definitions of dose limiting toxicities 
A dose limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value 
assessed as unrelated to disease, disease progression, inter-current illness, or concomitant 
medications that occurs when taking study drugs. Dosage of study drugs is according to product 
label. Patients who meet any of the DLTs defined in the product label will be withdrawn from 
this study. 
3.3.3 Dose modifications 


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Dose modifications are according to investigator’s discretions and follow the local product 
label. 
3.4 
Interim analyses 
The interim analysis (IA) and endpoint analysis will be performed in this study. An interim 
analysis will be performed when half of the required sample size (110 patients) have completed 
the 12-month treatment and follow-up period or prematurely withdrawn from study after at 
least one ARNI treatment, aiming at analyzing the study endpoints and safety, as well as re-
evaluating the minimum sample size required. 
For this interim analysis, the efficacy analysis will include efficacy data from 117 eligible 
subjects (i.e., subjects who have used ARNI at least once before freezing of the interim analysis 
data and completed the trial or early withdrawn). 
Other analyses include all data from these 117 subjects and all subjects enrolled before these 
subjects. 
4. Study Endpoints 
4.1 
Efficacy Endpoints 
4.1.1 Primary endpoints 
● 
Assessment of ventricular arrhythmia events 
The proportion of subjects with VA events over 6 months of ACEI/ARB and 6 months of ARNI 
treatment will be statistically summarized. 
Cardiac arrhythmia of ≥ 3 consecutive complexes originating in the ventricles at a rate > 100 
bpm (cycle length: < 600 ms). Ventricular arrhythmia events that will be measured through 
device to determine SVT, NSVT and PVC: 
1. Sustained ventricular tachycardia (SVT) is defined as tachycardia lasting for ≥ 30 seconds 
or with hemodynamic disorder as determined by Holter and/or device. 
2. Non-sustained ventricular tachycardia (NSVT) is defined as recorded by Holter and/or 
device 
3. Premature ventricular contraction (PVC) is defined as an early ventricular depolarization 
as determined by the device, and/or detected by Holter 
● 
Assessment of anti-tachycardia pacing and implantable cardioverter-defibrillator 
shocks 
The proportion of subjects with ATP, ICD, or CRT-D shocks over 6 months of ACEI/ARB and 
6 months of ARNI treatment will be statistically summarized. 
Once VA are detected, ICD can treat with high-energy shocks or ATP. ATP consists of one or 
more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a 
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Subjects with sustained VA events will receive ICD or CRT-D shock therapy. Inappropriate 
shocks may occur in subjects with atrial fibrillation, SVT, or other intracardiac or extra cardiac 
signals. An inappropriate shock is defined as a shock not delivered for VT or VF and ending if 
sinus rhythm is redetected by the ICD. If a subsequent episode started within 5 minutes after 
the previous episode ended, it will be not considered as a new episode (van Rees et al 2011). 
4.1.2 Secondary endpoints 
● 
Number of occurrences of VA 
The episodes of VA events over 6 months of ACEI/ARB and 6 months of ARNI treatment will 
be measured. 
● 
Left ventricular ejection fraction 
Left ventricular ejection fraction (%) will be compared at baseline, Month 6 and EOS. 
● 
NYHA level 
NYHA level will be recorded by investigators and compared at baseline, Month 6 and EOS. 
● 
NT-proBNP 
The measurements of NT-proBNP will be obtained from serum and plasma. Samples will be 
obtained before patients take their morning study drug dose. NT-proBNP (pg/mL) will be 
compared between ACEI/ARB and ARNI treatments at baseline, Month 6 and EOS. 
● 
Number of hospitalizations 
Number of hospitalizations for arrhythmia or HF related hospitalizations will be recorded 
during ACEI/ARB and ARNI treatments. 
 
 
 
 
 
 
4.2 
Safety Endpoints 
4.2.1 Duration of exposure and exposure dose 
In this study, detailed information such as date, time, dose and frequency of administration will 
be recorded in the CRF. The extent of exposure to ACEI/ARB and ARNI will be investigated, 
and the duration of exposure and planned and actual doses will be calculated. 
Duration of exposure  (days) = date of the last dose of the IMP - date of the first dose of the 
IMP + 1 If the subject’s duration of drug exposure is discontinuous, the number of days without 
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Total planned dose (mg) = total planned daily dose recorded in CRF * duration of exposure 
(days). Total actual dose (mg) = total actual daily dose recorded in CRF * duration of exposure 
(days). 
4.2.2 Adverse Events 
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 clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. Abnormal laboratory values or test results constitute AEs 
only if they fulfill at least one of the following criteria: 
• they induce clinical symptoms or signs; 
• they are considered clinically significant 
• they require therapy 
Treatment Emergent Adverse Event 
A treatment emergent adverse event (TEAE) is an adverse event that occurs from the first dose 
of the study drug to 30 days after the last study treatment, or events occurring before the start 
of the treatment period and meeting any of the following three changes, as determined by the 
same preferred term (PT) under the same system organ class (SOC) based on MedDRA coding. 
(1) Events which are present prior to the start of the treatment period but increased in 
severity; 
(2) Events that change from being not suspected to being suspected of study drug 
relationship; 
(3) Events that develop into SAEs after the start of the treatment period. 
The increase in severity described above means that the same PT under the same SOC is present 
before the first administration of the investigational drug, but the severity of the PT during 
treatment is higher than the most severe grade before administration, or a new adverse event 
that occurs during treatment has a more severe grade (the same PT under the same SOC). 
Severity is graded as mild, moderate and severe: 
• Mild: usually transient in nature and generally not interfering with normal activities. 
• Moderate: sufficiently discomforting to interfere with normal activities. 
• Severe: prevents normal activities. 
Treatment emergent adverse events will be counted for the specific treatment period. TEAEs 
in the ACEI/ARB treatment group refers to the adverse events that occur after the subject’s 


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first ACEI/ARB administration and before ARNI administration. If the subject has not taken 
ARNI, TEAEs in the ACEI/ARB treatment group refer to adverse events that occur from the 
subject’s first ACEI/ARB administration to 30 days after the subject’s last ACEI/ARB 
administration. TEAEs in the ARNI treatment group refer to adverse events that occur from 
the subject’s first ARNI administration to 30 days after the subject’s last ARNI administration. 
Pre-treatment events 
Pre-treatment adverse events are defined as those that occur after the signing of the informed 
consent form and before the day of first administration of the investigational drug. 
Drug-related adverse events (adverse reactions) 
An adverse drug reaction (ADR) is a toxic and adverse reaction to a drug. An ADR indicates 
that there is at least a reasonable likelihood of a causality between the drug and an adverse 
event. In this study, the causality between an adverse event and the investigational drug is 
judged according to “suspected” and “not suspected”. “Suspected” adverse events are judged 
as adverse reactions. If the event is due to lack of efficacy or progression of underlying illness 
(i.e. progression of the study indication), the assessment of causality will usually be ‘Not 
suspected.’ 
AEs leading to death 
Adverse events leading to death will be recorded by the investigator on the CRF Adverse 
Events Form. In addition, there is a specialized CRF to record deaths. 
Serious adverse events 
SAEs will be collected between time patient signs ICF until 30 days after the patient has 
discontinued or stopped study treatment. An SAE is defined as any adverse event [appearance 
of (or worsening of any pre-existing)] undesirable sign(s), symptom(s), or medical conditions(s) 
which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of an SAE refers to a reaction in which the patient is 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 is more severe. 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly or birth defect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
○ 
routine treatment or monitoring of the studied indication, not associated with 
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○ 
elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing 
the informed consent. 
○ 
social reasons and respite care in the absence of any deterioration in the 
patient’s general condition. 
○ 
treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of an SAE given above and not resulting in hospital admission. 
• 
is medically significant, e.g. defined as an event that jeopardizes the participant or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately 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. Such 
events should be considered as “medically significant”. Examples of such medical events are: 
allergic bronchospasm that requires intensive treatment in the emergency room or at home, 
blood dyscrasias or convulsions that did not lead to hospitalization or development of 
dependency or abuse. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred. Serious adverse events will be determined by the investigator 
on the original document or certified copy and entered into the CRF. 
Adverse events leading to permanent discontinuation 
In the study, action taken with study drug is drug discontinued or the subject will be withdrawn 
from treatment in response to these AEs. 
4.2.3 Laboratory test 
It will be done at the study site according to the laboratory requirements and standards of the 
study site. Laboratory tests include hematology, blood biochemistry, kidney function, 
biomarkers, and pregnancy tests. 
Category 
Items 
Hematology 
Red blood cells count, white blood cells count, platelet count, 
hemoglobin, hematocrit, and WBC differential 
Blood chemistry 
Potassium, creatinine, glucose, sodium, chloride, calcium, blood urea 
nitrogen, total bilirubin, fractionated bilirubin (if total bilirubin >2x 
ULN), aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase, total protein, albumin, uric acid, cholesterol, 
triglyceride, low density lipoprotein, high density lipoprotein, eGFR, 


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glycosylated haemoglobin 
Kidney function 
Serum creatinine 
Biomarkers 
NT-proBNP 
Pregnancy test 
Serum/urine pregnancy test 
4.2.4 12-lead ECG examination 
The CRF collects the test results of heart rate, RR interval, PR interval, QT interval, QRS 
interval and QTcF interval and their clinical assessments (normal, abnormal with no clinical 
significance, abnormal with clinical significance). 
4.2.5 Holter 
The CRF collects the results of ventricular premature beat, atrial premature beat, mean heart 
rate, ventricular tachycardia, and atrial tachycardia. 
4.2.6 Echocardiography 
The CRF collects the test results of left ventricular ejection fraction (LVEF) (%) and left 
ventricular end-diastolic diameter (LVEDD) (mm). 
4.2.7 Vital signs 
The CRF collects subjects’ mean systolic blood pressure, mean diastolic blood pressure, body 
temperature, heart rate, and respiratory rate measurements and their clinical assessments 
(normal, abnormal with no clinical significance, abnormal with clinical significance). 
4.2.8 Physical examination 
The CRF collects subjects’ skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, limbs, blood vessels, nervous system, rectum, external genitalia, breasts, pelvis, 
and other examinations and their clinical assessments (normal, abnormal with no clinical 
significance, abnormal with clinical significance). 
4.2.9 Pregnancy test (only for women of childbearing) 
The CRF collects subjects’ (women of reproductive age) blood and urine pregnancy test results. 
4.3 
Demographics and Disease Characteristics 
The CRF collects subjects’ date of birth, age, gender, ethnicity, height, weight, and BMI. 
The CRF collects current and past medical history, and history of heart failure. 
4.4 
Past and concomitant medication and concurrent treatment 
The CRF collects the drug name, total daily dose and unit, frequency of administration, route 
of administration, start date, end date, ongoing or not, and indication for prior and concomitant 
medications. 
The CRF collects the name, start date, end date, ongoing or not, and indication of concomitant 
treatments (non-drug concomitant treatments, including surgery). 


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4.5 
Protocol Deviation and Medication Compliance 
Protocol deviations will be recorded by the clinical monitor. 
Medication compliance for ACEI/ARB and ARNI is defined as: total actual dose/total planned 
dose *100%. Overall medication compliance for ACEI/ARB and ARNI will be summarized. 
5. Statistical Hypotheses 
For details, see section 7.4 Efficacy Analysis. 
6. Analysis Datasets 
The analysis data sets of this study are as follows. 
Screened set 
It includes all subjects who have signed the informed consent form. 
Safety Analysis Set, SS 
It includes all subjects who had received at least one dose of study treatment. Analyses will be 
performed according to the study treatment received. The safety analysis set will be used for 
all analyses except the efficacy analysis. 
Efficacy Analysis Set 
It includes SS subjects who have received ARNI at least once and completed 12 months of 
complete treatment and follow-up or who have early withdrawn from the study after receiving 
ARNI at least once. The efficacy analysis set will be used as the primary population to analyze 
the efficacy variables. 
Per Protocol Set, PPS 
It includes subjects in efficacy analysis set who had no major protocol violations, and the PP 
population will be used for efficacy analysis. 
7. Statistical Methods 
7.1 
Overall Statistical Considerations 
All statistical analyses are performed using SAS9.4. 
All subjects related, efficacy related and safety related data should be collected and included 
in the statistical analysis. Notes or descriptive text records are only listed. For other data, 
descriptive statistical analysis would be performed, also statistical inference would be applied 
if needed. 
In the statistical tabulations, screening number of subjects is the universal unique identifier of 
subjects in the study. 
General rules of descriptive statistics: Quantitative variables are described by mean, standard 
deviation, standard error, median, minimum, maximum, Q1 and Q3. Categorical variables are 


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described by number and percentage of each category. Two-sided 95% confidence intervals 
will also be calculated for efficacy endpoints. 
In the laboratory test part and the efficacy analysis part, 2 digits will be retained for the upper 
and lower limits of means and their confidence intervals, 3 digits for standard deviations, and 
2 digits for medians, minimums, maximums, Q1 and Q3. In other parts, 1 digit more than the 
original values can be retained for the upper and lower limits of means and their confidence 
intervals, 2 digits more for standard deviations, and the original value digits for medians, 
minimums, maximums, Q1 and Q3. One decimal place will be retained for percentages and the 
upper and lower limits of their confidence intervals (but for efficacy analysis, 2 decimal places 
will be retained). 
General principles of statistical inference: paired t test and Wilcoxon rank sum test will be used 
to compare quantitative data. McNemar test, exact test (binomial sign test) and Liddell’s exact 
test will be used to compare categorical variables. All statistical tests will be subjected to two-
sided tests (unless otherwise specified), and a P-value less than or equal to 0.05 will be 
considered to indicate a statistically significant difference (unless otherwise specified). 
For values such as “< xxx”, half of the number following the less-than sign will be used to 
summarize and calculate statistics. For values such as “> xxx”, xxx will be used to summarize 
and calculate statistics. For values such as “xx-xx”, the average of the numbers before and after 
“-” will be used to summarize and calculate statistics. P value is rounded to 4 decimal places. 
If P < 0.0001, it is presented as ‘< .0001’; if P > 0.9999, it is presented as ‘> .9999’. 
Baseline definition: Visit 1 data will be used as baseline of ACEI/ARB, and Visit 4 data as 
baseline of ARNI. If Visit 4 data are missing, the last available data before Visit 4 will be used. 
Unless otherwise specified, the statistical description by visit only included the data of 
scheduled visits. For the evaluation involving maximum change, minimum change, 
abnormality, and clinically significant findings, the data of scheduled visits and unscheduled 
visits should be included. 
Adverse events and medical history will be coded using MedDRA (see DMP for the specific 
version number). 
Prior medications and concomitant medications will be coded using WHO Drug Dictionary 
(see DMP for the specific version number). 
7.2 
Methods for Data Processing 
7.2.1 Early withdrawal and missing data 
No missing data will be imputed unless otherwise specified. In case of missing categorical data, 
it will be listed as a missing item. Missing dates for concomitant medications and adverse 
events (AEs) will be imputed. 
Missing dates for concomitant medications will be imputed as follows. Missing dates for 


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concomitant medications will be imputed only to judge the classification (prior/concomitant), 
and the list still shows unimputed dates. 
● 
Starting date of concomitant medication is missing 
1) 
If the year and month are known, the missing day will be imputed as the first day 
of the corresponding month. 
2) 
If only the year is known, the missing month and day will be imputed as January 
1. 
● 
The end date of concomitant medications is missing 
1) 
If the year and month are known, the missing day will be imputed as the last day 
of the corresponding month. 
2) 
If only the year is known, the missing month and day will be imputed as 31 
December. 
The imputed start date of the concomitant medication should not be earlier than the subject’s 
date of birth, and the imputed end date should not be later than the subject’s date of death. The 
imputed start date of the concomitant medication should be earlier than or equal to the end date 
of the concomitant medication. 
Missing dates of AEs are imputed as follows: missing dates of AE are imputed for the purpose 
of AE classification only, and unimputed dates are still displayed when AE-related data listings 
will be generated. 
● 
Missing of start date of AE 
1) 
If the year and month are known and both are earlier than those of the first dose 
of the investigational drug, the last day of the known month will be used for 
imputation. 
2) 
If the year and month are known and equal to the year and month of the first 
administration of the investigational drug, and the end date is missing or equal 
to or later than the date of the first administration of the investigational drug, the 
start date of the AE should be equal to the date of the first administration of the 
investigational drug [date means “xx xx (month day)”]; if the end date is earlier 
than the date of first administration of the investigational drug, the first day of 
the known month will be used for imputation. 
3) 
If the year and month are known and later than those of the first dose of the 
investigational drug, it will be imputed with the first day of the known month. 
4) 
If only the year is known and earlier than that of the first dose of the 
investigational drug, “December 31” will be used for imputation. 
5) 
If only the year is known and same as that of the first dose of the investigational 


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drug, and the end date is missing or the same as or later than the date of the first 
dose, the start date of AE is the date of the first dose of the investigational drug 
(date refers to “month, day”). 
6) 
If only the year is known and later than that of the first dose of the investigational 
drug, it will be imputed with “January 1”. 
7) 
If the year, month, and day are all missing, and the end date is missing or equal 
to or later than the date of first administration of the investigational drug, the 
date of first administration of the investigational drug will be used as the 
corresponding start date. 
8) 
Other conditions are regarded as missing. 
● 
Missing of end date of AE 
1) 
If the year and month are known, it will be imputed with the last day of the 
known month. 
2) 
If only the year is known, it will be imputed with “December 31”. 
3) 
Other conditions are regarded as missing. 
The imputed AE start date should not be earlier than the subject’s date of birth, and the imputed 
AE end date should not be later than the subject’s date of death. The imputed AE end date 
should be later than or equal to the AE start date. 
7.2.2 Derived and converted data 
Except for the calculation of certain study endpoints based on the data collected from CRF, no 
other data are derived or converted. For outliers, data queries are reported to the DM and solved 
or verified before database lock. No special data processing is performed. 
7.3 
Study Subjects 
7.3.1 Subject disposition 
The number of subjects who had signed the informed consent form but not enrolled are 
calculated, making the distinction between screen failures and subjects who do not fail 
screening but are not enrolled. Screen failures and subjects who did not fail screening but are 
not enrolled are listed, providing the reasons. 
Based on safety analysis set, the number and percentage of subjects who had completed and 
early withdrawn from the study are calculated, as well as the number and percentage of subjects 
who early withdrew due to various reasons. Reasons for early withdrawal are listed. 
7.3.2 Protocol deviations 
Based on the safety analysis set, details of subjects with major protocol deviations should be 
listed. 


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7.3.3 Analysis datasets 
Based on the safety analysis set, the number and percentage of subjects included in the efficacy 
analysis set and per protocol set will be calculated. Reasons for non-inclusion are listed. 
7.3.4 Demographics and baseline characteristics 
The analysis is performed based on the SS. 
The age, sex, ethnicity, height, weight, BMI, and other demographic data are statistically 
described. Past medical history, history of present illness, history of heart failure and NYHA 
classification will be statistically described. 
Demographic data, past medical history, history of present illness, history of heart failure, and 
NYHA classification will be listed. 
7.3.5 Prior and concomitant medications and therapies 
The analysis is performed based on the SS. 
The duration of non-investigational drug use will be compared with the duration of study drug 
use, and non-investigational drug use will be divided into prior and concomitant medications. 
Prior medication refers to a non-investigational drug that is started and ended before the first 
dose of study drug. Concomitant medication refers to a non-investigational drug that meets one 
of the following conditions: 
1) 
Starting at or after the first dose of the investigational drug 
2) 
Starting before the first dose of the investigational drug and continuing at or after 
the first dose of the investigational drug. 
The number and percentage of subjects using various drugs will be calculated for prior and 
concomitant medications respectively. The prior and concomitant medications will be listed. 
Concomitant treatments (including all non-drug concomitant treatments such as surgery) will 
be listed. 
7.3.6 Treatment compliance 
The analysis is performed based on the SS. 
The study drug compliance will be described statistically as a quantitative variable. 
 
 


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7.4 
Efficacy Analysis 
7.4.1 Efficacy analysis of primary endpoint 
The analysis will be based on the efficacy analysis set and the per protocol set. 
● 
Proportion of paired patients who developed at least one SVT over 6 months of 
ACEI/ARB and 6 months of ARNI treatment. 
● 
Paired proportion of patients by the occurrence of at least one NSVT over 6 months 
of ACEI/ARB and 6 months of ARNI treatment. 
● 
Paired proportion of patients by the occurrence of at least one PVC over 6 months of 
ACEI/ARB and 6 months of ARNI treatment. 
● 
Paired proportion of patients by the occurrence of at least one ICD or CRT-D shock 
over 6 months of ACEI/ARB and 6 months of ARNI treatment. 
● 
Paired proportion of patients by the occurrence of at least one ATP event over 6 
months of ACEI/ARB and 6 months of ARNI treatment. 
Different hypothesis testing will be done on different types of variables: 
Analysis of paired patient proportion 
Occurrence events to be considered are SVT, NSVT, PVC, ICD or CRT-D shocks and ATP. 
For each of the occurrence event, number of patients with at least one event stratified by 
treatments, will be presented in a 2 × 2 contingency table as follow: 
Table 5-1 Matched pairs 2 × 2 contingency table 
ARNI (case) 
ACEI/ARB (control) 
At least one event 
No event 
Total 
At least one event 
a 
b 
a + b 
No event 
c 
d 
c + d 
Total 
a + c 
b + d 
N = a + b + c + d 
The following statistical hypothesis under 95% significance level will be tested to address the 
primary objective: 
Null hypothesis:  pb= pc versus alternative hypothesis: pb ≠ pc, where pb and pc are b⁄N and c⁄N, 
respectively. The test statistic considered is McNemar Test statistic as follow: 
 
which has a chi-squared distribution with degree of freedom of one. 
However, an exact test (binomial sign test) will be used if the discordant cells have low values 
(b +c < 25). 


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Supportive analyses 
In addition to the primary analysis, all the paired proportion will also be analyzed using the 
Liddell’s exact test (Liddell 1983) as supportive analysis. From Table 5-1, the maximum 
likelihood estimate of relative risk (Mantel and Haenszel 1959), R̂ is given as follow: 
 
Null hypothesis:R̂ = 1 versus alternative hypothesis: R̂ ≠1 The test statistic considered, F is 
given as follow: 
 
which has a F-distribution with degrees of freedom of 2(c+1) and 2b. Two-sided probability 
and 95% confidence interval of estimated relative risk will be presented as well. 
For all primary endpoints, the proportion of patients with at least one event over 3 months of 
ACEI/ARB and 3 months of ARNI treatment will be analyzed. 
7.4.2 Efficacy analysis of secondary endpoints 
The analysis will be based on the efficacy analysis set and the per protocol set. 
● 
Paired numbers of VA (SVT and NSVT in separate), PVC, ICD or CRT-D shocks and 
ATP over 6 months of ACEI/ARB treatment and 6 months of ARNI treatment. 
● 
Change in LVEF from date of treatment initiation over 6 months of ACEI/ARB 
treatment and 6 months of ARNI treatment. 
● 
Change of NYHA level over 6 months of ACEI/ARB treatment and 6 months of ARNI 
treatment. 
● 
Change proportion of NT-proBNP from date of treatment initiation over 6 months of 
ACEI/ARB treatment and 6 months of ARNI treatment. 
● 
Number of hospitalizations for all causes and HF related hospitalizations during 
ACEI/ARB and ARNI treatments. 
● 
Paired numbers of VA (SVT and NSVT in separate), PVC, ICD or CRT-D shocks and 
ATP over 3 months of ACEI/ARB treatment and 3 months of ARNI treatment. 
● 
Number of hospitalizations for all causes and HF related hospitalizations during 3 
months of ACEI/ARB and ARNI treatments. 
Analysis of change from date of treatment initiation after 6 months of treatment (for 
paired quantitative endpoints) 
Variables involved are number of SVT experienced, number of NSVT experienced, number of 
hourly PVC experienced, number of ICD or CRT-D shocks experienced, number of ATP 
experienced and time duration of NSVT experienced, as well as number of hospitalizations for 


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all causes and HF related hospitalizations. 
The number of occurrences or duration of each variable within 3 months and 6 months and 
their changes from baseline will be descriptively analyzed by treatment group and compared 
between groups. The changes will be summarized by mean, standard error, median, quartiles, 
minimum and maximum. Because the baseline and post-treatment device data collection cycles 
are different, data will be standardized on a daily basis before the analysis of changes. 
Normality will be checked for the values of each variable and changes calculated. If the data is 
parametric, paired t-tests will be performed; else if the data is non-parametric, Wilcoxon 
signed-rank test will be used. 
Analysis of change from date of treatment initiation after 6 months of treatment (for 
continuous endpoints) 
Variables involved are LVEF, NYHA and NT-proBNP. 
The values of each variable at visits following 3 months and 6 months of treatment and their 
changes from baseline will be descriptively analyzed by treatment group and compared 
between groups. The changes will be summarized by mean, standard error, median, quartiles, 
minimum and maximum. 
Normality will be checked for the values of each variable and changes calculated. If the data is 
parametric, paired t-tests will be performed; else if the data is non-parametric, Wilcoxon 
signed-rank test will be used. 
NYHA is a qualitative variable, and NYHA level will be subject to Ridit transformation into a 
numerical Ridit value before the above analysis is carried out. The basic idea of Ridit 
transformation is to first determine a standard group (the sum of the frequencies of each 
treatment group of each grade is taken as the standard group), and then obtain the Ridit value 
R of each grade of the standard group. The weighted average of the frequency of each grade in 
each group and the R value of each grade in the standard group will be respectively used to 
obtain the average Ridit value of each group, and then compare between groups. 


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7.5 
Safety Analysis 
7.5.1 Drug exposure 
The analysis is performed based on the SS. 
The exposure to the study drug (duration of exposure, total planned dose, total actual dose) will 
be statistically described and summarized by treatment group and by mean, standard deviation, 
median, minimum, and maximum. 
The number and percentage of patients in each treatment group will be summarized for duration 
of exposure in the following groups. 
● 
< 30 days 
● 
30 days <= duration of exposure <60 days 
● 
60 days <= duration of exposure <90 days 
● 
90 days <= duration of exposure <120 days 
● 
120 days <= duration of exposure <150 days 
● 
150 days <= duration of exposure <180 days 
● 
Duration of exposure >=180 days 
7.5.2 Adverse events 
The analysis is performed based on the SS. The safety summary only analyzes data during 


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treatment. 
The overall occurrence of adverse events during treatment will be summarized by treatment 
group, and the overall incidence of adverse events during various treatment periods will be 
calculated. The number and percentage (%) of subjects (n) with treatment emergent adverse 
events, treatment emergent serious adverse events, drug-related treatment emergent adverse 
events, treatment emergent adverse events leading to withdrawal from treatment, and treatment 
emergent adverse events leading to death will be summarized. A separate summary of deaths 
will also be provided, including the number of deaths during and after treatment. Upon 
calculating the frequency and percentage of subjects that experienced adverse events, if a 
subject developed multiple adverse events in the same classification, it would be counted once. 
Among treatment emergent adverse events, the number (n) and percentage (%) of subjects with 
various adverse events by system organ class (SOC) and preferred term (PT) thereunder will 
be calculated by each treatment group. These include treatment emergent adverse events, 
serious adverse events, drug-related adverse events, and adverse events leading to withdrawal 
from treatment. For the calculation of the number and percentage of subjects, if a subject had 
multiple adverse events of the same SOC and PT, only one event will be counted. 
Among treatment emergent adverse events, the incidence (number and percentage of subjects) 
of various treatment emergent adverse events and drug-related adverse events will be 
calculated by system organ class (SOC), preferred term (PT), and severity (mild, moderate, 
severe). If a subject had multiple adverse events with the same preferred term, such event is 
counted only once within such preferred term, and the event with the highest severity is counted. 
System organ class (SOC) and/or preferred term (PT) will be presented in a descending order 
of incidence in the ARNI treatment group and incidence in the ACEI/ARB treatment group. 
All adverse events, serious adverse events, and adverse events leading to withdrawal from 
treatment will be listed separately. A detailed list describing details of subject deaths will be 
provided. 
7.5.3 Laboratory test results 
The analysis is performed based on the SS. 
From baseline, the quantitative laboratory tests results of each visit and their changes from 
baseline will be calculated and summarized in descriptive statistics. Pre-treatment and post-
treatment laboratory test results are classified into abnormal with clinical significance, 
abnormal with no clinical significance, normal and not tested in an order of abnormal with 
clinical significance > abnormal with no clinical significance > normal > not tested, and then a 
shift table will be generated. 
The listing for all abnormal findings in laboratory data will be provided. 
7.5.4 12-lead ECG 


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The analysis is performed based on the SS. 
The 12-lead ECG results and their changes from baseline are statistically described by visit. 
The pre-treatment and post-treatment ECG results are classified in the order of abnormal with 
clinical significance, abnormal with no clinical significance, normal, not examined, and then a 
shift table will be generated. 
12-Lead ECG results of all subjects will be listed. 
7.5.5 Holter 
The analysis will be performed based on the SS. 
The quantitative Holter results and their changes from baseline will be statistically described 
by visit. All Holter results will be tabulated in detail. 
7.5.6 Echocardiogram 
The analysis will be performed based on the SS. 
The echocardiogram results and their changes from baseline will be statistically described by 
visit. The pre-treatment echocardiogram results and post-treatment echocardiogram results will 
be classified in the order of abnormal with clinical significance, abnormal with no clinical 
significance, normal, not examined, and then a shift table will be generated. 
All echocardiogram results will be listed. 
7.5.7 Vital signs 
The analysis will be performed based on the SS. 
From baseline, the mean systolic blood pressure, mean diastolic blood pressure, body 
temperature, heart rate and respiratory rate at each visit and their changes from baseline will 
be statistically described. 
The pre-treatment vital sign results and post-treatment vital sign results will be classified into 
abnormal with clinical significance, abnormal with no clinical significance, normal and not 
tested in an order of abnormal with clinical significance > abnormal with no clinical 
significance > normal > not tested, and then a shift table will be generated. 
All vital sign results will be tabulated. 
7.5.8 Physical examination 
The analysis will be performed based on the SS. 
All physical examination results will be tabulated. 
7.5.9 Pregnancy test 
The analysis will be performed based on the SS. 
All pregnancy test results will be tabulated. 


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Statistical Analysis Plan 
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8. References 
(1) Guidelines on Biostatistics in Clinical Trials 
(2) Guidelines on Planning and Reporting of Clinical Trial Data Management and 
Statistical Analysis 
(3) CLCZ696BCN04_Protocol_01_20200508_CN.pdf 
(4) CLCZ696BCN04_Protocol_02_Clean Version_CN.pdf 
9. Templates of Statistical Figures and Tables 
Details are provided in separate documents CLCZ696BCN04 Mock-up Shell_V1.0.rtf and 
CLCZ696BCN04 Mock-up Shell_16.2 listing_V1.0.docx