Conditions: Acute Myocardial Infarction
Keywords: Spontaneous AMI HF hospitalization outpatient HF LV systolic dysfunction pulmonary congestion STEMI NSTEMI randomized clinical trial LCZ696 ramipril
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5669
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily.

Detailed description:
The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily, in addition to conventional post-AMI treatment, in reducing the occurrence of composite endpoint of CV death, HF hospitalization and outpatient HF (time-to-first event analysis) in post-AMI patients with evidence of LV systolic dysfunction and/or pulmonary congestion, with no known prior history of chronic HF.

Arms:
arm 1: Following randomization, patients will receive LCZ696 in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily).

Patients will be required to take a total of two pills, (one tablet from the LCZ696 pack and one capsule from ramipril matching placebo pack) twice a day for the duration of the study.

Patients randomized to LCZ who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will receive a valsartan bridge for one day. These patients will receive two doses of valsartan for 1 day in a blinded manner prior to beginning double-blind LCZ696 treatment. arm 2: Following randomization, patients will receive the Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily).

Patients will be required to take a total of two pills, (one capsule from the ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study.

Patients randomized to ramipril who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will immediately start on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients will receive two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo.

Interventions: intervention 1: LCZ696 (sacubitril/valsartan) intervention 2: Ramipril intervention 3: Placebo of LCZ696 intervention 4: Placebo of ramipril intervention 5: Valsartan intervention 6: Placebo of valsartan
Intervention descriptions: intervention 1: LCZ696 (sacubitril/valsartan) tablet will be available in 24/26 mg, 49/51 mg and 97/103 mg, respectively intervention 2: Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules intervention 3: Matching placebo of LCZ696 tablets intervention 4: Matching placebo of ramipril capsule intervention 5: Valsartan (VAL489) 40 mg and 80 mg tablets, two doses for 1 day to patients who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization intervention 6: matching placebo of valsartan for one day to patients who will be randomized to received ramipril

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
[LCZ696]
Clinical Trial Protocol LCZ696G2301 / NCT02924727
PARADISE-MI:  Prospective ARNI versus ACE inhibitor trial to 
DetermIne Superiority in reducing heart failure Events after 
Myocardial Infarction
A multi-center, randomized, double-blind, active-controlled, parallel-
group Phase 3 study to evaluate the efficacy and safety of LCZ696 
compared to ramipril on morbidity and mortality in high risk 
patients following an acute myocardial infarction
Document type:
Clinical Trial Protocol
EUDRACT number:
2016-002154-20
Version number:
00 (Original Protocol)
Clinical trial phase:
III
Release date:
18-May-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................18
2
Study objectives and endpoints .........................................................................................19
2.1
Primary objective(s)...............................................................................................19
2.2
Secondary objective(s)...........................................................................................19
19
3
Investigational plan ...........................................................................................................20
3.1
Study design...........................................................................................................20
3.2
Rationale for study design .....................................................................................24
3.3
Rationale for dose/regimen, route of administration and duration of treatment....24
3.4
Rationale for choice of comparator .......................................................................25
3.5
Purpose and timing of interim analyses/design adaptations..................................25
3.6
Risks and benefits..................................................................................................25
4
Population..........................................................................................................................26
4.1
Inclusion criteria ....................................................................................................26
4.2
Exclusion criteria...................................................................................................27
5
Treatment...........................................................................................................................29
5.1
Study treatment......................................................................................................29
5.1.1
Investigational and control drugs..........................................................29
5.1.2
Additional treatment..............................................................................30
5.2
Treatment arms ......................................................................................................30
5.3
Treatment assignment and randomization.............................................................30
5.4
Treatment blinding.................................................................................................30
5.5
Treating the patient................................................................................................31
5.5.1
Patient numbering, ................................................................................31
5.5.2
Dispensing the study drug.....................................................................31
5.5.3
Handling of study and additional treatment..........................................32
5.5.4
Instructions for prescribing and taking study treatment........................32


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........33
5.5.6
Rescue medication ................................................................................35
5.5.7
Concomitant medication .......................................................................35
5.5.8
Prohibited medication ...........................................................................36
5.5.9
Emergency breaking of assigned treatment code..................................37
5.6
Study Completion and Discontinuation.................................................................37
5.6.1
Study completion and post-study treatment..........................................37
5.6.2
Discontinuation of Study Treatment .....................................................38
5.6.3
Withdrawal of informed consent...........................................................39
5.6.4
Loss to follow-up ..................................................................................39
5.6.5
Early study termination by the sponsor.................................................39
6
Visit schedule and assessments .........................................................................................39
6.1
Information to be collected on screening failures..................................................45
6.2
Patient demographics/other baseline characteristics .............................................45
6.3
Treatment exposure and compliance .....................................................................45
6.4
Efficacy..................................................................................................................45
6.4.1
Efficacy assessment 1 ...........................................................................45
6.4.2
Efficacy assessment 2 ...........................................................................46
6.4.3
Appropriateness of efficacy assessments..............................................46
6.5
Safety.....................................................................................................................47
6.5.1
Physical examination ............................................................................47
6.5.2
Vital signs..............................................................................................47
6.5.3
Height and weight .................................................................................47
6.5.4
Laboratory evaluations..........................................................................47
6.5.5
Electrocardiogram (ECG) .....................................................................49
6.5.6
Pregnancy and assessments of fertility .................................................49
6.5.7
Angioedema ..........................................................................................50
6.5.8
Appropriateness of safety measurements..............................................50
50
50
51
51
7
Safety monitoring ..............................................................................................................52
7.1
Adverse events.......................................................................................................52
7.2
Serious adverse events...........................................................................................54
7.2.1
Definition of SAE .................................................................................54


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7.2.2
SAE reporting........................................................................................54
7.3
Protocol specific unblinding rules for SUSARs that are also efficacy 
endpoints................................................................................................................55
7.3.1
Primary and secondary endpoints .........................................................55
7.3.2
Adverse events that are commonly seen in the study population .........56
 
57
7.4
Liver safety monitoring .........................................................................................57
7.5
Reporting of study treatment errors including misuse/abuse ................................58
7.6
Pregnancy reporting...............................................................................................59
7.7
Monitoring of safety data by the Data Monitoring Committee .............................59
8
Data review and database management.............................................................................59
8.1
Site monitoring ......................................................................................................59
8.2
Data collection.......................................................................................................60
8.3
Database management and quality control............................................................60
8.4
Data Monitoring Committee..................................................................................61
8.5
Adjudication Committee........................................................................................61
9
Data analysis......................................................................................................................62
9.1
Analysis sets ..........................................................................................................62
9.2
Patient demographics and other baseline characteristics.......................................62
9.3
Treatments .............................................................................................................63
9.4
Analysis of the primary variable(s) .......................................................................63
9.4.1
Variable(s).............................................................................................63
9.4.2
Statistical model, hypothesis, and method of analysis..........................64
9.4.3
Handling of missing values/censoring/discontinuations.......................65
9.4.4
Sensitivity analyses ...............................................................................66
9.5
Analysis of secondary variables ............................................................................66
9.5.1
Efficacy variables..................................................................................66
68
68
69
69
69
70
9.7
Interim analyses .....................................................................................................70
9.8
Sample size calculation..........................................................................................71
10 Ethical considerations........................................................................................................73


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10.1
Regulatory and ethical compliance........................................................................73
10.2
Informed consent procedures.................................................................................74
10.3
Responsibilities of the investigator and IRB/IEC..................................................74
10.4
Publication of study protocol and results...............................................................75
10.5
Quality Control and Quality Assurance.................................................................75
11 Protocol adherence ............................................................................................................75
11.1
Protocol Amendments ...........................................................................................75
12 References .........................................................................................................................76
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................79
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................80
15 Appendix 3:  Killip Classification.....................................................................................82
16 Appendix 4: Guidelines for the management of blood pressure .......................................83
17 Appendix 5: Treatment guidelines for hyperkalemia (serum potassium greater than 
5.3 mmol/L [mEq/L]) ........................................................................................................84
List of tables
Table 3-1
Study drug dose levels during treatment epoch ....................................21
Table 3-2
Total daily doses of commonly used ACE inhibitors and ARBs 
corresponding to dose level 2 of study drug .........................................22
Table 3-3
Safety monitoring criteria that must be met for dose uptitration ..........23
Table 5-1
Study drug dispensed during the treatment epoch by study visit..........33
Table 5-2
Prohibited medication ...........................................................................36
Table 6-1
Assessment schedule.............................................................................41
Table 6-2
Routine laboratory examinations ..........................................................48
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................59
Table 9-1
Cumulative event rates assumed for the sample size calculation .........71
Table 9-2
Total sample size required to achieve 800 primary events for 
different event rate assumptions............................................................72
Table 9-3
Summary of power to reject secondary hypotheses..............................73
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................80
Table 14-2
Follow-up Requirements for Liver Events and Laboratory Triggers....80
List of figures
Figure 3-1
Study design..........................................................................................20


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Figure 3-2
Study drug initiation and up-titration in PARADISE-MI.....................22


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List of abbreviations
ACE
Angiotensin converting enzyme 
ACEi
Angiotensin converting enzyme inhibitor
AE
Adverse Event
AESI
Adverse event of special interest
ALB
Albumin
ALP
Alkaline phosphatase
ALT
Alanine Aminotransferase
AMI
Acute myocardial infarction
ARB
Angiotensin receptor blocker
ARNI
Angiotensin receptor neprilysin inhibitor
AST
Aspartate aminotransferase
AUC
Area under the curve
BB
Beta blocker
bid
twice a day
BMI
Body mass index
BNP
B-type natriuretic peptide
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CCB
Calcium channel blocker
CCU
Coronary/critical care unit
CEC
Clinical Event Committee
CFR
US Code of Federal Regulations 
CDS
Core Data Sheet (for marketed drugs) 
CEC
Clinical Event Committee
CHF
Chronic heart failure
COPD
Chronic obstructive pulmonary disease
CPO
Country Pharma Organization
CRF
Case Report/Record Form 
eCRF
Electronic Case Report/Record Form
CRT
Cardiac resynchronization therapy 
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Terminology Criteria
CTRD 
Clinical Trial Results Database 
CV
Cardiovascular
DBP
Diastolic blood pressure
DM
Diabetes mellitus
DMC
Data Monitoring Committee


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DS&E
Drug Safety & Epidemiology
EC
Ethics Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EF
Ejection fraction
eGFR
Estimated glomerular filtration rate
EOS
End of study
ER
Emergency room
ESRD
End stage renal disease
FAS
Full analysis set
FDA
Food and Drug Administration 
FWER
FamilyWise Error Rate
GCP
Good Clinical Practice
hCG
Human chorionic gonadotropin
HF
Heart failure
HFpEF
Heart failure with preserved ejection fraction
HFrEF
Heart failure with reduced ejection fraction
Hgb
Hemoglobin
hsTnT
High-sensitivity troponin T
HTN 
Hypertension
IA
Interim analysis
IB
Investigator brochure
ICD
Implantable cardioverter defibrillator
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICU
Intensive care unit
IEC
Independent Ethics Committee
IN
Investigator notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine system
iv
Intravenous
LFT
Liver function test 
LV
Left ventricular
LVAD
Left ventricular assist device
LVEF
Left ventricular ejection fraction 
LVH
Left ventricular hypertrophy
MACE
Major Adverse Cardiac Events
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume


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MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities 
MI
Myocardial infarction
MMRM
Mixed model of repeated measurements 
MRA
Mineralocorticoid antagonist
NEP
Neprilysin
NEPi
Neprilysin inhibitor
NSTEMI
Non-ST-elevation myocardial infarction
NT-proBNP
N-terminal pro-brain natriuretic peptide
OC/RDC
Oracle Clinical/Remote Data Capture 
od
once a day
PCI
Percutaneous coronary intervention
PDE-5
Phosphodiesterase-5
po
oral(ly)
PRO
Patient reported outcomes
PT
Preferred term
RAS
Renin angiotensin system 
RBC
Red blood cell
RDW
Red blood cell distribution width
RRR
Relative risk reduction 
SAE
Serious Adverse Event
SBP
Systolic blood pressure
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SMQ
Standardized MedDRA Query
STEMI
ST-elevation myocardial infarction
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TD
Study Treatment Discontinuation
ULN
Upper limit of normal
WBC
White blood cell
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of patients fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug(s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
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Protocol summary
Protocol number
LCZ696G2301
Title
A multi-center, randomized, double-blind, active-controlled, parallel-group 
Phase 3 study to evaluate the efficacy and safety of LCZ696 compared to 
ramipril on morbidity and mortality in high risk patients following an acute 
myocardial infarction
Brief title
PARADISE-MI:  Prospective ARNI versus ACE inhibitor trial to DetermIne 
Superiority in reducing heart failure Events after Myocardial Infarction
Sponsor and Clinical 
Phase
Novartis; Phase III
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this study is to evaluate the efficacy and safety of 
LCZ696 compared to ramipril, in reducing the occurrence of cardiovascular 
(CV) death, heart failure (HF) hospitalization and outpatient HF (time-to-first 
event analysis) in post-AMI patients with evidence of left ventricular (LV)
systolic dysfunction and/or pulmonary congestion, without a known prior 
history of chronic HF.   
This is an event-driven study which is a well-established study design for 
long-term cardiovascular outcome trials in post-acute myocardial infarction 
(AMI) patients. While the composite of CV death or HF hospitalization is a 
well-established mortality and morbidity endpoint, the addition of the 
outpatient HF component, which in this study represents the confirmed 
diagnosis of new onset symptomatic HF, aims to capture the clinically 
important outpatient event that contributes to the totality of HF morbidity 
following an AMI presenting as either inpatient (i.e., HF hospitalization) or 
outpatient (i.e., outpatient HF) events.   
Ramipril is chosen as an active comparator of the study representing the 
guideline-recommended standard-of-care angiotensin converting enzyme 
(ACE) inhibitors shown to improve survival and reduce HF morbidity in 
high-risk post-AMI patients.
Primary Objective(s) 
To demonstrate that LCZ696 is superior to ramipril in delaying the time-to-
first occurrence of the composite endpoint of CV death, HF hospitalization 
or outpatient HF* in patients with LV systolic dysfunction and/or pulmonary 
congestion following an AMI.
(*The outpatient HF endpoint event is defined as an adjudicated event of 
clinical development of symptomatic HF (either urgent/unscheduled or non-
urgent) in the outpatient setting with symptoms and signs requiring 
initiation/intensification of intravenous or qualifying oral HF treatment.)
Secondary Objectives

To demonstrate the superiority of LCZ696, compared to ramipril, in
delaying the time-to-first occurrence of CV death or HF hospitalization 

To demonstrate the superiority of LCZ696, compared to ramipril, in 
delaying the new onset of symptomatic HF defined as time-to-first 
occurrence of HF hospitalization or outpatient HF

To demonstrate the superiority of LCZ696, compared to ramipril, in 
delaying the time-to-first occurrence of CV death, non-fatal
spontaneous MI or non-fatal stroke 


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
To demonstrate the superiority of LCZ696, compared to ramipril, in 
reducing the rate of the composite endpoint of CV death and total (first 
and recurrent) hospitalizations  due to HF, non-fatal spontaneous MI or 
non-fatal stroke

To demonstrate the superiority of LCZ696, compared to ramipril, in 
delaying the time to all-cause mortality

To evaluate the safety and tolerability of LCZ696 compared to ramipril
Study design
This study is a multicenter, randomized, double-blind, active controlled, 
event-driven phase III clinical trial designed to evaluate the efficacy and 
safety of LCZ696 compared to ramipril when added to standard therapy in 
post-AMI patients with LV systolic dysfunction and/or pulmonary congestion
over a period of approximately 32 months.
The study is event-driven and will continue until the requirement of total 
confirmed endpoint events, i.e., 800 primary composite endpoint events 
and 633 CV death or HF hospitalization events, has been achieved.
Population
Approximately 4,650 male and female high risk patients ≥18 who have 
sustained a spontaneous acute myocardial infarction (ST segment 
elevation MI (STEMI) or non-ST segment elevation MI (NSTEMI) within the 
last 12 hours to 7 days prior to randomization) with evidence of LV systolic 
dysfunction and/or pulmonary congestion associated with index MI. In 
addition, patients have to have at least one predefined risk factor and 
without known prior history of chronic HF.  
Key Inclusion criteria
1.
Written informed consent must be obtained before any assessment is 
performed. 
2.
Male or female patients ≥ 18 years of age. 
3.
Diagnosis of spontaneous AMI based on the universal myocardial 
infarction (MI) definition* with randomization to occur between 12 hours 
and 7 days after index event presentation**.  
Spontaneous AMI is defined when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischemia due to 
primary coronary event. Under these conditions, the following criteria 
have to be met for the diagnosis of spontaneous AMI:

Detection of rise and/or fall of cardiac enzymes (cardiac troponin, 
cTn or the MB fraction of creatinine kinase, CKMB) with at least 
one value above the 99th percentile of the upper reference limit 
(URL) or the local laboratory MI diagnosis cut-off value, together 
with evidence of myocardial ischemia with at least one of the 
following:
•
Ischemic discomfort or other ischemia symptom(s)
•
Electrocardiogram (ECG) characteristics of STEMI or 
NSTEMI including new or presumably new significant ST-
segment-T wave (ST-T) changes
•
Newly developed pathological Q waves or left bundle 
branch block (LBBB) in the ECG
(*Patients with a spontaneous MI event determined to be secondary to 
another medical condition such as anemia, hypotension, or an 
arrhythmia OR thought to be caused by coronary vasospasm with 
documented normal coronary arteries are not eligible)
4. Evidence of LV systolic dysfunction and/or pulmonary congestion 
requiring intravenous treatment associated with the index MI event 
defined as:


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
Left ventricular ejection fraction (LVEF) ≤40% assessed locally by 
echocardiography, magnetic resonance imaging, cardiac CT, 
radionuclide or contrast ventriculography after index MI 
presentation** and prior to randomization.
(These examinations may be performed as part of patient standard-of-
care. In case multiple LVEF measurements have been performed during 
index event, the last one performed prior to randomization should be 
considered as the qualifying measurement), and/or

Pulmonary congestion requiring intravenous treatment during the 
index hospitalization supported by clinical assessment (worst Killip 
class, II or above) or radiological findings.  Radiological evidence of 
pulmonary congestion is defined as pulmonary venous congestion 
with interstitial or alveolar edema and must be supported by at 
least one chest X-ray or CT scan.   
(**Index MI presentation is the time of patient presentation at either the 
ER/ED, ICU/CCU or hospital ward etc., at study center, for the 
treatment of the index MI.)
5.
At least one of the following 8 risk factors: 

Age ≥ 70 years

eGFR <60 mL/min/1.73 m2 based on Modification of Diet in Renal 
Disease (MDRD) formula at screening visit

Type I or II diabetes mellitus

Documented history of prior MI supported by ECG changes and/or 
elevation of cardiac enzymes consistent with MI diagnosis.

Atrial fibrillation as noted by ECG, associated with index MI

LVEF < 30% associated with index MI

Worst Killip class III or IV associated with index MI requiring 
intravenous treatment

STEMI without reperfusion therapy within the first 24 hours after 
presentation
6.
Hemodynamically stable defined as: 

Systolic blood pressure (SBP) ≥ 100 mmHg at randomization for 
patients who received ACE inhibitor/angiotensin receptor blocker 
(ARB) during the last 24 hours prior to randomization  (ACE 
inhibitor/ARB Yes patients)

SBP ≥ 110 mmHg at randomization for patients who did not receive 
ACE inhibitor/ARB during the last 24 hours prior to randomization 
(ACE inhibitor/ARB No patients)

No intravenous treatment with diuretics, vasodilators, vasopressors 
and/or inotropes during the last 24 hours prior to randomization.
Key Exclusion criteria
1.
Known history of chronic HF prior to randomization
2.
Cardiogenic shock within the last 24 hours prior to randomization
3.
Persistent clinical HF at the time of randomization 
4.
Coronary artery bypass graft (CABG) performed or planned for index 
MI
5.
Clinically significant right ventricular MI as index MI
6.
Symptomatic hypotension at screening or randomization
7.
Patients with a known history of angioedema
8.
Stroke or transient ischemic attack within one month prior to 


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randomization
9.
Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy
11. Open-heart surgery performed within one month prior to randomization 
or planned cardiac surgery within the 3 months after randomization
12. eGFR < 30 ml/min/1.73 m2 as measured by the Modification of Diet in
Renal Disease (MDRD) formula at screening
13. Serum potassium > 5.2 mmol /L at screening
14. Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL 
or increased ammonia levels, if performed), or history of cirrhosis with 
evidence of portal hypertension such as varices
15. Previous use of LCZ696 or EntrestoTM
16. Use of other investigational drugs within 30 days prior to screening
17. History of hypersensitivity to the study drugs or drugs of similar 
chemical classes
18. Known intolerance or contraindications to study drugs or drugs of 
similar chemical classes including ACE inhibitors, ARB or NEP 
inhibitors
19. Patients taking medications prohibited by the protocol that cannot be 
discontinued for the duration of the study
20. History of malignancy of any organ system (other than localized basal 
cell carcinoma of the skin) within the past 3 years with a life expectancy 
of less than 1 year
21. Any surgical or medical condition which might significantly alter the 
absorption, distribution, metabolism, or extraction of study drug at 
investigators’ discretion
22. History or evidence of drug or alcohol abuse within the last 12 months
23. Patients considered unsuitable for the study, including patients with 
psychiatric, behavioral or cognitive disorders, sufficient to interfere with 
the patient’s ability to understand and comply with the protocol 
instructions or follow-up procedures
24. 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 
25. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using basic methods of 
contraception during dosing of investigational drug
Study treatment
LCZ696*
50 mg (dose level 1), 100 mg (dose level 2) and 200 mg (dose level 3)
twice daily
(* LCZ696 dose levels 1, 2 and 3 are equivalent to sacubitril/valsartan 
24/26 mg, 49/51 mg and 97/103 mg, respectively)
Ramipril 
1.25 mg (dose level 1), 2.5 mg (dose level 2), and 5 mg (dose level 3) twice 
daily
Valsartan (VAL489)**
40 mg (dose level V1) and 80 mg (dose level V2) twice daily for one day
(** Patients who are randomized to LCZ696 and received ACE inhibitors in 
last 36 hours prior to randomization will be given a valsartan bridging in a 


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blinded manner for one day with two doses at dose level V1 or V2: 40 or 80 
mg twice daily, prior to beginning the double-blind LCZ696 treatment)
Efficacy assessments

CV death, 

Heart failure hospitalization 

Outpatient heart failure

Non-fatal spontaneous MI 

Non-fatal stroke

All-cause mortality
Key safety 
assessments

All adverse events (AE)s for the first two weeks

All suspected AEs 

AEs of special interest (Section 7.1)

AEs leading to a change in dose (down titration) or discontinuation of 
study medication

All serious adverse events (SAEs)

Sitting systolic blood pressure (SBP), sitting diastolic blood pressure 
(DBP), and heart rate 

Laboratory values (including monitoring for hyperkalemia, renal 
dysfunction)

Angioedema surveillance
Other assessments


 


 



 

 


 


,

Data analysis
The primary efficacy variable is time to first occurrence of CV death, HF 
hospitalization or outpatient HF. 
The secondary efficacy variables are:

Time to first occurrence of CV death or HF hospitalization

Time to first occurrence of HF hospitalization or outpatient HF 
(censoring will occur at the time of all-cause death)

Time to first occurrence of CV death,  non-fatal spontaneous MI or non-
fatal stroke

Cumulative number of events, including HF hospitalization, 
hospitalization due to non-fatal spontaneous MI, hospitalization due to 
non-fatal stroke and CV death. 

Time to all-cause mortality


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Time-to-event is computed as the number of days from randomization to 
the start date of the endpoint event (first occurrence).
The primary endpoint will be analyzed using a Cox proportional hazards 
model stratified by STEMI/NSTEMI, with Treatment, PCI use at baseline 
and region included as factors in the model. The hazard ratio for LCZ696 
vs. ramipril, the associated 2-sided 95% confidence interval and the 1-
sided and 2-sided p-values will be presented from the analysis.
The primary endpoint and the first four secondary endpoints will be 
included in a hierarchical statistical testing strategy to control the familywise 
type I error rate at the 1-sided 2.5% level (in the strong sense). 
One interim analysis for efficacy is planned when approximately two-thirds 
of the target number of primary adjudicated events has been obtained.
Sample size calculation: 
A sample size of 4,650 patients, randomized to LCZ696:ramipril using a 1:1 
allocation ratio, has been chosen with the aim to obtain at least 800 first 
primary events and at least 633 CV death or HF hospitalization events in 
this event-driven study.  Eight hundred primary events provide at least 80% 
power assuming a true Relative Risk Reduction (RRR) of 18% (i.e. a 
hazard ratio of 0.82) for LCZ696 vs. ramipril with statistical testing at the 
overall 2.5% 1-sided type I error rate (with strong control of the FWER).  
Six hundred and thirty three CV death or first HF hospitalization events will 
provide at least 80% nominal power assuming a true RRR of 20% (for the 
intent-to-treat analysis) for this secondary endpoint for the same type I error 
rate. These calculations assume a 24 month recruitment period and 8 
month follow-up of the last randomized patient.
Key words
Spontaneous AMI, HF hospitalization, outpatient HF, LV systolic 
dysfunction, pulmonary congestion, STEMI, NSTEMI, randomized clinical 
trial, LCZ696, ramipril


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1
Introduction
1.1
Background 
Acute myocardial infarction (AMI) is one of the common reasons for cardiac hospitalization 
and its annual incidence in US, EU-5, Japan and China is currently estimated at 2.5 million 
per year. In the US alone, approximately 683,000 patients were discharged from hospitals in 
2009 with a diagnosis of acute coronary syndrome (O’Gara, et al 2013). Although the 
community incidence rates for ST elevation myocardial infarction (STEMI) have declined 
over the past decade, those for non-ST-elevation myocardial infarction (NSTEMI) have 
increased. The overall incidence rate of AMI is expected to continuously increase in the next 
decades due to an ageing population and global rise in diabetes (Mozaffarian, et al 2015).
The in-hospital mortality of post-AMI patients has decreased in several parts of the world as a 
result of more frequent use of reperfusion strategies.  Due to increasing numbers of post-AMI 
survivors, the prevalence of developing heart failure (HF), a frequent complication following 
an AMI, has increased worldwide (Jhund and McMurray 2009; Sulo, et al 2016). For example, 
of 63,853 patients discharged alive from their first AMI without a diagnosis of HF during 
2001-2009 in The Cardiovascular Disease in Norway Registry (CVDNOR), 12.6% of patients 
developed HF during a median follow-up time of 3.2 years and nearly half of these cases 
occurred within 1 year from the index myocardial infarction (MI) discharge (Sulo, et al 2016). 
In addition, high-risk patients with left ventricular ejection fraction (LVEF) ≤40% following 
an AMI representing approximately 1/4 to 1/3 of the overall post-AMI patient population, are 
known to have significantly greater risk of HF morbidity and mortality (Miller, et al 2012; van 
Diepen, et al 2015; Vasaiwala, et al 2012). In the VALIANT study of high-risk post-AMI 
patients (LVEF ≤40% and/or transient HF signs with no prior history of chronic HF) who
received percutaneous coronary intervention (PCI), approximately 20% of these patients 
experienced cardiovascular (CV) death or HF hospitalization over the approximate 2-year 
follow-up period (Pfeffer, et al 2003; Novartis data analyses on file). These real-world 
registry and controlled clinical trial data underscore the need for additional therapeutic 
approaches to reduce HF-related morbidity and mortality in post-AMI patients.
There are several mechanisms contributing to an unfavorable long-term prognosis in post-
AMI patients. The most notable mechanism underlying the significantly greater risk of HF 
morbidity events following an AMI is pathological cardiac remodeling resulting from the loss 
of myocardium and maladaptive changes in the surviving myocardium. This remodeling 
process with changes in left ventricular (LV) geometry, size, and function is induced by 
altered myocardial loading conditions and dysregulated neurohumoral system (Pfeffer and 
Braunwald, et al 1990; Udelson and Konstam, et al 2002; White, et al 1987). 
Factors triggering cardiac remodeling are activated within hours after an AMI. As supported 
by multiple clinical outcome studies conducted in the 1990s, early inhibition of the Renin 
Angiotensin System (RAS) with angiotensin converting enzyme (ACE) inhibitors has shown 
to reverse pathological remodeling, improve survival, and reduce HF hospitalization in post-
AMI patients with LV systolic dysfunction and/or HF (AIRE Study Investigators, 1993;
GISSI-12 Study Investigators, 1994; ISIS-12 Collaborative Group 1995; Kober, et al 1995;


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Pfeffer et al 1992). As a consequence, guidelines recommend early initiation of ACE
inhibitors after an AMI in patients with LV systolic dysfunction and/or HF for indefinite use 
(IA recommendation) (Anderson, et al 2007; Antman, et al 2008; Roffi, et al 2015; Steg, et al 
2012). Despite this progress and a number of other evidence-based pharmacotherapies (β 
blockers, mineralocorticoid antagonists, etc.), the prognosis of high risk post-AMI patients 
with LV dysfunction and/or HF remains poor. Novel preventive strategies to reduce the risk 
for CV mortality and the clinical development of HF are clearly warranted.
Several lines of evidence have suggested that increasing natriuretic peptides in addition to 
RAS inhibition in post-AMI patients may offer greater benefits over the RAS inhibition alone. 
The potential mechanisms may include but are not limited to the anti-hypertrophic, anti-
fibrotic, anti-ischemic, anti-inflammatory and sympatholytic effects of natriuretic peptides 
(Braunwald, 2015; D’Souza, et al 2004; Molkentin, 2003). In a small study of 24 anterior 
wall STEMI patients, the recombinant form of human BNP, nesiritide, given early after index 
MI presentation for 72 hours was well tolerated and associated with improved LVEF and 
reduced ventricular remodeling (i.e., smaller LV end-systolic volume) after 1 month (Chen, et 
al, 2009). A larger clinical study in Japanese STEMI patients (N=569) demonstrated that 
intravenous administration of atrial natriuretic peptide for 3 days after reperfusion treatment 
reduced infarct size and improved LVEF at 6-12 months (Kitakaze, et al 2007).
Entresto™(sacubitril/valsartan, LCZ696) is a combination of neprilysin inhibitor and 
angiotensin II type 1 receptor blocker, providing concomitant neprilysin inhibition and 
angiotensin type 1 receptor blockade. Upon oral administration, LCZ696 delivers systemic 
exposure of sacubitril, a neprilysin inhibitor prodrug, and valsartan, an angiotensin receptor 
blocker (ARB). Sacubitril is then further metabolized by esterases to the active metabolite, 
sacubitrilat (LBQ657), which inhibits the degradation of natriuretic peptides and therefore 
enhances the effects of their biological activity. The efficacy and safety of LCZ696 titrated to 
a target dose of 200 mg twice daily in chronic HF patients with reduced ejection fraction 
(HFrEF) (LVEF ≤40%) was evaluated in the PARADIGM-HF study (N=8,442) and 
demonstrated that LCZ696 significantly reduced the primary composite endpoint of CV death 
or HF hospitalization by 20%, as compared to enalapril (McMurray, et al 2014). 
Given these positive results for the use of LCZ696 in the HFrEF patient population, and the 
improvement in LVEF, reduction in infarct size and ventricular remodeling observed in the 
STEMI patient population all of which suggest that increasing natriuretic peptides in addition 
to RAS inhibition may offer greater benefit in the post-AMI patient population, we 
hypothesize that early and sustained treatment with LCZ696 in high-risk patients with LV 
systolic dysfunction and/or pulmonary congestion following an AMI with no known prior 
history of chronic HF will be superior to the guideline recommended first-line treatment with 
ACE inhibitor as measured by a reduction in the composite endpoint of CV death, HF 
hospitalization or outpatient HF.
1.2
Purpose 
The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target 
dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily, 
in addition to conventional post-AMI treatment, in reducing the occurrence of composite 
endpoint of CV death, HF hospitalization and outpatient HF (time-to-first event analysis) in 


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post-AMI patients with evidence of LV systolic dysfunction and/or pulmonary congestion, 
with no known prior history of chronic HF.
2
Study objectives and endpoints
2.1
Primary objective(s)
To demonstrate that LCZ696 is superior to ramipril in delaying the time-to-first occurrence of 
the composite endpoint of CV death, HF hospitalization or outpatient HF* in patients with LV 
systolic dysfunction and/or pulmonary congestion following an AMI
(*The outpatient HF endpoint event is defined as an adjudicated event of clinical development 
of symptomatic HF (either urgent/unscheduled or non-urgent) in the outpatient setting with 
symptoms and signs requiring initiation/intensification of intravenous or qualifying oral HF 
treatment.  See Section 6.4.1 for full definition)
2.2
Secondary objective(s)

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time-to-
first occurrence of CV death or HF hospitalization 

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to
new onset of symptomatic HF defined as time-to-first occurrence of HF hospitalization or 
outpatient HF

To demonstrate the superiority of LCZ696 compared to ramipril, in delaying the time-to-
first occurrence of CV death, non-fatal spontaneous MI or non-fatal stroke 

To demonstrate the superiority of LCZ696, compared to ramipril, in reducing the rate of 
the composite endpoint of CV death and total (first and recurrent) hospitalizations  due to 
HF, non-fatal spontaneous MI or non-fatal stroke

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to 
all-cause mortality

To evaluate the safety and tolerability of LCZ696 compared to ramipril 
(All secondary efficacy hypotheses except all-cause mortality will be included in a statistical 
testing strategy to control the familywise type I error rate) (Section 9.5)
  
 
 
 
 
 
 


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3
Investigational plan
3.1
Study design
Figure 3-1
Study design
This study is a multicenter, randomized, double-blind, active controlled, event-driven phase 
III clinical trial designed to evaluate the efficacy and safety of LCZ696 compared to ramipril 
when added to standard therapy in post-AMI patients with LV systolic dysfunction and/or 
pulmonary congestion.  Potential study candidates will consist of high-risk patients who have 
sustained a spontaneous acute myocardial infarction (STEMI or NSTEMI) with evidence of 
LV systolic dysfunction defined by LVEF ≤40% and/or pulmonary congestion (worst Killip 


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class ≥ II or radiological findings requiring intravenous treatment). In addition, patients must 
have at least one risk factor (age 70 yrs; diabetes; estimated glomerular filtration rate (eGFR)
< 60 ml/min; history of prior MI; occurrence of atrial fibrillation during index hospitalization; 
LVEF < 30% or Killip class III or IV associated with the index MI, or diagnosis of STEMI 
without reperfusion therapy within the first 24 hours of the index MI) and should not have 
known prior history of chronic HF.  Study candidates must also be hemodynamically stable 
defined as systolic blood pressure (SBP) ≥100 mmHg if on ACE inhibitors or ARBs or SBP 
≥ 110 mmHg if not on ACE inhibitors or ARBs at time of randomization, must not have 
received intravenous diuretics, vasodilators, vasopressors or inotropes in the last 24 hours 
prior to randomization, and be considered clinically stable in the opinion of the investigator.
After assessing eligibility during the screening period, consenting patients who meet the study 
inclusion and exclusion criteria will be randomized 1:1 to receive LCZ696 titrated to a target 
dose of 200 mg twice daily or ramipril titrated to a target dose of 5 mg twice daily in a 
double-blind manner for the duration of the study.  In addition, in order to minimize the 
potential risk of angioedema, patients who were previously treated with ACE inhibitors 
receiving the last dose of that agent during the last 36 hours prior to randomization will 
receive a valsartan bridge for one day. To achieve this, those who are subsequently 
randomized to LCZ696 will receive two doses of valsartan in a blinded manner prior to 
beginning double-blind LCZ696 treatment. Patients randomized to ramipril will immediately 
start on double-blind ramipril without valsartan bridging. Randomization must occur no 
earlier than 12 hours and no more than 7 days after index MI presentation.    
A screening period, or epoch, of no more than 7 days after index MI presentation will be used 
to determine if patients qualify to enter the double-blind treatment phase of the study. Patients 
may be randomized on the same day that they are consented and screened.
Eligible patients will be randomized 1:1 to receive LCZ696 titrated to a  target dose of 200 
mg twice daily or ramipril titrated to a target dose of 5 mg twice daily.  Three dose levels of 
study medication will be administered in a stepwise titration (Table 3-1).  The goal of 
treatment is to ensure that each patient receives the target dose or maximal tolerated dose of 
study medication (Figure 3-2).  
Table 3-1
Study drug dose levels during treatment epoch
Dose Level
LCZ696 Treatment Arm*
Ramipril Treatment Arm
1
50 mg b.i.d.†
1.25 mg b.i.d.
2
100 mg b.i.d.†
2.5 mg b.i.d.
3
200 mg b.i.d.
5 mg b.i.d.
* LCZ696 dosing is based on the total amount of both components of sacubitril/valsartan; dose levels 
1, 2 and 3 are equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, respectively.  
† Patients who are randomized to LCZ696 and received ACE inhibitors in the 36 hours prior to 
randomization will be given a bridging valsartan dose in a blinded manner for one day (two doses at 
either dose level V1 or V2: 40 or 80 mg b.i.d.) prior to beginning double-blind LCZ696 treatment.


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Figure 3-2
Study drug initiation and up-titration in PARADISE-MI
The starting dose level of the study drugs will be determined based on the patient’s clinical 
condition and taking into consideration their prior standard background therapy.  Patients who 
did not receive an ACE inhibitor or ARB in the last 24 hours prior to randomization ( ACE 
inhibitor/ARB No patients) will start at dose level 1. Patients who did receive an ACE 
inhibitor or ARB in the last 24 hours prior to randomization (ACE inhibitor/ARB Yes patients) 
will start at dose level 1, or at investigator’s discretion, dose level 2, after taking into 
consideration the patients’ prior dose level of ACE inhibitor/ARB therapy (Table 3-2) and 
clinical condition (SBP, renal function, etc.).
Table 3-2
Total daily doses of commonly used ACE inhibitors and ARBs 
corresponding to dose level 2 of study drug 
ACE inhibitor
Dose
ARB
Dose
Benazepril
20 mg
Azilsartan
40 mg
Captopril
100 mg
Candesartan
16 mg
Cilazapril
2.5 mg
Eprosartan
400 mg
Enalapril
10 mg
Irbesartan
150 mg
Fosinopril
20 mg
Losartan
50 mg
Imidapril
10 mg
Olmesartan
10 mg
Lisinopril
10 mg
Telmisartan
40 mg
Moxepril
7.5 mg
Valsartan
160 mg
Perindopril
4 mg
Quinapril
20 mg


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ACE inhibitor
Dose
ARB
Dose
Ramipril
5 mg
Trandolapril
2 mg
Zofenopril
30 mg
ACE inhibitor/ARB No patients (no treatment with ACE inhibitor/ARB therapy during the 24 
hours prior to randomization):

Start at dose level 1, if SBP is ≥ 110 mmHg 
ACE inhibitor/ARB Yes patients (treated with ACE inhibitor/ARB therapy during the 24 
hours prior to randomization): 

Start at dose level 1, if SBP is ≥100 mmHg OR

At investigator’s discretion, patients may also start at dose level 2, taking into 
consideration patient’s prior dose level of ACE inhibitor/ARB therapy (Table 3-2) and 
clinical condition (SBP, renal function, etc.).
In order to minimize the potential risk of angioedema, patients who are randomized to 
LCZ696 but who were previously treated with an ACE inhibitor during the 36 hours prior to 
randomization will receive valsartan bridging for one day before beginning the double-blind 
LCZ696 treatment. Two doses of blinded valsartan (dose level V1, valsartan 40 mg or dose 
level V2 valsartan 80 mg) will be available.  As outlined above (Figure 3-2), the dose level of 
the 1-day valsartan bridging will also be determined based on the patient’s prior dose level of 
ACE inhibitor therapy and clinical condition at the investigator’s discretion (Figure 3-2).  
Patients randomized to ramipril will immediately start on double-blind ramipril without 
valsartan bridging.
Following initiation of study drug, patients should be uptitrated to the next dose level no 
earlier than 24 hours after the initial dose of study drug.  The aim is to achieve the target dose 
level 3 within 2 weeks after randomization; however, slower up-titration will be permitted if 
necessary to manage patient safety and tolerability.  Patients that cannot tolerate dose level 3 
will be allowed to stay at level 1 or 2 as maintenance dose. Study drug dose level adjustments 
should be based on overall safety and tolerability with special focus on a) symptomatic 
hypotension, b) any clinically significant decrease in eGFR/increase in serum creatinine (SCr)
and c) hyperkalemia (Table 3-3). Treatment guidelines for blood pressure management and 
hyperkalemia are provided in Appendix 4 and Appendix 5, respectively.  Every attempt 
should be made to maintain patients on the target study drug dose (dose level 3) or maximally 
tolerated dose levels throughout the trial. If the patient does not tolerate the target study drug 
dose level the investigator should consider, if appropriate, adjusting non-disease-modifying 
background medications (e.g., diuretics, nitrates or calcium channel blockers) to rectify the 
situation before considering down-titration to the next lower study drug dose level.
Table 3-3
Safety monitoring criteria that must be met for dose uptitration
Parameter 
Criteria
Blood pressure
SBP ≥100 mmHg
Renal function
eGFR ≥30 mL/min/1.73m2 or serum creatinine 


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Parameter 
Criteria
increase  < 0.5 mg/dl 
Serum potassium
K < 5.5 mmol/L (mEq/L)
AEs or conditions
No postural symptoms or any AEs that preclude up-
titration according to the investigator’s judgment
This is an event-driven trial, the study will continue until a total of 800 confirmed primary 
triple composite endpoint events and 633 confirmed double composite events of CV death or
HF hospitalization (i.e., first secondary endpoint) have been achieved. Approximately 4,650
randomized post-AMI patients will be required to accrue the necessary number of confirmed 
endpoints. Once randomized, all patients will be followed until the total numbers of required 
confirmed endpoint events have been achieved and final follow-up has been performed. 
It is anticipated that the total trial duration will be approximately 32 months, with a projected 
recruitment period of 24 months, followed by approximately 8 months of follow-up after the 
last patient is enrolled. The overall estimated mean follow-up time will be 20 months for the 
study.  Although these are the estimated timelines, they may change according to the rate of 
randomization and rates of occurrence of the primary and first secondary endpoints.
3.2
Rationale for study design
This phase III outcome study in post-AMI patients is designed as a multicenter, randomized, 
double-blind, active-controlled, event-driven study in order to assess the efficacy and safety of 
LCZ696 when added to standard therapy for high-risk post-AMI patients with left ventricular 
systolic dysfunction and/or pulmonary congestion. Patients entering the study will be 
randomized to either LCZ696 or ramipril and are required to receive standard-of-care 
background therapy according to regional or local guidelines / institutional standards
throughout the study. Once randomized, all patients will be followed until the total required 
numbers of confirmed endpoint events have accrued. The study design reflects prior pivotal,
long-term, cardiovascular outcome trials in post-AMI patients.  
The primary endpoint of this study is a composite of CV death, HF hospitalization or 
outpatient HF in patients with left ventricular systolic dysfunction and/or pulmonary 
congestion following an AMI who do not have known prior history of chronic HF. While the 
composite of CV death or HF hospitalization is a well-established mortality and morbidity 
endpoint, the addition of the outpatient HF component, which in this study represents the 
confirmed diagnosis of new onset symptomatic HF, aims to capture the clinically important 
outpatient event that contributes to the totality of HF morbidity following an AMI presenting 
as either inpatient (i.e., HF hospitalization) or outpatient (i.e., outpatient HF) events.   The 
diagnostic criteria for adjudication of HF symptoms and signs are identical whether the 
patient is seen in an inpatient or outpatient setting.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The selection of LCZ696 200 mg given orally twice daily as the target dose for this study was 
based primarily on the superior efficacy and safety results of LCZ696 200 mg compared to 
enalapril 10 mg each given twice daily in the PARADIGM-HF study, in which 60% of the 


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HFrEF patients enrolled had an ischemic etiology and 43% had prior MI. LCZ696 200 mg 
twice daily delivers similar valsartan exposure (assessed by AUC) as valsartan 160 mg twice 
daily, which was demonstrated in the VALIANT study to be as effective as standard-of-care 
ACE inhibitor in patients with AMI complicated by LV systolic dysfunction and/or HF. 
Further, biomarker analysis and modeling indicate that this dose of LCZ696 delivers 
approximately 90% of its maximal neprilysin (NEP) inhibition. The twice daily dosing 
schedule is considered necessary for sustained NEP inhibition over a 24-hour period and it is 
also anticipated to reduce the incidence of hypotension, compared to a once daily regimen, 
particularly in elderly patients.  
3.4
Rationale for choice of comparator
Major clinical trials have established ACE inhibitors as the standard-of-care for RAS
blockade and ACE inhibitors are recommended by treatment guidelines as the first-line 
therapy for post-AMI patients with LV systolic dysfunction and/or HF. The primary objective 
of study LCZ696G2301 is to demonstrate superiority of LCZ696 over an ACE inhibitor in 
reducing CV mortality and HF morbidity in post-AMI patients with LV systolic dysfunction
and/or pulmonary congestion. Ramipril is one of the most commonly used ACE inhibitors in 
post-AMI patients and is selected as the active comparator of this study. In the AIRE study, 
ramipril at target dose of 5 mg twice daily compared to placebo demonstrated a significant 
27% relative reduction in mortality (p=0.002; principally CV death), also 26% and 23% 
reductions in the risks of HF hospitalization and progression to severe/resistant HF, 
respectively (AIRE Investigators 1993).  Ramipril in the same daily dose was subsequently 
shown to reduce cardiovascular mortality in a broader population of patients at cardiovascular 
risk (The HOPE Investigators, 2000).
3.5
Purpose and timing of interim analyses/design adaptations
One interim analysis (IA) is planned to assess efficacy.  The cut-off time for the IA is planned 
to be when approximately two-thirds of the target number of primary adjudicated events (i.e. 
approximately 540 of CV death, HF hospitalization or outpatient HF) have occurred. 
3.6
Risks and benefits 
The risk to patients participating in the study will be minimized by compliance with the 
inclusion/exclusion criteria and close clinical monitoring.  Patients will be instructed not to 
take any RAS blockade medications (ACE inhibitor or ARB) from the day they start study 
drug to avoid excess RAS blockade. The risk of discontinuation of concomitant ACE 
inhibitors or ARBs will be minimal as the study treatment will be reflective of the typical 
dosing schedule of most ACE inhibitors and ARBs. All patients will be required to continue 
receiving the rest of their standard of care background CV medications. In addition, for 
patients randomized to LCZ696 who received ACE inhibitors in the last 36 hours prior to 
randomization, a one day bridging period with 2 doses of valsartan before starting LCZ696 
treatment is instituted to minimize the risk of angioedema (Section 3.1).
In women of child-bearing potential, a possible risk of developmental toxicity cannot be 
excluded. Women of child-bearing potential should therefore use a highly effective method of 


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contraception during dosing. If there is any question that the patient will not reliably comply, 
they should not be entered in the study.   
Since this is a long-term outcome study, participating patients will benefit from careful 
monitoring and follow-up during the entire study duration regardless of whether they are 
receiving the study medication.
4
Population
The study population will consist of male and female patients age 18 years or older with a 
diagnosis of acute spontaneous MI and evidence of left ventricular (LV) systolic dysfunction
and/or pulmonary congestion associated with the index MI. Patients will be randomized 
between 12 hours and 7 days following the index acute MI.  At the time of randomization, 
patients should be hemodynamically stable and without persistent clinical HF. The goal is to 
randomize approximately 4,650 patients in approximately ~650 centers worldwide.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed. 
2. Male or female patients ≥ 18 years of age. 
3. Diagnosis of spontaneous AMI based on the universal MI definition* with randomization 
to occur between 12 hours and 7 days after index event presentation**.  
Spontaneous AMI is defined when there is evidence of myocardial necrosis in a clinical 
setting consistent with myocardial ischemia due to primary coronary event. Under these 
conditions, the following criteria have to be met for the diagnosis of spontaneous AMI:

Detection of rise and/or fall of cardiac enzymes (cardiac troponin, cTn or the MB 
fraction of creatinine kinase, CKMB) with at least one value above the 99th percentile 
of the upper reference limit (URL) or the local laboratory MI diagnosis cut-off value, 
together with evidence of myocardial ischemia with at least one of the following:
•
Ischemic discomfort or other ischemia symptom(s)
•
Electrocardiogram (ECG) characteristics of STEMI or NSTEMI including new 
or presumably new significant ST-segment-T wave (ST-T) changes
•
Newly developed pathological Q waves or left bundle branch block  in the 
ECG
(* Patients with a spontaneous MI event determined to be secondary to another medical 
condition such as anemia, hypotension, or an arrhythmia OR thought to be caused by 
coronary vasospasm with documented normal coronary arteries are not eligible)
4. Evidence of LV systolic dysfunction and/or pulmonary congestion requiring intravenous 
treatment associated with the index MI event defined as:

LVEF ≤40% assessed locally by echocardiography, magnetic resonance imaging, 
cardiac CT, radionuclide or contrast ventriculography after index MI presentation**
and prior to randomization.
(These examinations may be performed as part of patient standard-of-care. In case 
multiple LVEF measurements have been performed during index event, the last one 


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performed prior to randomization should be considered as the qualifying 
measurement), and/or

Pulmonary congestion requiring intravenous treatment during the index hospitalization 
supported by clinical assessment (worst Killip class, II or above; see Appendix 3 for 
Killip class definition) or radiological findings.  Radiological evidence of pulmonary 
congestion is defined as pulmonary venous congestion with interstitial or alveolar 
edema and must be supported by at least one chest X-ray or CT scan.
(** Index MI presentation is the time of patient presentation at either the emergency 
room/emergency department (ER/ED), intensive care unit/coronary care unit (ICU/CCU)
or hospital ward etc., at study centers, for the treatment of the index MI.)
5. At least one of the following 8 risk factors: 

Age ≥ 70 years

eGFR <60 mL/min/1.73 m2 based on MDRD formula at screening visit

Type I or II diabetes mellitus

Documented history of prior MI supported by ECG changes and/or elevation of 
cardiac enzymes consistent with MI diagnosis.

Atrial fibrillation as noted by ECG, associated with index MI

LVEF <30% associated with index MI

Worst Killip class III or IV associated with index MI requiring intravenous treatment

STEMI without reperfusion therapy within the first 24 hours after presentation
6. Hemodynamically stable defined as: 

SBP ≥ 100 mmHg at randomization for patients who received ACE inhibitor/ARB 
during the last 24 hours prior to randomization  (ACE inhibitor/ARB Yes patients)

SBP ≥ 110 mmHg at randomization for patients who did not receive ACE 
inhibitor/ARB during the last 24 hours prior to randomization (ACE inhibitor/ARB No 
patients)

No intravenous treatment with diuretics, vasodilators, vasopressors and/or inotropes 
during the last 24 hours prior to randomization.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Known history of chronic HF prior to randomization
2. Cardiogenic shock within the last 24 hours prior to randomization
3. Persistent clinical HF at the time of randomization 
4. Coronary artery bypass graft (CABG) performed or planned for index MI
5. Clinically significant right ventricular MI as index MI
6. Symptomatic hypotension at screening or randomization
7. Patients with a known history of angioedema
8. Stroke or transient ischemic attack within one month prior to randomization


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9. Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy
11. Open-heart surgery performed within one month prior to randomization or planned cardiac 
surgery within the 3 months after randomization
12. eGFR < 30 ml/min/1.73 m2 as measured by the Modification of Diet in Renal Disease 
(MDRD) formula at screening
13. Serum potassium > 5.2 mmol /L at screening
14. Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL or increased 
ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension 
such as varices
15. Previous use of LCZ696 or EntrestoTM
16. Use of other investigational drugs within 30 days prior to screening
17. History of hypersensitivity to the study drugs or drugs of similar chemical classes
18. Known intolerance or contraindications to study drugs or drugs of similar chemical classes 
including ACE inhibitors, ARB or NEP inhibitors
19. Patients taking medications prohibited by the protocol that cannot be discontinued for the 
duration of the study
20. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin) within the past 3 years with a life expectancy of less than 1year.
21. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or extraction of study drug at investigators’ discretion.
22. History or evidence of drug or alcohol abuse within the last 12 months
23. Patients considered unsuitable for the study, including patients with psychiatric, 
behavioral or cognitive disorders, sufficient to interfere with the patient’s ability to 
understand and comply with the protocol instructions or follow-up procedures
24. 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
25. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to Visit 1). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient 

Combination of any two of the following (a+b or a+c, or b+c), according to country 
approvals and availability 


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a.
use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception 
b. placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c.
barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment

Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment is she 
considered not of child bearing potential
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
All eligible patients will be randomized 1:1 to either LCZ696 titrated to a target dose of 200 
mg twice daily or ramipril titrated to a target dose of 5 mg twice daily in a double-blind 
manner for the duration of the study. In addition, patients will continue to receive optimal 
standard of care background therapy to treat the index MI event and co-morbid conditions, as 
considered appropriate by the investigator and in accordance with the local/institutional 
guidelines, with the exception of an ACE inhibitor or ARB as this will be replaced by study 
drug. The use of an open label ACE inhibitor or an ARB in addition to randomized study drug 
is strictly prohibited. 
The following study drugs will be provided:

LCZ696 50 mg, 100 mg and 200 mg tablets, and matching placebo (LCZ696 doses are 
equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, respectively)

Ramipril 1.25 mg, 2.5 mg, and 5 mg capsules, and matching placebo

Valsartan (VAL489) 40 mg and 80 mg tablets, and matching placebo (two doses for 1 day 
in a subset of randomized patients) (Section 3.1)
All study medications will be supplied in bottles or blister cards. Sufficient medication will be 
provided for the treatment according to study protocol, including additional medication to 
allow for delayed visits. Medication labels will be in the local language and comply with the 
legal requirements of the country. They will include storage conditions for the drug and the 
medication number, but no information about the patient.


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5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
Patients will be assigned to one of the following two treatment arms in a ratio of 1:1 at Visit 
101.

LCZ696 at dose levels 1-3 (50, 100 and 200 mg twice daily)

Ramipril at dose levels 1-3 (1.25, 2.5 and 5 mg twice daily)
5.3
Treatment assignment and randomization 
At Visit 101 all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified by region and type of index MI (STEMI or NSTEMI).
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Randomization Group.
5.4
Treatment blinding
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will not
be accessible by anyone involved in the study with the following exceptions:
1. The independent and unblinded statistician, programmer and data personnel who are
involved in preparing safety and efficacy interim analysis reports for the Data
Monitoring Committee (DMC). These personnel will not be involved in any other
trial conduct related activities.
2. DMC members.


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
The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, labeling, schedule of administration, appearance, taste 
and odor.

A double-dummy design is used because the identity of the study drug cannot be disguised, 
as the drug products are visibly different.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9), at the time 
of an interim analysis by the DMC and at the conclusion of the study.
For any patient whose treatment code has been broken the patient must permanently 
discontinue the study treatment.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering,
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. 
Upon signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number , and subsequent 
patients/subjects are assigned consecutive numbers (e.g. the second patient is assigned patient 
number , the third patient is assigned patient number ). The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the patient to register 
them into the IRT. For studies using eCRFs, only the assigned patient number must be entered 
in the field labeled “Patient ID” on the electronic data capture (EDC) data entry screen (e.g. 
enter 
, etc.). Once assigned to a patient, the patient number will not be reused. 
If the patient fails to be randomized for any reason, the IRT must be notified within 2 days 
that the patient was not randomized. The reason for not being randomized will be entered on 
the Screening Log, and the screening eCRFs should also be completed.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the two treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number. 


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5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis country 
pharma organization (CPO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at each study visit or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Novartis will supply the investigators with all study medications required for the course of the 
study. Patients will be provided with medication packs containing study drug corresponding 
to their assigned treatment arm and dose level, sufficient to last until the next scheduled visit. 
In order to adequately blind the study, patients will be required to take a total of two pills, 
(one tablet from the LCZ696/LCZ696 matching placebo pack and one capsule from the 
ramipril/ramipril matching placebo pack) twice a day for the duration of the study. 
For patients randomized to LCZ696 who were previously treated with an ACE inhibitor 
receiving the last dose of that agent within 36 hours prior to randomization, a valsartan bridge 
for one day will be administered in a blinded manner prior to initiating the LCZ696 treatment. 
To achieve this, those who are subsequently randomized to LCZ696 will receive two doses of 
valsartan in a blinded manner prior to beginning double-blind LCZ696 treatment. Patients 
randomized to ramipril will immediately start on double-blind ramipril without valsartan 
bridging.  
Table 5-1 summarizes the study drug that will be taken during the treatment epoch.


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Table 5-1
Study drug dispensed during the treatment epoch by study visit
Study 
visitc
Dose 
level
LCZ696
Ramipril
Valsartanb
101
1a
50 mg or matching 
placebo b.i.d.
1.25 mg or matching 
placebo b.i.d.
40 mg or matching 
placebo b.i.d.
101a/102
2
100 mg or matching 
placebo b.i.d.
2.5 mg or matching 
placebo b.i.d.
80 mg or matching 
placebo b.i.d.
103
3
200 mg or matching 
placebo b.i.d.
5 mg or matching 
placebo b.i.d.
a At Investigator’s discretion, dose level 2 can be administered at Visit 101 for the [ACE inhibitor/ARB: 
Yes] patients.
b For patients who were previously treated with ACE inhibitor receiving the last dose within 36 hours 
prior to randomization;
If randomized to LCZ696, they will receive a valsartan bridging for one day before beginning the 
double-blind LCZ696 treatment. 

Two doses of blinded valsartan dose level V1 (valsartan 40 mg) or dose level V2 (valsartan 80 
mg) will be available at Visit 101.  

At investigator’s discretion dose level V1 or V2 can be administered for one day followed by 
active LCZ696; these patients will also receive ramipril matching placebo from Visit 101 
onwards. 
If randomized to ramipril, they will receive active ramipril, and two doses of valsartan matching 
placebo for one day followed by active ramipril and LCZ696 matching placebo.
c If the study drug is up-titrated during the index hospitalization, increase to the next dose level can 
occur prior to next study visit if tolerable but should be no early than 24 hours; slower up-titration will 
also be permitted if necessary to manage patient safety and tolerability.  
Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 
AM) and their evening study drug dose at approximately 20:00 (8 PM). The study drugs 
should be taken with water, with or without food. If the patient misses taking any study drug 
dose, he/she should take it as soon as possible, unless it is almost time for the followin g 
scheduled dose. In this case, the patient should skip the missed dose and return back to his/her 
regular study drug administration schedule.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record case report form (CRF). All kits of 
study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose level 
adjustments and/or temporary interruptions of study treatment are permitted in order to keep 
the patient on study drug. The following guidelines should be followed: 
Every attempt should be made to maintain patients at the target study drug dose level 
throughout the trial. If the patient does not tolerate the target study drug dose level, the 


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investigator can, if appropriate, adjust concomitant background medications for co-morbid 
conditions to rectify the situation, and if necessary down titrate to the next lower study drug 
dose level. For hypotension or dizziness, consideration should be given to adjusting the dose
of diuretic and/or concomitant antihypertensive agents (e.g., calcium channel blockers) and 
non-antihypertensive agents that lower blood pressure (BP) (e.g., nitrates). It is important to 
note that dose adjustment of disease-modifying background therapy, e.g., β blockers, or 
mineralocorticoid (aldosterone) antagonists is discouraged under these circumstances.
Adjustment of study drug dose level
If in the investigator’s opinion down titration of study drug to a lower dose level is deemed 
necessary it should be done in accordance with the following instructions: 
During the treatment epoch, down titration of the study drug at any time during the study 
based on the judgment of the investigator will be allowed according to the safety and 
tolerability criteria defined in Appendix 4, and Appendix 5. If down titration is necessary, the 
patient should be down titrated to the next lower study drug dose level in the titration scheme. 
The patient may continue receiving the lower dose level for a recommended period of 1 to 4 
weeks before being re-challenged at the next higher dose level. For example, a patient who 
encounters tolerability problems at the target study drug dose level (i.e., dose level 3) should 
receive the study drug at dose level 2 for 1 to 4 weeks at the discretion of the investigator. 
Then, he/she should be re-challenged with up-titration back to dose level 3.
If the tolerability issues are not alleviated despite down titration by one dose level, the 
investigator may down titrate further to the next lower study drug dose level for 1 to 4 weeks, 
up to temporary discontinuation of the study drug. Again, once stable, the patient should be 
re-challenged with up titration to the next higher dose level every 1 to 4 weeks in an attempt 
to bring back the patient gradually to the target study drug dose level (i.e., dose level 3). The 
investigator may choose the next dose level for down- or up-titration according to his or her 
judgment. The IRT system should be contacted to register any changes in the patient’s study 
drug dose level, including in cases of temporary and permanent discontinuation of the study 
drug, and to obtain the medication numbers of the study drug supplies required for the new 
study drug dose level. In some instances, according to the safety and tolerability criteria and 
the investigator’s judgment, dose level 1 or 2 could be maintained if he/she considers that the 
patient’s condition would not allow any further up titration to the target dose level of study 
drug (i.e., dose level 3). In this case, it would be acceptable to maintain the patient at dose 
level 1 or level 2, whichever is the higher and tolerated dose level by the patient.
These changes must be recorded on the Dosage Administration Record CRF.
Study drug restart after temporary treatment interruption
Study drug should be reintroduced in those patients who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator. Once the investigator considers the 
patient’s condition appropriate for receiving the study drug, the investigator should re-start the 
patient on the study drug at the most appropriate and allowable dose level per his/her medical 
judgment. If tolerated, the patient should be up-titrated one dose level every 1 to 4 weeks to 
the target dose level 3, as per the investigator’s judgment. Should the patient not tolerate the 
re-start study drug dose level, he/she may be down titrated again (if appropriate) or 


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temporarily discontinue the study medication again and a new attempt to up titrate or 
reintroduce the study drug could be considered by the investigator as soon as medically 
justified in his/her judgment. 
The use of an open-label ACE inhibitor, ARB, commercially available Entresto™ or a direct 
renin inhibitor is strictly prohibited while patient is taking study drug. However, if for any 
reason a patient off study drug has started open-label treatment with an ACE inhibitor or 
Entresto™, it must be discontinued ≥36 hours prior to restarting study drug. For patients off 
study drug treated with an ARB or a direct renin inhibitor it must be discontinued prior to re-
initiation of study drug.
Reinitiation of study medications or any changes in concomitant medications must be 
recorded on the appropriate eCRFs.  
In case of pregnancy discovered during the screening epoch, the patient will be withdrawn 
from the study immediately. In case of pregnancy discovered during the treatment epoch, the 
patient should be instructed to temporarily discontinue study drug immediately. Study drug 
intake should be resumed as soon as possible after the completion of the pregnancy and 
lactation period. Meanwhile, the patient should continue to attend scheduled study visits. 
See Section 7.6 for further details on pregnancies and reporting guidelines
5.5.6
Rescue medication
Guidance on handling hypotension and hyperkalemia are provided to investigators in
Appendix 4, and Appendix 5, respectively. Patients may receive open-label ACE inhibitors, 
ARBs, commercially available Entresto™ or direct renin inhibitors during the study ONLY if 
the study drug has been temporarily or permanently discontinued (Table 5-1). If the patient is 
to be started on open-label ACE inhibitor or Entresto™, the study drug must be stopped ≥36 
hours prior to initiating ACE inhibitor or Entresto™. If reinitiating study drug, the open-label 
ACE inhibitor or Entresto™ must be stopped ≥36 hours prior to resuming study drug. Open-
label ARBs or a direct renin inhibitor must also be stopped prior to resuming study drug.
Use of rescue medication must be recorded on the Concomitant medications/Significant 
nondrug therapies CRF.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medic ations 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.


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CV Medications
The patient should be on an optimal medical regimen of background medications to 
effectively treat the index MI event and comorbidities, such as hypertension, diabetes, 
dyslipidemia and atrial fibrillation, etc. Investigators should take into consideration the 
patient’s risk factors, such as age and comorbidities, and make every effort to control a 
patient’s BP, lipid and glucose levels in accordance with international and local treatment 
guidelines. 
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements and any other medications known to raise 
potassium levels should be used with caution while the patient is receiving the study drug due 
to the increased possibility of occurrence of hyperkalemia. The investigator is encouraged to 
assess patients’ potassium levels regularly, especially in those who are receiving these 
medications.
Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of the occurrence of hypotension.
HMG-CoA reductase inhibitors
Caution is recommended when co-administering LCZ696 with atorvastatin or other statins 
because of the potential to raise its plasma level.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-2 is NOT allowed after the start of study drug due 
to safety reason, unless the actions specified are taken.   
Table 5-2
Prohibited medication
Medication
Action taken
Any ACE 
inhibitor
Discontinue study drug. The open label ACE inhibitor must be stopped for ≥36 hours 
prior to re-initiation of study drug
Any ARB
Discontinue study drug. The open label ARB must be stopped prior to re-initiation of 
study drug
Any direct 
renin 
inhibitor
Discontinue study drug. The open label direct renin inhibitor must be stopped prior to 
re-initiation of study drug
Entresto™*
Discontinue study drug. The open label Entresto™must be stopped for ≥36 hours prior 
to re-initiation of study drug
*Commercially available sacubitril/valsartan
The concomitant use of open-label ACE inhibitor, ARBs, commercially available Entresto™
or a direct renin inhibitor is strictly prohibited while the patient is receiving study drug. If the 
addition of an ACE inhibitor, ARB, Entresto™or direct renin inhibitor is necessary, then 
study drug must be temporarily discontinued. If the patient is to be started on open-label ACE 
inhibitor or Entresto™, the study drug must be stopped ≥36 hours prior to initiating ACE 


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inhibitor or Entresto™. If study drug is to be re-started, the open-label ACE inhibitor or 
Entresto™must also be stopped ≥36 hours prior to re-initiating study drug. ARBs or a direct 
renin inhibitor should be stopped prior to resuming study drug. 
5.5.9
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un -
blinding can be performed at any time. 
An assessment will be done by the appropriate site personnel and the Medical Lead (or 
designee) after an emergency treatment code break and the patient must discontinue the study 
treatment.
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment
The study will be completed when either the predefined target total number of adjudicated 
events has been obtained or a recommendation is made by the DMC to prematurely stop the 
study. At the end of the study, all patients will return for the final end of study (EOS) visit 
(Visit 199) and be asked to return the remaining study drug.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from study drug, or must refer them for appropriate ongoing care. An open-label 
extension study may also be initiated to allow for study medication to be mad e available to 
qualified patients participating in the trial, upon formal request, if the study is positive and 
demonstrates the superiority of LCZ696 over ramipril.


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5.6.2
Discontinuation of Study Treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. However,
study treatment discontinuation does not constitute withdrawal from the study, does not 
constitute withdrawal of consent and should not lead to the patient being withdrawn from the 
entire study. Patients who have permanently discontinued study drug should be encouraged to 
attend all the protocol specified study visits and perform, at a minimum, AE/endpoint 
assessments as stipulated in the visit schedule (Table 6-1) and remain in follow-up for the 
duration of the trial. 
If they fail to return for these assessments for unknown reasons, every effort should be made 
to contact them. The investigator must also contact the IRT to register the patient’s 
discontinuation from study treatment and record it on the Dosage Administration Record CRF. 
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 
study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits: 

new / concomitant treatments

adverse events (AE)/Serious Adverse Events (SAE)
The emergence of the following circumstances will require permanent study drug 
discontinuation: 

Withdrawal of informed consent

Investigator thinks that continuation of study drug would be detrimental to the patient’s 
well-being

Suspected occurrence of clinically significant angioedema. A patient with any signs or 
symptoms of clinically significant angioedema should be thoroughly evaluated by the 
investigator
The emergence of the following circumstances will require temporary or permanent 
discontinuation (study drug may be restarted once these circumstances no longer exist): 

Use of an open label ACE inhibitor, ARB, Entresto™(commercially available 
sacubitril/valsartan) or direct renin inhibitor

Any laboratory abnormalities that in the judgment of the investigator warrant 
discontinuation of study drug after taking into consideration the patient’s overall status

Pregnancy and post-pregnancy during lactation period (Section 7.7)
Study drug may be discontinued at the investigator’s discretion if any of the following occurs:

Any severe suspected drug-related AE

Any other protocol deviation that results in a significant risk to the patient’s safety
Study drug should be permanently discontinued for any patient whose treatment code has 
been broken inadvertently for any reason. 


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5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  However, withdrawal of consent occurs only when a patient does not want to 
participate in the study anymore and does not want any further visits or assessments and does 
not want any further study related contacts and does not allow analysis of already obtained 
biologic material. 
If a patient withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the patient 
are not allowed unless safety findings require communicating or follow-up.  All efforts should 
be made to complete the assessments prior to study withdrawal.  A final evaluation at the time 
of the patient’s study withdrawal should be made as detailed in Table 6-1.
Patients can also refuse to participate in specific aspects of the study and/or take study 
medication at any time without withdrawing consent and permission should be requested of 
the patient to conduct follow-up visits or calls.  Investigators should make every effort to 
accommodate the needs of the patients to make it possible for them to continue to participate 
in the remaining aspects of the study.
This includes performing telephone visits to obtain 
health status and/or mortality and endpoint information for patients who are unable to or 
refuse to return for clinic visits.
5.6.4
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
contacting the patient, the patient’s family, friends and family physician as agreed in the 
informed consent and by documenting in the eSource/source documents steps taken to contact 
the subject, e.g. dates of telephone calls, registered letters, etc. A patient should not be 
considered lost to follow-up until just prior to database lock, after every effort to contact the 
patient has been exhausted.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient 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 investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.


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Patients should be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF.
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.
Patients who prematurely discontinue the investigational treatment remain in the study and 
should undergo all the assessments illustrated in Table 6-1. Patients can also refuse to 
participate in specific aspects of the study and/or take study medication at any time without 
withdrawing consent and permission should be requested of the patient to conduct follow-up 
visits or calls.  Investigators should make every effort to accommodate the needs of the 
patients to make it possible for them to continue to participate in the remaining aspects of the 
study. This includes performing telephone visits to obtain health status and/or mortality and 
endpoint information for patients who are unable to or refuse to return for clinic visits.
If a patient withdraws from participation in the study, refuses to return for study assessments 
or is unable to do so, every effort should be made to contact them or a knowledgeable 
informant by telephone and/or other measures to determine the patient’s survival status during 
the follow-up period.
Patients eligible to participate in this study must be randomized between 12 hours to 7 days 
after index AMI event presentation.  
Prospective study candidates will be identified either during the hospitalization for the index 
AMI or post discharge up to 7 days after the index MI presentation.  After identifying a 
potential patient, an informed consent form (ICF) must be signed before performing study-
related screening procedures that are not considered standard of care for AMI patients at that 
site.  Procedures that are part of a site’s standard of care for an individual with AMI may pre -
date the signed ICF.  The AE and SAE reporting period will begin at the time the ICF is 
signed. Screening will continue until the patient has been deemed eligible for randomization
into the study up to 7 days after the index MI.  Screening and randomization can occur on the 
same day. 
Visit 101 will be considered the reference visit for all study visits during the treatment epoch. 
Regardless of the occurrence of any unscheduled visits, scheduled visits should be performed 
within the specified timeframe in relation to Visit 101 as outlined in Table 6-1. If a visit is 
completed earlier than scheduled or postponed, it should not result in the next visit being 
brought forward or postponed.
Visits are planned to occur at weeks 1, 2, 4 (month 1), month 2, month 4, and then every 4 
months until study end.


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Table 6-1
Assessment schedule
Epoch 
Screen
Treatment
Visit
1
101
102
103
104
105
106
107
108
109
110
111
112
199 
and 
PSD
Day
1
7
14
28
61
122
243
365
486
608
730
851
973
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
Month
1
2
4
8
12
16
20
24
28
32
Obtain informed consent
X
Inclusion/exclusion criteria
X
X
Medical History – Protocol 
Solicited Events
X
Relevant Medical 
History/Current Medical 
Conditions/ Demography
X
Medical History Possibly 
Contributing to Liver 
Dysfunction1
X1
History/Smoking
History/Alcohol History
X
12-lead ECG assessment2
XS
Cardiac enzymes2
X
Chest X-ray or CT scan2, 3
XS
Evaluation of left ventricular 
systolic dysfunction2
X
Record Killip Class2,3
S
X
Risk factor assessment
X
X
Qualifying AMI Event
X
Index AMI Hospitalization 
X


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Epoch 
Screen
Treatment
Visit
1
101
102
103
104
105
106
107
108
109
110
111
112
199 
and 
PSD
Day
1
7
14
28
61
122
243
365
486
608
730
851
973
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
Month
1
2
4
8
12
16
20
24
28
32
Summary
Physical exam4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (pulse and BP)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAEs6
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete laboratory 
evaluation7
X
X
X
X
X
X
Abbreviated laboratory 
evaluation8
X
X
X
X
X
X
X
Local laboratory evaluation9
X
X
X
X
Endpoint assessment
X
X
X
X
X
X
X
X
X
X
X
X
Angioedema assessment
X
X
X
X
X
X
X
X
X
X
X
X
Visit Contact Information
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum/urine pregnancy 
testing11
S
S
S
S
S
FSH12
S


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Epoch 
Screen
Treatment
Visit
1
101
102
103
104
105
106
107
108
109
110
111
112
199 
and 
PSD
Day
1
7
14
28
61
122
243
365
486
608
730
851
973
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
Month
1
2
4
8
12
16
20
24
28
32
Dispense Study Medication
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening disposition
X
Study Completion form
X
TD = Study treatment  discontinuation; PSD = Premature patient discontinuation
X = assessment to be recorded on clinical data base
S = assessment to be recorded on eSource/source documentation only
1Collected retrospectively for patients who experience protocol defined liver events (See Appendix 2).
2Assessments typically performed as standard of care for index AMI according to local guidelines. Procedures that are part of a site’s standard of 
care for an individual with AMI may pre-date the signed ICF.
3Pulmonary congestion is assessed by worst Killip class AND/OR chest x-ray or CT scan findings during index hospitalization.  
4Complete physical examinations are required at Visit 1 and yearly (Visits 108, 111) thereafter up until Visit 199 (EOS). Short physical examinations 
are required at all interim visits.
5 CV medications (e.g., β-blockers, aldosterone antagonists, anti-hypertensives, lipid lowering drugs, antiplatelet agents, etc.) and  classes of non-
cardiovascular medications will be collected.
6 All adverse events and all serious adverse events occurring through the first two weeks post-randomization will be collected.  After the first two 
weeks post-randomization, the following safety data will be collected in this study: all serious adverse events, adverse events of special interest 
(Section 7.1), adverse events leading to a change in dose (down titration) or discontinuation of study medication, and all suspected non-serious 
adverse events.
7 Complete laboratory evaluations will be collected and sent to the central lab at all specified visits for all patients. If the study is extended beyond 
Visit 112 a complete laboratory evaluation will be performed annually. 
8 Abbreviated laboratory evaluations includes: blood urea nitrogen (BUN), serum creatinine, serum potassium and eGFR and will be collected and 
sent to the central lab at all specified visits for all patients. If the study is extended beyond Visit 112 an abbreviated laboratory evaluation will be 


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Epoch 
Screen
Treatment
Visit
1
101
102
103
104
105
106
107
108
109
110
111
112
199 
and 
PSD
Day
1
7
14
28
61
122
243
365
486
608
730
851
973
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
Month
1
2
4
8
12
16
20
24
28
32
performed at all interval visits except annual visits.
9 Local laboratories for serum potassium, serum creatinine and eGFR are to be performed prior to initial dosing and prior to each dose titration step 
until target dose is achieved (Visits 1, 101, 102 and 103; additional visits may be added as necessary until target dose level is achieved and/or during 
dose adjustments throughout the study). If screening (Visit 1) and randomization (Visit 101) occur on the same day, only one local laboratory 
assessment will be required.
11 Serum and urine pregnancy tests will be performed locally.  Serum pregnancy test (not required for post-menopausal women) to be performed at 
Visit 1. Urine pregnancy tests at visits 101 and annually (not required for post-menopausal women).  If screening (Visit 1) and randomization (Visit 
101) occur on the same day, only serum pregnancy test will be required. If serum pregnancy test is positive during the screening and on a 
confirmatory serum β-hCG test, the patient must not be randomized and must be discontinued from the trial. After randomization (Visit 101) a positive 
urine pregnancy test requires immediate interruption of study drug and confirmation by serum pregnancy test. If positive upon confirmation test, the 
patient must discontinue study drug until after the pregnancy and lactation period.
12 FSH will be performed locally.  Not required for males or pre-menopausal women.
 


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6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the eSource/source data.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients at least 
include date of birth, age, sex, race, and ethnicity. A detailed medical history (including CV 
and other conditions relevant to the study population to be enrolled) and current medical 
conditions present before the signing of informed consent, including the presentation and 
management of index MI event will also be recorded.
6.3
Treatment exposure and compliance
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient or care giver. This information should be 
captured in the eSource/source document at each visit. The investigator and/or study 
personnel should counsel the patient if compliance is below 80% at any time during the study. 
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
The duration of randomized treatment exposure will be calculated based upon the start and 
stop dates of study drug recorded in the CRF.
6.4
Efficacy
6.4.1
Efficacy assessment 1
The primary efficacy endpoint is defined as the time to the first confirmed occurrence of CV 
death, heart failure hospitalization* or outpatient heart failure**.
* Heart failure hospitalization also includes the development of new symptomatic heart failure 
during an ongoing hospitalization including the index AMI hospitalization.  
** Outpatient heart failure is defined as:

An urgent/unscheduled visit to an ED, acute/urgent care facility or outpatient clinic or a 
non-urgent office/practice or study visit for a primary diagnosis of HF that does not 
require an overnight hospital stay.

Patients must exhibit at least one documented new HF symptom with objective evidence 
of clinical HF consisting of at least 2 physical examination findings or one physical 
examination findings and at least one laboratory criteria.

The event requires initiation or intensification of treatment specifically for HF. Such 
treatment can include administration of intravenous agent (e.g., diuretic, vasodilator, 
vasopressor, or inotrope) or mechanical or circulatory intervention for HF,  
OR initiation of oral loop diuretic treatment, or intensification of oral maintenance loop 
diuretics for the diagnosis of HF, over a sustained period (i.e., initiation or doubling of 


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total daily dose through a period of ≥ 4 weeks), which is confirmed at a subsequent 
outpatient visit
6.4.2
Efficacy assessment 2
The secondary endpoints are: 

Time-to-first occurrence of CV death or HF hospitalization (days)

Time-to-first occurrence of HF hospitalization or outpatient HF (days)

Time-to-first occurrence of CV death, non-fatal spontaneous MI or nonfatal stroke (days)

The cumulative number of composite events, including hospitalization due to HF, 
hospitalization due to non-fatal spontaneous MI, hospitalization due to non-fatal stroke 
and CV death. This endpoint is based on the total number of recurrent composite 
endpoints (count) and patient-specific follow-up time from randomization to end of 
study/death (days).

Time to all-cause mortality (days)
A blinded central Clinical Endpoint Committee (CEC) will be responsible for adjudicating 
and classifying all death events (CV vs. non-CV) and for determining whether pre-specified 
endpoint criteria are met for the primary and secondary non-fatal endpoint events.  The CEC 
will also be responsible for adjudicating and classifying all investigator-reported outpatient 
HF events as the clinical development of HF under an outpatient setting (urgent/unscheduled 
or non-urgent) with symptoms and signs requiring initiation/intensification of intravenous or 
qualifying oral HF treatment. The diagnostic criteria for HF symptoms and signs will be 
identical whether the patient is seen in an inpatient or outpatient setting. The detailed 
definitions of the endpoints, required documentation and the adjudication process will be 
provided to all sites in a separate endpoint manual.
6.4.3
Appropriateness of efficacy assessments 
The composite of CV death or HF hospitalization is a well-established mortality and 
morbidity endpoint. The addition of the outpatient HF component here aims to capture the 
clinically important outpatient symptomatic HF event that contributes to the totality of HF 
morbidity following an AMI presenting as either inpatient (i.e., HF hospitalization) or 
outpatient (i.e., outpatient HF) events. The clinical significance of HF events in the outpatient 
setting has been increasingly recognized by medical communities and health authorities 
(Hicks, et al 2014). Outpatient HF events reported in randomized chronic HF trials, of which 
the definition is analogous to the outpatient HF event proposed for LCZ696G2301 study, have 
been shown to be associated with significantly increased risks of (CV) mortality. Furthermore, 
the outpatient HF events are also modifiable events that are equally sensitive to the evidence-
based HF therapeutics as are the mortality and composite CV death/HF hospitalization 
endpoints, which underscores the similar pathology contributing to these events (Skali, et al 
2014; Okumura, et al 2016).


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6.5
Safety 
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety 
profile of the study drugs. Such information may include diagnostic procedure reports, 
discharge summaries, autopsy reports, and other relevant information that may help in 
assessing the reported AE. All additional information will be de-identified prior to collection 
by Novartis or its agents.  
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will include the examination of general appearance and vital signs (BP 
[SBP and diastolic blood pressure (DBP)] and pulse). A short physical exam will be 
conducted at all visits starting from Visit 101 except where a complete physical examination 
is required (see Table 6-1). 
Information from all physical examinations must be included in the eSource/source 
documentation at the study site. Significant findings that are present prior to signing informed 
consent must be included in the Medical History part of the CRF. Significant findings made 
after signing the informed consent which meet the definition of an AE must be recorded on 
the AE section of the CRF.
6.5.2
Vital signs 
Vital signs include BP and pulse measurements. BP will be measured in the sitting position 
after 5 minutes of rest using an automated validated device (e.g., OMRON) or a standard 
sphygmomanometer with an appropriately sized cuff on the non-dominant arm. Guidelines for 
the management of BP are provided in Appendix 4.
6.5.3
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.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of most specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
Complete central laboratory evaluations (hematology and blood chemistry) for the assessment 
of safety in this study will be performed at Visits 1, 101, 104, 106, 108, 111 and end of study
(199). Abbreviated laboratory central evaluations will be performed as indicated in Table 6-1.


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In addition to the required central laboratory assessments, a local laboratory may be used for 
the assessment of serum potassium, serum creatinine and eGFR during the screening period as 
indicated in Table 6-1. The results from the local laboratory at Visits 101, 102, 103 and 104
will be allowed to make decisions regarding study drug administration and dose titration/dose 
level adjustments, and will be recorded in the eSource/source documents at the study sites. In 
addition, local laboratory assessments of serum potassium, serum creatinine and eGFR may 
be performed on an as-needed basis to monitor tolerability to study drug and dose adjustments 
at unscheduled visits during the treatment epoch. 
Laboratory values that exceed the boundaries of a notable laboratory abnormality should be 
assessed for AEs and additional evaluations should be performed, as judged appropriate by 
the investigator. If the laboratory abnormality induces clinical signs or symptoms, results in a 
dose adjustment of the study medications, is suspected to be study drug-related or requires 
therapeutic intervention, then the diagnosis or medical condition must be entered on the AE 
CRF. If the laboratory abnormality is the primary reason for an unforeseen hospitalization or 
otherwise fulfills the seriousness category of an AE, then the procedure for rapid notification 
of SAEs must be followed. If the laboratory abnormality leads to study drug discontinuation 
(temporarily or permanently), the patient must be followed until the abnormality resolves or 
until it is judged to be permanent. The investigation may include continued monitoring by 
repeat laboratory testing or by performing additional laboratory tests as deemed necessary by 
the investigator or the Novartis medical monitor.
Table 6-2
Routine laboratory examinations
Hematology 
Biochemistry 
Hematocrit
Alanine aminotransferase (ALT)
Hemoglobin
Albumin (Alb)
Platelet count
Alkaline phosphatase (ALP)
Red blood cell count (RBC)
Aspartate aminotransferase (AST)
White blood cell count (WBC)
Blood urea nitrogen (BUN)*
WBC differential
Calcium
Red blood cell distribution width (RDW)
Chloride
Mean corpuscular volume (MCV)
Creatinine*
Mean corpuscular hemoglobin
concentration (MCHC)
Glucose
Hemoglobin A1C
Lipid profile (total cholesterol, LDL, HDL, and 
triglycerides)
Phosphate
Potassium*
Serum pregnancy test
Sodium
Total bilirubin (TBL)
Fractionated bilirubin (if total bilirubin >2x ULN)
Total protein


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Uric acid
*Laboratory assessments of BUN, serum creatinine and serum potassium for the abbreviated central 
laboratory evaluation at visits where the complete laboratory evaluation is not performed; eGFR is 
derived from serum creatinine values following MDRD formula
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count (RBC), red blood cell distribution width (RDW), 
mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), 
white blood count (WBC) with differential, and platelet count will be measured.
6.5.4.2
Clinical chemistry
Blood urea nitrogen (BUN), creatinine, total bilirubin, fractioned bilirubin (if total 
bilirubin >2x upper limit of normal(ULN)), Aspartate aminotransferase (AST), Alanine 
aminotransferase (ALT), alkaline phosphatase, sodium, glucose (plasma), hemoglobin A1C, 
lipid profile, potassium, chloride, calcium, total protein, albumin, and uric acid will be 
measured. Potassium, BUN and creatinine will be obtained at study visits where abbreviated 
central laboratory evaluations are scheduled.
6.5.4.3
eGFR
Estimated GFR will be calculated by the central or local laboratory using the following 
MDRD formula (Stevens et al 2006): 
Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154 × (age in 
years)-0.203 × (0.742 if female) × (1.212 if black), where SCr is the standardized serum 
creatinine value.
6.5.4.4
Urinalysis
No urinalysis will be performed. 
6.5.5
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed locally in association with the index MI and 
recorded at Visit 1. Interpretation of the tracing must be made by a qualified physician and the 
ECG interpretation and the person interpreting the ECG must be recorded in the 
eSource/source documents at the study sites. The ECG tracing should be labeled with the 
study and patient number, date, and kept in the eSource/source documents at the study site. 
Clinically significant abnormalities should also be recorded on the Medical History/AE CRF 
page as appropriate.
6.5.6
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
performed locally at Visit 1. A urine dip-stick pregnancy test will be performed locally on an 
annual basis. The urine dip-stick pregnancy test is not required for post-menopausal women. 
A positive urine pregnancy test requires immediate interruption of study drug and 


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confirmation by serum pregnancy test. If positive upon confirmation test, the patient must 
discontinue study drug until after the pregnancy and lactation period.
6.5.7
Angioedema 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway 
compromise. A patient with any signs or symptoms of clinically significant angioedema 
should be thoroughly evaluated by the investigator and study medication must be permanently
discontinued.
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an 
Angioedema-like event form (provided by Novartis) to summarize the event, its treatment, 
and its ultimate outcome.  This report along with the requisite medical documentation must be 
submitted to Novartis as soon as possible. Follow-up reports must be communicated to 
Novartis as soon as new information regarding the event becomes available. All hospital 
records related to the event must be communicated to Novartis.
The investigator may be also be contacted by Novartis regarding AEs that may resemble an 
angioedema-like event. A list of terms that are considered “angioedema-like” (e.g., periorbital 
swelling) will be provided to sites in a manual. The investigator or his/her delegated staff 
must complete the required forms and provide the required medical records for all such events, 
regardless of whether the investigator views the event in question as angioedema or not.
All angioedema reports will be forwarded to an Angioedema Adjudication Committee by 
Novartis for independent adjudications. 
Information regarding this committee is outlined in Section 8.5. Details on the procedures for 
reporting angioedema events will be provided to investigators in a manual.
6.5.8
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
 
 
 
 
 


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7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.  
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
In this study, all adverse events and all serious adverse events occurring through the first two 
weeks post-randomization will be collected.  After the first two weeks post-randomization, the 
following targeted safety data will be collected in this study: 

all serious adverse events, 

adverse events of special interest (angioedema, hyperkalemia, hypotension, renal 
impairment, cognitive impairment, hepatotoxicity, hypersensitivity, malignancy, 
pregnancy and exposure during breast feeding), 

adverse events leading to a change in dose (down titration) or discontinuation of study 
drugs, and 

all suspected non-serious adverse events. 
Targeted collection of safety data will permit the further characterization of identified risks, 
potential risks, and missing information for LCZ696.  Non-suspected, non-serious adverse 
events that do not result in discontinuation or dose down titration will not be collected after 
the first two weeks post-randomization.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.


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Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment:

Yes

No
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only)

treatment dosage increased/reduced

treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB 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 has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s eSource/source documents; however, if the AE meets the criteria of an SAE, it 
must be reported to Novartis.


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7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day 


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period after the last study visit should only be reported to Novartis if the investigator suspects 
a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Protocol specific unblinding rules for SUSARs that are also 
efficacy endpoints
In studies such as this one, where the efficacy endpoints potentially meet the requirements for 
SUSAR reporting, the integrity of the study may be compromised if the endpoints are 
systematically unblinded for expedited reporting to competent authorities/relevant ECs and 
investigators. In such cases, regulations allow an exemption from SUSAR unblinding and 
expediting aimed at ensuring the validity of an outcome study (EU Guidance 2011/C 172/01;
FDA Guidance 2012). Therefore, the following rules for unblinding SUSARs during the study 
period will be applied.
7.3.1
Primary and secondary endpoints
The primary and secondary endpoints (CV death, HF hospitalization, outpatient HF, non-fatal
spontaneous MI, and non-fatal stroke) will not be unblinded even if they meet the definition 
of a SUSAR.  Novartis will not expedite a report to competent authorities/relevant ECs and 


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will not issue an investigator notification (IN). However, non-CV death, a secondary endpoint 
for the study, will be unblinded if it meets the criteria for a SUSAR. 
If specifically requested by a local Health Authority, pre-specified endpoints that also meet 
criteria for SUSARs will be expedited to this Health Authority as blinded reports.  
Investigator notifications will not be issued for these events.
7.3.2
Adverse events that are commonly seen in the study population
Investigators will report AEs or SAEs that are commonly seen in the study population but 
they will not be unblinded and will not be reported as SUSARs to regulatory agencies, ECs, or 
investigators during the study. 
In clinical trials evaluating treatments for high morbidity and/or high mortality disease states, 
SAEs that are known consequences of the underlying disease or condition under investigation, 
or events common in the study population, are anticipated to occur with some frequency 
during the course of the trial, regardless of drug exposure. While the investigator must still 
report all SAEs and all the targeted non-serious AEs during and after the first two weeks after 
randomization, respectively, as outlined in Section 7.1 SUSARS considered consistent with 
the following SAE Preferred Terms (PT) will not be unblinded and reported in an expedited 
timeframe to regulatory agencies, ECs or investigators during the course of the study.  These 
events will be presented in the clinical study report  at the end of the study.
abdominal pain, acute coronary syndrome, acute pulmonary oedema, anaemia, angina 
pectoris *, anxiety, arthralgia, asthenia, azotaemia, back pain, blood creatinine *, 
blood pressure *, blood urea nitrogen *, bronchitis *, cardiac arrest, cardiac 
arrhythmias (all Preferred Terms presenting any type of arrhythmia excluding
electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT 
syndrome, torsade de pointes), cardiac asthma, cardiac catheterization, cardiac failure 
*, cardiac output *, cardiac pacemaker *, cardiac resynchronization therapy, cardiac 
surgery (including coronary artery bypass grafting), cardiac tamponade, cardiogenic 
shock, cardiorenal syndrome, cerebrovascular accident, chest pain, chronic obstructive 
pulmonary disease, confusional state, constipation, cor pulmonale *, cough *, 
creatinine renal clearance  *, delirium, diarrhea, dizziness, dyspnea *, ejection fraction 
*, fatigue, generalized oedema, glomerular filtration rate  *, gout, headache, heart 
transplant, hepatic congestion, hyperglycemia, hyperkalemia, hyperlipidemia, 
hypertension *, hyperuricaemia, hypoglycemia, hypokalemia, hypernatremia, 
hypotension *, implantable defibrillator *, influenza *, insomnia, intra-aortic balloon 
pump, loss of consciousness, muscle spasm, musculoskeletal pain, myocardial 
infarction*, nasopharyngitis, nausea, oedema, oedema due to cardiac disease, oedema 
peripheral, osteoarthritis, pain in extremity, percutaneous coronary intervention, 
pericardial effusion, pleural effusion, pneumonia *, presyncope, pulmonary 
hypertension, pulmonary oedema, renal failure *, renal impairment, respiratory 
distress *, respiratory failure *, respiratory tract infection *, stroke*, syncope, transient 
ischemic attack, urinary tract infection, valve insufficiency*, valve stenosis*, 
ventricular failure *, ventricular assist device, vomiting, weight increased
*More than 1 preferred term can contain this term.


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
If specifically requested by a local Health Authority, pre-specified AEs commonly 
observed in the study population (see above) that also meet the criteria for SUSARs will 
be expedited to the requesting Health Authority as blinded reports without issuing INs, or

Pre-specified AEs commonly observed in the study population that occur in patients under 
the jurisdiction of the requesting Health Authority will be expedited to the Health 
Authority as unblinded reports; INs will be issued for these events.
 
 
 
7.4
Liver safety monitoring
Liver Function Test (LFT) elevations, including both aspartate transaminase (AST) and 
alanine transaminase (ALT), are common in patients following an AMI. In a study with a 
total of 1,783 patients presenting with STEMI, 59.1% patients with Killip class II had AST 
increase greater than 3x ULN and 5.1% had ALT increase greater than 3x ULN. For patients 
with liver enzyme increase, AST and ALT levels in majority of them return to baseline within 
2 weeks (Lofthus, et al. 2012).
Evaluation of LFT elevations should focus on the potential drug-induced LFT changes. As 
described by Lofthus et al, any LFT elevations during the first 2 weeks post-AMI are very 
likely caused by the underlying disease. Therefore, AST and/or ALT elevations within 2 week 
post-AMI will not be reported as SAEs unless investigators suspect the liver transaminase 
change is due to the investigational drug. A similar consideration is also applicable to the 
recurrent MI during the trial.
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Liver events, which cannot be solely explained by apparent AMI (either index or recurrent 
spontaneous MI event) as the underlying cause, are divided into two categories:

LFT increases without associated symptoms which will require repeated assessments of 
the abnormal laboratory parameter 

Liver events (i.e., significant LFT increases or liver-toxicity related symptoms with or 
without LFT increases), which will require close observation, follow-up monitoring and 
completion of the standard base liver CRF pages
Please refer to Appendix 2 Table 14-1 for complete definitions of liver laboratory triggers and 
liver events. 
Every liver laboratory trigger of liver event without apparent AMI (either index or recurrent 
MI event) as the underlying cause and as defined in Appendix 2 Table 14-1 should be 


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followed up by the investigator or designated personnel at the trial site as summarized below. 
Detailed information is outlined in Appendix 2 Table 14-2.
For the liver laboratory trigger: 

Repeating the LFT within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For significant LFT increases or liver-toxicity related symptoms with or without LFT 
increases:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
It is the investigator’s responsibility to investigate the potential occurrence of these events.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.  In addition, independent assessments of the biochemical Hy’s 
law cases (defined as ALT or AST > 3x ULN and total bilirubin > 2x ULN) reported during 
the study will be performed by an external liver safety expert.
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) 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.


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Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (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
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
7.7
Monitoring of safety data by the Data Monitoring Committee
An external independent Data Monitoring Committee (DMC) (Section 8.4) will be appointed 
to monitor the safety of study participants and to ensure that the program is being conducted 
with highest scientific and ethical standards. This DMC will review the endpoint and SAE/AE 
of special interest data throughout the trial in an unblinded manner. Should the DMC make 
recommendations on the conduct of the trial that are considered to have significant bearing on 
the benefit-risk of the trial, these will be communicated by Novartis to HAs, ECs and 
investigators within an appropriate timeframe and implement any additional actions required.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to GCP, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 


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monitoring of each site’s data may be performed by a centralized Novartis Clinical Research 
Associate (CRA) organization.  Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain eSource/source documents for each patient in the study, 
consisting of case and visit notes (hospital or clinic medical records) containing demographic 
and medical information, laboratory data, electrocardiograms, and the results of any other 
tests or assessments. All information on CRFs must be traceable to these eSource/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 eSource/source documents to 
confirm their consistency with the CRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the eSource/source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in eSource/source documents about the 
identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Oracle 
Clinical/Remote Data Capture (OC/RDC) system. Designated investigator site staff will not 
be given access to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis staff or Clinical Research Organization (CRO) working on behalf of Novartis review 
the data entered into the CRFs by investigational staff for completeness and accuracy and 
instruct the site personnel to make any required corrections or additions. Queries are sent to 
the investigational site using an electronic data query. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. If the electronic query system 
is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete 
and sign the faxed copy and fax it back to Novartis staff that will make the correction to the 
database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
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Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee
An external data monitoring committee (DMC) independent of Novartis will be appointed to 
monitor the study conduct and to review the results of the interim analyses for safety on a 
regular basis and determine if it is safe to continue the study according to the protocol. In 
addition, they will review the results from one interim analysis to allow for early stopping due 
to overwhelming efficacy. Any major recommendation from the DMC will be communicated 
to the Executive Committee and must be reviewed and ratified by the Executive Committee in 
consultation with Novartis prior to its enactment.
The membership of the DMC and the responsibilities of the DMC and Novartis will be 
defined in a separate document entitled the “Data Monitoring Committee Charter”. The DMC 
Charter will include information about data flow, purpose and timing of DMC meetings, 
guidance in the decision making process, communication strategy, procedures for ensuring 
confidentiality, procedures to address conflicts of interest and statistical monitoring guidelines.
8.5
Adjudication Committee
Clinical Endpoint Committee
All clinical events, which could potentially fulfill the criteria for the primary, secondary, or 
other selected endpoints will be assessed during the study and reported to a blinded central 
Clinical Endpoint Committee (CEC) for adjudication.  The CEC will be responsible for 
adjudicating and classifying all death events (CV vs. non-CV) and for determining whether 
pre-specified endpoint criteria are met for selected non-fatal events.  The detailed definitions 
of the endpoints, required documentation and the adjudication process will be provided to all 
sites in a separate endpoint manual.
Angioedema Adjudication Committee
All angioedema or angioedema-like events will be assessed during the study and reported a 
blinded angioedema adjudication committee for adjudication. If such an event occurs, the 


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investigator will complete an Adjudication Questionnaire for an Angioedema-like Event form 
(provided by Novartis). Details on the process of reporting angioedema and angioedema like 
events are outlined in a manual provided to investigators.
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
If an angioedema-like event satisfies the definition of an SAE, the investigator must submit an 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event.
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites.
9
Data analysis 
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. Additional details of the statistical analyses will be documented in 
a Statistical Analysis Plan (SAP).  
9.1
Analysis sets
The following analysis populations will be defined for statistical analysis:

Randomized (RAN) set – All patients who received a randomization number, regardless 
of receiving trial medication.

Safety set (SAF) - All patients who received at least one dose of study drug. Of note, the 
statement that a patient had no adverse events also constitutes a safety assessment. 
Patients will be analyzed according to treatment received. 

Full analysis set (FAS) – All patients in the RAN population who were not mis-
randomized patients*.  Following the intent-to-treat (ITT) principle, patients are analyzed 
according to the treatment they have been assigned to at the randomization. 

The Per-protocol set (PPS) will be a subset of the FAS which will consist of the patients 
who do not have major deviations. Major protocol deviations will be pre-specified prior to 
unblinding.
* Mis-randomized patients are those who were not qualified for randomization and who did 
not take study drug, but have been inadvertently randomized into the study.
9.2
Patient demographics and other baseline characteristics
Summary tables will be provided by treatment group for demographic characteristics:  
including age, age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years), sex, race, 
ethnicity, weight, height, body mass index (BMI) and baseline characteristics: including but 
not limited to information about the index MI event, (STEMI/NSTEMI; PCI/medical 
management; LVEF; Killip class, BP, renal function etc.), medical history and CV risk factors,   
and category of prior CV medications.
Continuous variables will be summarized using n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized using frequency and 
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The FAS will be the patient population for the above analyses.
9.3
Treatments 
The overall duration on the randomized study drug will be summarized by treatment group 
using mean, standard deviation, median, minimum, and maximum. Additionally, the number 
and percentage of patients will be summarized by treatment group for duration category. 
Mean doses and dose levels will be summarized by treatment group and visit.  A Kaplan-
Meier plot of time to discontinuation of study medication will be provided.  A summary table 
by treatment group will be provided to display the number of patients who discontinued study 
medication and the number of patients who subsequently received the following medications 
during the study: ACE inhibitors, ARB, and Entresto™, (sacubitril/valsartan). 
The duration of randomized study drug will also be calculated excluding temporary treatment 
discontinuations. 
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date respectively, will be summarized by therapeutic class, preferred term, and 
treatment group for the safety set. 
The number and percentage of patients on different CV background medications (e.g., aspirin, 
P2Y12 inhibitors, β-blockers, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, 
statins, and diuretics, etc.) will be tabulated by treatment at baseline and during the treatment 
epoch.
The SAF will be used for the summaries of exposure data and the FAS will be used for the 
summaries of concomitant medications.
9.4
Analysis of the primary variable(s)
All patients in the Full Analysis Set (FAS) will be included in the primary analysis. 
9.4.1
Variable(s)
The primary efficacy variable is time to first occurrence of a confirmed composite endpoint of 
cardiovascular death, HF hospitalization or outpatient HF. The confirmation of the primary 
composite events will be based on an adjudication process by an independent CEC. 
Note that deaths which cannot be classified by the adjudication committee as CV or non-CV 
death (for example due to lack of information), will be counted as a CV death for the purpose 
of the primary endpoint. 
Time-to-event is computed as the number of days from randomization to the start date of the 
primary endpoint event (first occurrence). A patient without an event will be censored at the 
last date the endpoint status was completely known* or at the time of death from non-CV
causes (i.e. any death which is confirmed to be a non-CV death by the CEC). 
* This date could include the date of withdrawal of informed consent, date of the patient’s last 
visit prior to the cut-off date of the analysis (whichever occurred first).


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9.4.2
Statistical model, hypothesis, and method of analysis
The following null hypothesis versus the alternative will be tested at the 1-sided 2.5% type I 
error rate. 
H0 : λ2/λ1 ≥ 1 (i.e., the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is greater than or equal to the hazard rate in the ramipril group (λ1)) versus
H1 : λ2/λ1 < 1 (i.e. the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is less than the hazard rate in the ramipril group (λ1))
λ2/λ1 is called the hazard ratio of LCZ696 relative to ramipril.
The time-to-first confirmed primary endpoint will be analyzed using a Cox proportional 
hazards model stratified by STEMI/NSTEMI, with Treatment, PCI use at baseline and region 
included as factors in the model. The hazard ratio for LCZ696 vs. ramipril, the associated 2-
sided 95% confidence interval and the 1-sided and 2-sided p-values will be presented from the 
analysis.
The Kaplan-Meier estimates of the cumulative event rate (1-survival function) for each 
treatment (and strata) will be plotted.
Supportive Analysis
The composition of the first confirmed composite primary efficacy endpoint will be 
summarized by treatment group descriptively. The time to reach the first of each individual 
component will be analysed using the same methodology as the described for the primary 
endpoint.  Note that for the components CV death and HF hospitalization, all events observed 
will be included in the individual component analyses and not just those which were counted 
as a ‘first event’ in the primary composite endpoint.  In addition to the standard censoring 
mechanism described in Section 9.4.3, for the analysis of time to outpatient HF, patients will 
be censored at the time of HF hospitalization or CV death. For the analysis of time to first HF
hospitalization, patients will be censored at the time of CV death.  
An ‘on-treatment’ analysis will also be performed for the primary endpoint whereby events 
that occurred more than 28 days after permanent study treatment discontinuation will be 
excluded from the analysis.  For patients without events before or at 28 days after treatment 
withdrawal, the censoring date will be the minimum of the date of permanent study treatment 
discontinuation + 28 days and the date of standard censoring for the endpoint.
Subgroup analysis
Subgroup analyses will be performed for the FAS only. 
Displays of treatment effects by subgroup categories (defined as marginal groupings) will be 
provided for descriptive purposes. 
The estimated hazard ratio, and 2-sided 95% confidence interval, will be provided for each 
individual subgroup using a Cox’s proportional hazards model stratified by STEMI/NSTEMI 
and including terms for treatment, region and PCI use at baseline in the model. The p-value
associated with the interaction term will be calculated from a Cox’s proportional hazards 
model, stratified by STEMI/NSTEMI, including treatment, PCI use at baseline, region, 


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subgroup, and treatment-by-subgroup as fixed-effect factors. Since no adjustment for multiple 
comparisons will be made, findings should be interpreted with caution.  Additionally, the 
frequency and percentage of patients reaching primary composite endpoint will be presented 
by treatment group for each of the subgroups listed below:

Age group (< 65 vs ≥65 years; < 75 vs ≥75 years)

Gender

Race

Region

STEMI vs. NSTEMI (for this analysis, do not stratify by STEMI/NSTEMI, but include as 
a factor in the model)

Baseline LVEF (by quartiles) 

Killip class (I vs. ≥II)

Infarct location (anterior, inferior, and other)

PCI use at baseline (PCI use versus medical management after index MI up to 
randomization) 

Time from the index MI presentation to randomization (two subgroups cut by the median 
time)

Baseline SBP (three groups: ≤110 mmHg; >110 mmHg and ≤140 mmHg; >140 mmHg) 

Baseline eGFR (<60 vs ≥60 mL/min/1.73 m2)

History of diabetes (yes/no)

Atrial Fibrillation associated with index MI at baseline (yes/no) 

Prior history of MI 

History of hypertension (yes/no)

Prior ACEi or ARB use (yes/no) 

Use of β-blocker at baseline (yes/no)

Use of mineralocorticoid antagonists at baseline (yes/no) 

Use of oral loop diuretics at baseline (yes/no)
9.4.3
Handling of missing values/censoring/discontinuations
For patients without a primary event prior to the analysis time point, the censoring date is 
defined as one of the following (whichever occurred first):

Date when the patient withdrew informed consent

Date of the patient’s last visit before analysis cut-off date (including telephone visit)

Date of death from non-CV causes (i.e. date of death which is confirmed as a non- CV 
death by the adjudication committee).
Note that every effort will be made to follow all patients until the end of the study, regardless 
of adherence to study treatment.


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9.4.4
Sensitivity analyses
As a sensitivity analysis treatment groups will be compared for the primary efficacy variable 
using a stratified log-rank test with STEMI/NSTEMI as a stratification factor.
9.5
Analysis of secondary variables
The Full Analysis Set (FAS) will be used for all secondary analyses.
9.5.1
Efficacy variables
The secondary variables are defined as follows; the censoring mechanism will be the same as 
defined for the primary endpoint unless indicated otherwise:
(1) Time from randomization to first occurrence of a confirmed composite of CV death or HF 
hospitalization
(2) Time from randomization to first occurrence of a confirmed composite of HF 
hospitalization or outpatient HF (censoring will occur at the time of all-cause death)
(3) Time from randomization to first occurrence of a confirmed composite of CV death, non-
fatal spontaneous MI or non-fatal stroke
(4) The cumulative number of composite events, including hospitalization due to HF, 
hospitalization due to non-fatal spontaneous MI, hospitalization due to non-fatal stroke and 
CV death. This endpoint is based on the total number of composite endpoints (count) and the 
patient-specific follow-up time from randomization to the last date the status of the patient 
was known (which could be the date of withdrawal from the study, the last visit prior to 
analysis cut off or the date of death).
(5) Time from randomization to all-cause mortality - patients without a death will be censored 
at the date of withdrawal from the study or the last day known to be alive (which may be 
established via telephone contact or the last visit prior to analysis cut off).
The secondary endpoints will be analyzed in order to compare LCZ696 vs ramipril using the 
ITT approach (i.e. estimation of the treatment effect under the ‘treatment policy’). Endpoints 
(1), (2), (3), and (5) will be analyzed using the same statistical analysis methods as specified 
for the primary analysis.  
Secondary endpoint (4) will be analyzed using a negative binomial regression model with a 
Weibull baseline intensity function to allow flexibility if the baseline intensity is non-constant 
(Lawless, 1987).  Treatment, STEMI/NSTEMI, PCI use at baseline and region will be 
included in the model as fixed effects.  The relative rate ratio will be presented for LCZ696 vs 
ramipril together with 2-sided 95% confidence interval and 1-sided p-value.  
Supportive analysis
It is recognized that at the time of the first onset of symptomatic HF event some patients may 
discontinue randomized treatment and may be prescribed an alternative treatment for HF 
which could be locally available Entresto TM (sacubitril/valsartan, LCZ696). For endpoints (1), 
(3), (4) and (5), the secondary analysis described above will estimate the treatment effect of 
LCZ696 vs ramipril including any effect of prescribed Entresto™for ramipril patients who 


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discontinued study drug and took Entresto™as an alternative treatment. Hence, the following 
supportive analyses aim to estimate the pure treatment effect as though in a situation whereby 
Entresto™was not an available treatment option for HFrEF. 
Endpoints (1), (3) and (5) will be analyzed using an inverse probability of censoring weighted 
(IPCW) Cox proportional hazards model (Robins and Finkelstein 2000)). In this analysis, the 
censoring mechanism will be the same as described for the primary analysis for patients who 
are not prescribed Entresto™. For patients who do, censoring will occur at the minimum of 
the last date the endpoint status was known, the time of death from non-CV causes or 28 days 
after study treatment discontinuation. To adjust for the potential informative censoring, 
patients with event times censored due to treatment switch will be dynamically replaced in the 
patient risk-set to be represented by patients in control arm with a matching prognostic profile 
by up-weighting such patients in the analysis set. The weights will be calculated using a 
logistic regression with clinical risk factors determinant of developing the endpoint as 
covariates in the model (both baseline and post-baseline). A weighted Cox proportional 
hazard model will be fitted to this modified risk set. The model will be stratified by 
STEMI/NSTEMI; region, PCI use at baseline will be included as covariates. The hazard ratio 
for LCZ696 vs. ramipril, the associated 2-sided 95% confidence interval and the 1-sided and 
2-sided p-values will be presented from the analysis. Further details on appropriate covariate 
adjustment and associated implementation will be prospectively provided in the statistical 
analysis plan.
Endpoint (4), the total number of confirmed hospitalizations for HF, MI and stroke (including 
CV death) will be redefined for the patients who are prescribed open label Entresto™as the 
total number of composite endpoints from randomization up to 28 days after the time of study 
treatment discontinuation. The analysis methods will remain the same as specified above.
Control of familywise type I error rate
The primary endpoint and the first four secondary efficacy endpoints will be included in a 
statistical testing strategy to control the familywise type I error rate at the 1-sided 2.5% level 
(in the strong sense). A hierarchical testing procedure will be employed whereby the primary 
hypothesis will be tested first, if rejected then the hypothesis associated with the first 
secondary endpoint will be tested and so on.  The order of testing of the composite endpoints 
will be as follows:
1. Primary endpoint
2. Time to first CV death or HF hospitalization
3. Time to first HF hospitalization or outpatient HF
4. Time to first CV death,  non-fatal spontaneous MI or non-fatal stroke
5. The total number of composite events (hospitalizations (including CV death) due to HF, 
non-fatal spontaneous MI or non-fatal stroke and CV death).      


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9.7
Interim analyses
One interim analysis for efficacy is planned. The cut-off time for this interim analysis will be 
when about two-thirds of the target number of primary events have been reported and 
adjudication-confirmed, approximately 540 of adjudication-confirmed CV deaths, HF 
hospitalizations and outpatient HF events. In the interim analysis, the analysis dataset will 
comprise of all patients who were randomized before the cutoff date. Haybittle-Peto 
boundaries will be adopted for the interim statistical comparisons between treatments. An 
alpha of 0.1% (1-sided alpha) will be spent for the comparison of primary endpoint at the 
interim analysis and the rest of alpha (1-sided 2.49% for the current specified boundary, based 
on East version 6.3) will be utilized at the final analysis. In the interim analysis, the study may 
be stopped for superior efficacy only when both the primary endpoint and CV death are 
significant at level of 0.1% (1-sided).
If the study is stopped early for superior efficacy at the interim analysis, the secondary 
endpoints will be tested using the same hierarchical testing procedure as described in Section 
9.5.1 for the same level of alpha (i.e. 1-sided alpha 0.1%).  If the study continues, then 
secondary endpoints will be tested at the final analysis using 1-sided alpha of 2.49%.
Interim analyses are also planned for the monitoring of safety data, and will be performed 
approximately every 6 months during the course of the study. Such safety analyses do not 
inflate the type I error for the primary efficacy hypothesis testing and thus no adjustment for 
multiplicity is required.  
Interim analyses will be performed by an independent statistician (at a CRO or academic 
institution) who will not be involved in the trial conduct. The results will be reviewed by an 
independent DMC. The trial investigators, Novartis employees and other personnel who are 


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involved in the conduct of the trial and in the analysis of the final trial results, or who have 
contact with study centers, will remain blinded to the treatment codes and interim analysis 
results until all monitoring decisions have been made and the database has been locked for 
final analysis. Full details of the interim analysis plan will be described in the DMC charter.
9.8
Sample size calculation
A sample size of 4,650 patients, randomized to LCZ696:ramipril using a 1:1 allocation ratio, 
has been chosen with the aim to obtain at least 800 first primary events and at least 633 CV 
death or HF hospitalization events in this event-driven study.  Eight hundred primary events 
provide at least 80% power assuming a true Relative Risk Reduction (RRR) of 18% (i.e. a 
hazard ratio of 0.82) for LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-sided 
type I error rate (with strong control of the FWER).  Six hundred and thirty three CV death or 
first HF hospitalization events will provide at least 80% nominal power assuming a true RRR 
of 20% (for the intent-to-treat analysis) for the secondary endpoint for the same type I error 
rate.
Additional assumptions are described below.

0.5% per year lost to follow-up rate

Recruitment duration of 24 months, with approximately 8 months follow-up anticipated 
for last randomized patient (i.e. 32 months total study duration) and constant recruitment 
rate

One interim analysis is planned to allow for stopping for efficacy, using a Haybittle-Peto 
boundary, thus 2.49% 1-sided alpha will be available for the final analysis, see Section 9.7.

Cumulative event rates of CV death or HF hospitalization were estimated from selected 
patients from the VALIANT database (Pfeffer et al, 2003) who were considered to be 
representative of the target patient population of this study.  In the calculation, adjustments 
were made for expected differences between the sample of patients from VALIANT and 
the patients likely to be recruited in PARADISE-MI. In particular PCI use is expected to 
increase (2/3 PCI use vs. 1/3 in VALIANT), and a larger number of NSTEMI patients are 
expected (60% NSTEMI patients vs. approximately 30% in VALIANT). Following these 
adjustments, a further 10% reduction in hazard rate for other changes in standard of care 
was also included. The cumulative event rates for the primary endpoint were based on a 
further 15% increase in hazard rate in order to account for the third component of 
outpatient HF.   See Table 9-1 for the cumulative event rates assumed for the sample size 
calculation.
Table 9-1
Cumulative event rates assumed for the sample size calculation
Time period following 
randomization
CV death or HF 
hospitalization
CV death, HF hospitalization or outpatient HF
(assuming 15% increase in hazard rate compared 
to CV death or HF hospitalization)
0-3 months
9.9%
11.3%
3-6 months
12.3%
14.0%
6-12 months
14.8%
16.8%
12-32 months
19.4%
21.9%


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The sample size calculations were carried out using PASS 2008, citation software and 
applying the Lakatos method (Lakatos,1988) and confirmed using East version 6.3.
Sample size sensitivity
This is an event driven study and the assumption about the event rates for the primary 
endpoint is a key driver for the sample size calculation. In this regard there are two main areas 
of uncertainty:

The hazard rates calculated from the post-hoc analysis of VALIANT data as described 
above are thought to reflect the contemporary setting, however, there may have been other 
changes over time which are difficult to quantify and may decrease the event rates, hence 
for the final sample size calculation an additional 10% discount of the hazard rate was 
assumed.   

The hazard rates for the primary endpoint were calculated as 1.15 x the hazard rate for the 
secondary endpoint of CV death or HF hospitalization (i.e. assuming a 15% increase in 
hazard will be observed when adjudicated outpatient HF is included in the composite 
endpoint together with CV death and HF hospitalization). However, there is no adequate
information available about the event rates of the primary triple composite endpoint which 
would be expected.
In order to understand the impact of the uncertainties described above, Table 9-2 provides the 
sample sizes estimated to achieve at least 800 primary events with different underlying 
assumptions.
Table 9-2
Total sample size required to achieve 800 primary events for different 
event rate assumptions
Increase in hazard 
rate when outpatient
HF is included in 
primary composite 
endpoint
Discount of event rates for change in SoC
0%↓
10%↓
20%↓
20%↑
4066
4468
4968
15%↑
4224
4643
5167
10%↑
4395
4834
5382
Number of randomized patients required calculated using East version 6.3
Power for secondary endpoints
Table 9-3 summarizes the nominal power for secondary endpoints which will be included in 
the statistical testing strategy. A 1-sided alpha of 2.5% has been used for the calculations.  All 
assumptions are based on exploratory analyses performed using VALIANT data (data on file).


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Table 9-3
Summary of power to reject secondary hypotheses 
Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(1) Time to first CV death or 
HF hospitalization
20% RRR
Expect 698 events1
84%
(2) Time to first HF
hospitalization or outpatient 
HF
17% RRR
Expect 536 events2
58%
(3) Time to first composite of 
CV death, non-fatal MI or 
non-fatal stroke
15% RRR
Expect 680 events3
56%
(4) Total number of 
hospitalizations for HF, MI 
and stroke related reasons 
including CV death
17% reduction in rate 
ratio
Over-dispersion=9;
Rate of events on 
ramipril per year = 
0.2364
46%
1Event rates as per Table 9-1
2 Cumulative event rates for HF hospitalization of 6.5%, 8.2%, 9.9% and 12.8% were assumed for 0-
3m, 3-6m, 6-12m and 12-32m periods respectively. Then event rates were increased by a further 15% 
to account for outpatient HF.
3 Cumulative event rates of 8.5%, 10.9%, 14.0% and 18.6% were assumed
4 For the power calculation the rate was assumed to be constant over time 
The number of events were calculated for a sample size of 4,650 patients; 24 months recruitment and 
8 months minimum follow-up. 
HF = Heart Failure; RRR = Relative Risk Reduction
The power calculations were carried out using East Version 6.3.
Blinded sample size re-estimation
When approximately 1/2 of patients have been randomized and have reached the 3 month 
time point, the piecewise hazard rates for the primary endpoint and the double composite 
endpoint (CV death or HF hospitalization) will be estimated based on blinded data.  
The piecewise hazard rates estimated from the observed data will be compared to the original 
assumptions. If there is reason to believe that the original assumptions about event rates may 
not hold, the sample size will be re-estimated taking into consideration the new information. 
The duration of the trial and minimum follow-up will also be reconsidered as part of the 
calculation. This approach will allow flexibility to achieve the required number of events in 
an acceptable time frame.
10
Ethical considerations
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the International Council for Harmonisation (ICH) Harmonized Tripartite 
Guidelines for Good Clinical Practice, with applicable local regulations (including European 


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Directive 2001/20/EC, US CFR 21, and Japanese Ministry of Health, Labor, and Welfare), 
and with the ethical principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approved informed consent, or, if incapable of doing so, after such consent has 
been provided by a legally acceptable representative(s) of the patient. In cases where the 
patient’s representative gives consent, the patient must be informed about the study to the 
extent possible given his/her understanding. If the patient is capable of doing so, he/she must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the patient eSource/source documents.*
[*] For Germany only, the first paragraph will read as follows: 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent. He/she should indicate 
assent by personally signing and dating the written informed consent document. Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient eSource/source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
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 


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clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group 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.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 


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study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request
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mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of 
heart failure. Lancet 1993;342:821-8.
Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 Guidelines for the 
management of patients with unstable angina/non-ST-Elevation myocardial infarction: a 
report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management 
of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in 
collaboration with the American College of Emergency Physicians, the Society for 
Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons 
endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and 
the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50:e1-157.
Antman EM, Hand M, Armstong PW, et al. 2007 Focused update of the ACC/AHA 2004 
guidelines for the management of patients with ST-elevation myocardial infarction: American 
College of Cardiology/American Heart Association Task force on Practice Guidelines, 
Developed in Collaboration with the Canadian Cardiovascular Society to review new 
evidence and update the ACC/AHA 2004 Guideline for the Management of Patient with ST-
Elevation Myocardial Infarction. J Am Coll Cardiol  2008;51:210-47.
Braunwald E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the 
treatment of heart failure. J Am Coll Cardiol 2015;65:1029-41.
Chen HH, Martin FL, Gibbons RJ, et al. Low-dose nesiritide in human anterior myocardial 
infarction suppresses aldosterone and preserves ventricular function and structure: a proof of 
concept study. Heart 2009;95:1315-9.
D'Souza SP, Davis M, Baxter GF. Autocrine and paracrine actions of natriuretic peptides in 
the heart. Pharmacol Ther 2004;101:113-29.
European Commission ENTR/CT3 (2011) Communication from the Commission — Detailed 
guidance on the collection, verification and presentation of adverse event/reaction reports 
arising from clinical trials on medicinal products for human use (‘CT-3’)
FDA (2012) Guidance for Industry and Investigators: Safety reporting requirements for INDs 
and BA/BE studies.
Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. GISSI-3: effects of 
lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and 
ventricular function after acute myocardial infarction. Lancet 1994;343:1115-22.
Hicks KA, Hung HMJ, Mahaffey KW, et al. Standardized Definitions for Cardiovascular and 
Stroke End Point Events in Clinical Trials. CDISC 2014.
ISIS 4 (Fourth International Study of Infarct Survival) Collaborative Group.  ISIS-4: A 
randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous 


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magnesium sulphate in 58 050 patients with suspected acute myocardial Infarction. Lancet. 
1995;345(8951):669-85
Jhund PS, McMurray JJ. Heart failure after acute myocardial infarction: a lost battle in the 
war on heart failure? Circulation 2008;118:2019-21.
Kitakaze M, Asakura M, Kim J, et al. Human atrial natriuretic peptide and nicorandil as 
adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised 
trials. Lancet 2007;370:1483-93.
Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-
enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial 
infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 
1995;333:1670-6.
Lakatos E. Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics 
1988;44:229-41.
Lawless JF. Regression Methods for Poisson Process Data. Journal of the American Statistical 
Association 1987; 82:808-15.
Lofthus DM, Stevens SR, Armstrong PW, et al. Pattern of liver enzyme elevations in acute 
ST-elevation myocardial infarction. Coronary Artery Disease 2012, 23:22–30.
McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in 
heart failure. N Engl J Med 2014;371:993-1004.
Miller AL, Dib C, Li L et al.  Left Ventricular Ejection Fraction Assessment Among Patients 
With Acute Myocardial Infarction and Its Association With Hospital Quality of Care and 
Evidence-Based Therapy Use.  Circ Cardiovasc Qual Outcomes. 2012;5:662-671.
Molkentin JD. A friend within the heart: natriuretic peptide receptor signaling. J. of Clin.
Invest. 2003;111:1275-7.
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a 
report from the American Heart Association. Circulation 2015;131:e29-322.
O’Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management 
of ST-elevation myocardial infarction: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll 
Cardiol 2013;61:e78-140.
Okumura N, Jhund PS, Gong J, et al. Importance of Clinical Worsening of Heart Failure 
Treated in the Outpatient Setting: Evidence from the Prospective Comparison of ARNI with 
ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial
(PARADIGM-HF).  Circulation 2016;Online ISSN: 1524-4539.
Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental 
observations and clinical implications. Circulation 1990;81:1161-72.
Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in 
patients with left ventricular dysfunction after myocardial infarction. Results of the survival 
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Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial 
infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 
2003;349:1893-906.
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AIDS Clinical Trial with Inverse Probability of Censoring Weighted (IPCW) Log-Rank Tests. 
Biometrics 2000; 56:779-88.
Roffi M, Patrono, C, Collet JP, et al 2015 ESC guidelines for the management of acute 
coronary syndromes in patients presenting without persistent ST-segment elevation Task 
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2016;37:3:267-315. 
Skali H, Dwyer EM, Goldstein R, et al. Prognosis and response to therapy of first inpatient 
and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT. Eur J Heart 
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The HOPE Investigators:  Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on 
cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53. 
Steg, GP, James SK, Atar D, et al.  ESC Guidelines for the management of acute myocardial 
infarction in patients presenting with ST-segment elevation The Task Force on the 
management of ST-segment elevation acute myocardial infarction of the European Society of 
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glomerular filtration rate. N Engl J Med 2006;354:2473-83.
Sulo G, Igland J, Vollset SE, et al. Heart Failure Complicating Acute Myocardial Infarction; 
Burden and Timing of Occurrence: A Nation-wide Analysis Including 86 771 Patients From 
the Cardiovascular Disease in Norway (CVDNOR) Project. J Am Heart Assoc 2016;5.
Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on 
mortality in patients with acute myocardial infarction. Results of the Cooperative New 
Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84.
Udelson JE, Konstam MA. Relation between left ventricular remodeling and clinical 
outcomes in heart failure patients with left ventricular systolic dysfunction. J Card Fail 
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myocardial infarction. Am Heart J 2014;167:267-273.e1. 
Vasaiwala S, Cannon CP, Fonarow GC, et al. Quality of Care and Outcomes Among Patients 
With Acute Myocardial Infarction by Level of Kidney Function at Admission: Report From 
the Get With The Guidelines Coronary Artery Disease Program. Clin. Cardiol 2012;35:9, 
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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:
Hematology
Hematocrit
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Platelet count
>75% increase, >50% decrease
RBC Count
>50% increase, >20% decrease
WBC count
>50% increase, >50% decrease
Blood Chemistry
Alkaline phosphatase >100% increase 
ALT (SGPT)
>150% increase
AST (SGOT)
>150% increase 
BUN
>50% increase 
Calcium
>10% increase, >10% decrease 
Chloride
>10% increase, >10% decrease 
Creatinine
>50% increase 
Potassium
>20% increase, >20% decrease 
Total bilirubin
>100% increase 
Uric acid
>50% increase


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


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


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15
Appendix 3:  Killip Classification
Pulmonary congestion following the index MI event will be assessed as the worst Killip class
between index MI presentation and randomization using the criteria outlined below:

Class 1 No rales, no 3rd heart sound 

Class 2 Rales in <1⁄2 lung field or presence of a 3rd heart sound 

Class 3 Rales in >1⁄2 lung field–pulmonary edema 

Class 4 Cardiogenic shock–determined clinically 


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16
Appendix 4: Guidelines for the management of blood 
pressure
Guidelines
1. Investigator should monitor BP closely 
2. If symptomatic hypotension occurs:
a.
Correct any treatable cause, e.g. hypovolemia
b. If hypotension persists, any non-disease modifying background antihypertensive 
drug such as diuretics, calcium channel blockers (CCBs), nitrates, and/or α-
blockers, can be down-titrated or stopped first per investigator’s clinical 
judgement before down-titration of the study drug is considered..
c.
It is important to note that dose adjustment of disease-modifying background 
therapy, e.g., β blockers, or mineralocorticoid antagonists is discouraged under 
these circumstances, unless they are believed to be the most likely cause of 
hypotension.
If hypotension persists, the study drug should be down-titrated or even temporarily withdrawn. 
The dose re-challenge and medications adjust guidelines described in Section 5.5.5 should be 
adhered to as much as possible.


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17
Appendix 5: Treatment guidelines for hyperkalemia (serum 
potassium greater than 5.3 mmol/L [mEq/L])
General principles
Elevation of serum potassium levels above the predefined values should be repeated and 
confirmed before any action is taken.
Any patient with a serum potassium > 5.3 mmol/L (mEq/L) at any time after randomization 
requires the Investigator to confirm the serum potassium concentration in a non-hemolyzed 
sample via an immediate repeat lab sample to both the clinic local lab and the study central 
lab.  Regular, repeated checks of serum potassium concentration (beyond that prescribed in 
the protocol) should continue until it is clear that the serum potassium concentration is stable 
and not rising into the range of concern (≥ 5.5 and < 6.0 mmol/L [mEq/L]) or potential danger 
(≥ 6.0 mmol/L [mEq/L]). 
Patients with elevated serum potassium value will be managed according to the corrective 
actions outlined below. Hyperkalemia should be followed until resolution.
Corrective action for management of hyperkalemia
Serum potassium greater than 5.3 and less than or equal to 5.5 mmol/L (mEq/L)

Confirm serum potassium concentration in a non-hemolyzed sample

Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
tomatoes, coffee, etc.) 

Correct metabolic acidosis if necessary. 

Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents:
o
Potassium-sparing diuretics (e.g. amiloride and triamterene) including in 
combination products with thiazide or loop diuretics 
o
Potassium supplements, e.g., potassium chloride
o
Salt substitutes 
o
Non-steroidal anti-inflammatory drugs (NSAIDs)
o
Cyclo-oxygenase-2 (COX-2) inhibitors
o
Trimethoprim and trimethoprim-containing combination products, such as 
Bactrim® and Septra® (trimethoprim/sulfamethoxazole fixed combination)
o
Herbal Supplements:


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For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, 
lily of the valley, Siberian ginseng, hawthorn berries

Assess patient for dehydration or any condition that could lead to dehydration (e.g., 
diarrhea, vomiting) and/or hypovolemia and initiate appropriate corrective measures of 
rehydration. 

Repeat serum potassium measurement within 3 to 5 days

If serum potassium remains > 5.3 and ≤ 5.5 mmol/L (mEq/L), regularly monitor serum 
potassium levels to ensure stability (suggested once monthly)

Consider down-titration of study drug, according to investigator’s medical judgment.
Serum potassium greater than 5.5 and less than 6.0 mmol/L (mEq/L)  

Confirm serum potassium concentration in a non-hemolyzed sample 

Consider 
down-titration 
or 
temporarily 
discontinue 
background 
therapy 
of 
mineralocorticoid antagonists (if they are believed to be the most likely cause of 
hyperkalemia).

Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L

Repeat serum potassium measurement after 2-3 days

If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat serum potassium within 5 days
Serum potassium greater than or equal to 6.0 mmol/L (mEq/L)

Immediately discontinue study drug

Confirm serum potassium concentration in a non-hemolyzed sample

Urgently evaluate patient and treat hyperkalemia as clinically indicated 

Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L (mEq/L)
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee.


Global Clinical Development - General Medicine 
[LCZ696]
Clinical Trial Protocol CLCZ696G2301
PARADISE-MI:  Prospective ARNI versus ACE inhibitor trial to 
DetermIne Superiority in reducing heart failure Events after 
Myocardial Infarction
A multi-center, randomized, double-blind, active-controlled, parallel-
group Phase 3 study to evaluate the efficacy and safety of LCZ696 
compared to ramipril on morbidity and mortality in high risk 
patients following an acute myocardial infarction
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2016-002154-20
Version number:
04 Clean
Clinical trial phase:
III
Release date:
06-Aug-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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Protocol No. CLCZ696G2301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 4 (06-Aug-2020) ..................................................................................................12
Amendment 3 (01-May-2019)..................................................................................................14
Amendment 2 (25-Apr-2017)...................................................................................................17
Amendment 1 (29-Jun-2016)....................................................................................................19
Protocol summary..............................................................................................................20
1
Introduction .......................................................................................................................26
1.1
Background............................................................................................................26
1.2
Purpose ..................................................................................................................27
2
Study objectives and endpoints .........................................................................................28
2.1
Primary objective(s)...............................................................................................28
2.2
Secondary objective(s)...........................................................................................28
28
3
Investigational plan ...........................................................................................................29
3.1
Study design...........................................................................................................29
3.2
Rationale for study design .....................................................................................34
3.3
Rationale for dose/regimen, route of administration and duration of treatment....34
3.4
Rationale for choice of comparator .......................................................................34
3.5
Purpose and timing of interim analyses/design adaptations..................................35
3.6
Risks and benefits..................................................................................................35
4
Population..........................................................................................................................35
4.1
Inclusion criteria ....................................................................................................36
4.2
Exclusion criteria...................................................................................................37
5
Treatment...........................................................................................................................39
5.1
Study treatment......................................................................................................39
5.1.1
Investigational and control drugs..........................................................39
5.1.2
Additional treatment..............................................................................40
5.2
Treatment arms......................................................................................................40
5.3
Treatment assignment and randomization.............................................................40
5.4
Treatment blinding.................................................................................................40
5.5
Treating the patient................................................................................................41


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5.5.1
Patient numbering .................................................................................41
5.5.2
Dispensing the study drug.....................................................................41
5.5.3
Handling of study and additional treatment..........................................42
5.5.4
Instructions for prescribing and taking study treatment........................42
5.5.5
Permitted dose adjustments and interruptions of study treatment ........44
5.5.6
Rescue medication ................................................................................45
5.5.7
Concomitant medication .......................................................................46
5.5.8
Prohibited medication ...........................................................................47
5.5.9
Emergency breaking of assigned treatment code..................................47
5.6
Study Completion and Discontinuation.................................................................48
5.6.1
Study completion and post-study treatment..........................................48
5.6.2
Discontinuation of Study Treatment.....................................................48
5.6.3
Withdrawal of informed consent...........................................................49
5.6.4
Lost to follow-up...................................................................................50
5.6.5
Early study termination by the sponsor.................................................50
6
Visit schedule and assessments .........................................................................................50
6.1
Information to be collected on screening failures..................................................56
6.2
Patient demographics/other baseline characteristics .............................................56
6.3
Treatment exposure and compliance .....................................................................56
6.4
Efficacy..................................................................................................................56
6.4.1
Efficacy assessment 1 ...........................................................................56
6.4.2
Efficacy assessment 2 ...........................................................................57
6.4.3
Appropriateness of efficacy assessments..............................................57
6.5
Safety.....................................................................................................................57
6.5.1
Physical examination ............................................................................58
6.5.2
Vital signs..............................................................................................58
6.5.3
Height and weight .................................................................................58
6.5.4
Laboratory evaluations..........................................................................58
6.5.5
Electrocardiogram (ECG) .....................................................................60
6.5.6
Pregnancy and assessments of fertility .................................................60
6.5.7
Angioedema ..........................................................................................61
6.5.8
Appropriateness of safety measurements..............................................61
.61
61
.62
62


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7
Safety monitoring..............................................................................................................63
7.1
Adverse events.......................................................................................................63
7.2
Serious adverse events...........................................................................................65
7.2.1
Definition of SAE .................................................................................65
7.2.2
SAE reporting........................................................................................65
7.3
Protocol specific unblinding rules for SUSARs that are also efficacy 
endpoints................................................................................................................66
7.3.1
Primary and secondary endpoints .........................................................66
7.3.2
Adverse events that are commonly seen in the study population .........67
68
7.4
Liver safety monitoring .........................................................................................68
7.5
Reporting of study treatment errors including misuse/abuse ................................69
7.6
Pregnancy reporting...............................................................................................70
7.7
Monitoring of safety data by the Data Monitoring Committee.............................70
8
Data review and database management.............................................................................70
8.1
Site monitoring ......................................................................................................70
8.2
Data collection.......................................................................................................71
8.3
Database management and quality control............................................................71
8.4
Data Monitoring Committee..................................................................................72
8.5
Adjudication Committee........................................................................................72
9
Data analysis......................................................................................................................73
9.1
Analysis sets ..........................................................................................................73
9.2
Patient demographics and other baseline characteristics.......................................74
9.3
Treatments .............................................................................................................74
9.4
Analysis of the primary variable(s) .......................................................................74
9.4.1
Variable(s).............................................................................................74
9.4.2
Statistical model, hypothesis, and method of analysis..........................75
9.4.3
Handling of missing values/censoring/discontinuations.......................76
9.4.4
Sensitivity analyses ...............................................................................77
9.5
Analysis of secondary variables ............................................................................77
9.5.1
Efficacy variables..................................................................................77
79
79
80
81


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81
82
.82
9.7
Interim analyses.....................................................................................................82
9.8
Sample size calculation..........................................................................................83
9.8.1
Original sample size planning...............................................................84
9.8.2
Blinded sample size re-estimation ........................................................87
10 Ethical considerations........................................................................................................90
10.1
Regulatory and ethical compliance........................................................................90
10.2
Informed consent procedures.................................................................................90
10.3
Responsibilities of the investigator and IRB/IEC..................................................90
10.4
Publication of study protocol and results...............................................................91
10.5
Quality Control and Quality Assurance.................................................................91
11 Protocol adherence ............................................................................................................91
11.1
Protocol Amendments ...........................................................................................91
12 References .........................................................................................................................92
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................96
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................97
15 Appendix 3:  Killip Classification.....................................................................................99
16 Appendix 4: Guidelines for the management of blood pressure .....................................100
17 Appendix 5: Treatment guidelines for hyperkalemia (serum potassium greater than 
5.3 mmol/L [mEq/L]) ......................................................................................................101
103
List of tables
Table 3-1
Study drug dose levels during treatment epoch ....................................31
Table 3-2
Total daily doses of commonly used ACE inhibitors and ARBs 
corresponding to dose level 2 of study drug .........................................32
Table 3-3
Safety monitoring criteria that must be met for dose uptitration ..........33
Table 5-1
Study drug dispensed during the treatment epoch by study visit..........43
Table 5-2
Prohibited medication ...........................................................................47
Table 6-1
Assessment schedule.............................................................................52
Table 6-2
Routine laboratory examinations ..........................................................59
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................70
Table 9-1
Cumulative event rates assumed for the sample size calculation .........84


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Table 9-2
Total sample size required to achieve 800 primary events for 
different event rate assumptions............................................................85
Table 9-3
Summary of power to reject secondary hypotheses..............................86
Table 9-4
Cumulative event rates (pooled) for the primary endpoint (first CV 
death, HF hospitalization or outpatient HF event)................................88
Table 9-5
Cumulative event rates (pooled) for the double composite endpoint 
(first CV death or HF hospitalization event).........................................88
Table 9-6
Summary of power to reject secondary endpoints’ null hypotheses.....89
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................97
Table 14-2
Follow-up Requirements for Liver Events and Laboratory Triggers....97
List of figures
Figure 3-1
Study design..........................................................................................29
Figure 3-2
Study drug initiation and up-titration in PARADISE-MI.....................31


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List of abbreviations
ACE
Angiotensin converting enzyme 
ACEi
Angiotensin converting enzyme inhibitor
AE
Adverse Event
AESI
Adverse event of special interest
ALB
Albumin
ALP
Alkaline phosphatase
ALT
Alanine Aminotransferase
AMI
Acute myocardial infarction
ARB
Angiotensin receptor blocker
ARNI
Angiotensin receptor neprilysin inhibitor
AST
Aspartate aminotransferase
AUC
Area under the curve
BB
Beta blocker
bid
twice a day
BMI
Body mass index
BNP
B-type natriuretic peptide
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CABG
Coronary artery bypass graft
CCB
Calcium channel blocker
CCU
Coronary/critical care unit
CEC
Clinical Event Committee
CDS
Core Data Sheet (for marketed drugs) 
CFR
US Code of Federal Regulations 
CHF
Chronic heart failure
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019 caused by severe acute respiratory syndrome 
coronavirus 2 (also called SARS-CoV-2)
CPK
Creatine phosphokinase
CPO
Country Pharma Organization
CRF
Case Report/Record Form 
eCRF
Electronic Case Report/Record Form
CRT
Cardiac resynchronization therapy 
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Terminology Criteria
CTRD 
Clinical Trial Results Database 
CV
Cardiovascular


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DBP
Diastolic blood pressure
DM
Diabetes mellitus
DMC
Data Monitoring Committee
DS&E
Drug Safety & Epidemiology
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiography
EDC
Electronic Data Capture
EF
Ejection fraction
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EOS
End of study
ER
Emergency room
ESRD
End stage renal disease
FAS
Full analysis set
FDA
Food and Drug Administration 
FWER
FamilyWise Error Rate
GCP
Good Clinical Practice
hCG
Human chorionic gonadotropin
HF
Heart failure
HFpEF
Heart failure with preserved ejection fraction
HFrEF
Heart failure with reduced ejection fraction
Hgb
Hemoglobin
HMG-CoA
3-hydroxy-3-methyl-glutaryl-coenzyme A 
HR
hsTnT
Hazard ratio
High-sensitivity troponin T
HTN 
Hypertension
IA
Interim analysis
IB
Investigator brochure
ICD
Implantable cardioverter defibrillator
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICU
Intensive care unit
IEC
Independent Ethics Committee
IN
Investigator notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine system
iv
Intravenous
LFT
Liver function test 


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LV
Left ventricular
LVAD
Left ventricular assist device
LVEF
Left ventricular ejection fraction 
LVH
Left ventricular hypertrophy
MACE
Major Adverse Cardiac Events
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities 
MI
Myocardial infarction
MMRM
Mixed model of repeated measurements 
MRA
Mineralocorticoid antagonist
NEP
Neprilysin
NEPi
Neprilysin inhibitor
NSTEMI
Non-ST-elevation myocardial infarction
NT-proBNP
N-terminal pro-brain natriuretic peptide
OC/RDC
Oracle Clinical/Remote Data Capture 
od
once a day
PCI
Percutaneous coronary intervention
PDE-5
Phosphodiesterase-5
po
oral(ly)
PRO
Patient reported outcomes
PT
Preferred term
PTA
Post-trial access program
RAS
Renin angiotensin system 
RBC
Red blood cell
RDW
Red blood cell distribution width
RRR
Relative risk reduction 
RU
Resource utilization
SAE
Serious Adverse Event
SAF
Safety set
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SMQ
Standardized MedDRA Query
STEMI
ST-elevation myocardial infarction
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TD
Study Treatment Discontinuation
ULN
Upper limit of normal
WBC
White blood cell


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WHO
World Health Organization 
WoC
Withdrawal of Consent


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


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Amendment 4 (06-Aug-2020)
Amendment rationale 
The purpose of this amendment is to add a second interim analysis in response to the 
COVID-19 pandemic with the stopping boundary for the primary endpoint at one-sided alpha 
of 0.005. 
A novel coronavirus that had not previously been identified is causing clinical disease in 
humans (COVID-19). On 11-Mar-2020, the World Health Organization (WHO) characterized 
COVID-19 as a pandemic. As acknowledged by global Health Authorities in their guidance to 
the pharmaceutical industry, the COVID-19 pandemic has a global impact on the conduct of 
clinical trials of medicinal products. Challenges arising include at-risk patient populations, 
site closures, travel restrictions, shelter-in-place orders, interruptions to the supply chain for 
the investigational product, and other considerations if trial patients and site personnel 
become infected with COVID-19.
The significant impact of COVID-19 on the safety of patients and study personnel has greatly 
impacted study conduct. We have already observed marked increase in missed visits, 
treatment interruption due to drug supply issues related to the pandemic and substantial 
reduction of HF hospitalization and outpatient HF events. This observation is consistent with 
the published data which showed a greater than 50% reduction in the occurrence of HF 
hospitalization during the COVID-19 pandemic (Hall, et al. 2020), adding to other serious 
challenges on the conduct of the PARADISE-MI study. 
Prior to 01-Mar-2020, timepoint before which clinical trial data has generally not been 
impacted by the COVID-19 pandemic at the global level, approximately 80% of the 708 
target total number of the primary events in the PARADISE-MI study had been accumulated. 
Considering the advanced state and documented impact of the COVID pandemic on the 
conduct of the trial, the PARADISE-MI Executive Committee recommended adding a second 
interim analysis using the primary events accrued prior to 01-Mar-2020 for the primary 
analysis. In case of early stopping, all additional endpoints occurring on or after 01-Mar-2020 
until study close out will be included as a sensitivity analysis.  In the event that the data 
accumulated prior to the adverse influence of the pandemic had already established 
convincing efficacy, as per the proposed second interim analysis criteria, it would represent 
the most reliable test of the study hypothesis.
Novartis will continue monitoring the impact of the COVID-19 pandemic, in the event that 
the COVID-19 pandemic continues over a prolonged period of time hampering the ability to 
complete the trial in a timely and appropriate fashion, Novartis may consider modifying the 
proposed interim analysis to be the final analysis and close out the study prematurely.
There is no impact of this amendment on the study population or endpoints. If the trial 
continues after the interim analysis, the main analysis of the study result will remain as per the 
original protocol but additional sensitivity analyses will be performed to evaluate the potential 
impact of COVID-19 on the interpretation of data generated post 01-Mar-2020. The alpha for 
the final analysis will be adjusted accordingly to control the overall type 1 error (across the 2 
interim analyses and the final analysis) at 1-sided alpha of 0.025.  


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Changes to the protocol
List of abbreviations was updated to include COVID-19. 
Previous Amendments were updated to include amendment finalization date as per current 
Novartis standard.
Protocol Summary Data Analysis section, Section 3.5 Purpose and timing of interim analyses/ 
design adaptations, and Section 8.4 Data Monitoring Committee were updated to reflect the 
introduction of a second interim analysis.  
Table 6-1 and Section 18 Appendix 6 Investigational Plan
 
 
Table 6-1 has also been 
updated to indicate echocardiograms performed as standard of care prior to consent are 
permitted.
Section 9 has been updated to reflect the general data analysis strategies for the added second 
interim analysis and possible early termination by sponsor if needed due to COVID-19.
Section 9.4.4 has been updated to define the approach for sensitivity analyses related to 
COVID-19.
Section 9.5 has been updated to describe the general strategies for the main and sensitivity 
analyses relative to the secondary efficacy endpoints. 
 
Section 9.7 Interim Analysis was updated to describe the plan for the added efficacy interim 
analysis.
Section 9.8 has been updated to discuss the impact on power for the primary endpoint in 
adding the second efficacy interim analysis.
Section 12 was updated with the added reference.
Other typographical corrections were also included.
All changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol may require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. The changes herein do NOT 
affect the trial specific model ICF.


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Amendment 3 (01-May-2019)
Amendment rationale 
The purpose of this amendment is to increase the sample size from 4,650 to 5,650 and adjust 
the assumption for the primary composite endpoint events of cardiovascular (CV) death, heart 
failure (HF) hospitalization, or outpatient HF treatment effect from 18% to 19%.  These 
changes were made as an outcome of the per-protocol sample size re-estimation that was 
conducted when approximately ½ of patients were randomized and reached the 3 month 
treatment time point as described in Section 9.8.  At the time of this protocol amendment 
release, over 3,500 patients have been randomized.  
PARADISE-MI is an event-driven outcomes study. In the per-protocol sample size re-
estimation, the estimated cumulative event rates based on the available blinded data were 
lower than the originally assumed event rates. This indicated that the original assumptions 
may not hold. Therefore, in order to limit the impact in terms of considerable increase in 
overall trial duration, sample size re-estimation was performed and sample size increase 
became necessary.  In addition, newly available efficacy data from the PIONEER-HF 
(CLCZ696BUS01) study showed a 46% relative risk reduction (RRR) (HR 0.54, 95% CI 0.37, 
0.79) in patients treated with sacubitril/valsartan for 8 weeks compared to enalapril for an 
exploratory composite of serious clinical endpoint of death, rehospitalization for heart failure, 
implantation of a left ventricular assist device, and inclusion on the list of patients eligible for 
heart transplantation (Velazquez, et al. 2019). The observed risk reduction on the composite 
endpoint from the PIONEER-HF study was primarily driven by rehospitalization.  Given a 
similar underlying pathophysiological mechanism between heart failure with reduced ejection 
fraction (HFrEF) and post- acute myocardial infarction (AMI) with left ventricular 
dysfunction, and also the acute setting for both PIONEER-HF and PARADISE-MI studies, 
this new data indicated that the initial hazard reduction assumption of the primary endpoint in 
PARADISE-MI may have been an underestimate. The increase in the sample size and the 
assumption for the treatment effect size maintain the statistical power of 80% for the primary 
composite endpoint. 
Additionally, Section 5.6.1 was updated to replace the described open-label extension study 
with a post-trial access program (PTA).  The purpose of the PTA is to make the 
investigational drug available to qualified patients participating in the trial after the 
completion of the trial, in line with local laws and regulations. 
Lastly, the assessment schedule has been clarified in regard to additional visits.  
PARADISE-MI is an event-driven trial and patients will continue to be treated until the 
required number of endpoints is met and the maximum treatment period is expected to extend 
beyond month 32.  Some minor changes are also made to clarify the entry criteria regarding 
risk factors, and to correct typographical errors and minor inconsistencies in the protocol.  
There is no impact of this amendment on the study population or the main analysis of the 
study results. 


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Amended Clinical Trial Protocol (Version 04 Clean)
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Changes to the protocol
The described changes under the amendment rationale regarding the sample size re-estimation 
are implemented throughout the protocol.  In addition, the following updates, clarifications, 
and omissions are included in this protocol amendment: 
Protocol Summary was updated to reflect the extended trial duration, updated sample size and 
endpoint event assumptions, to add clarity to Inclusion Criteria #5, 
 
In Figure 3-1, the duration of double-blind treatment epoch was expanded to reflect treatment 
until the number of required endpoints is met and patients return for the end of study (EOS) 
visit.
Table 3-3 The renal function criteria was corrected to estimated globular filtration rate (eGFR) 
≥ 30 mL/min/1.73m2 and creatinine increase  < 0.5 mg/dl from baseline as noted elsewhere in 
the protocol.
Section 3.1 The estimated trial duration was updated from 32 months to 43 months and the 
recruitment period was updated to approximately 37 months.  
Section 3.5 Estimated number of endpoints needed at the time of interim analysis was updated. 
Section 4 The number of centers with randomized patients was reduced from approximately 
650 to approximately 500. 
Section 4.1 Inclusion Criteria #5 was updated to clarify that if multiple left ventricular 
ejection fraction (LVEF) measurements have been performed during index event, the last one 
performed prior to randomization should be considered as the qualifying measurement.
Section 4.2 Exclusion Criteria #27 was added.  
 
 
 
Section 5.4, Section 5.5.9, and Section 5.6.2 were aligned to clarify that patients who are 
intentionally unblinded as per study process must permanently discontinue study treatment; 
whereas the appropriate personnel from the site and Novartis will assess whether study drug 
should be discontinued in instances where a patient is inadvertently unblinded for any reason.  
Section 5.6.1 Approach for the investigational drug to be made available to qualified patients 
participating in the trial was refined from an open-label extension study to a post-trial access 
(PTA) program and added that the mechanism for post-trial access to investigational drug 
must comply with the local laws and regulations in the participating countries in order to be 
made available.
Section 5.6.3 Withdrawal of Informed Consent section was updated to align with new laws 
regarding personal data.
Section 6 Language was added to specify that in addition to vital status, primary endpoint 
information should be collected for every patient.  


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Table 6-1 was expanded to reflect patients’ continuation in the trial until the number of 
required events is met and patients are asked to return for the EOS and reflect assessments 
which are considered standard of care at time of screening and randomization.  
Section 6.5.4 Section was updated as per Table 6-1.  
Section 6.5.6 Section was updated to reflect that the patient must interrupt, rather than 
discontinue, study drug in case of pregnancy. Update is also reflected in Table 6-1.
Section 9.3 Section was updated to align with the statistical analysis plan.
Section 9.6.1 Secondary efficacy endpoint regarding changes in serum creatinine was clarified.
Section 9.7 Section was updated to reflect that the interim analysis will be conducted when 
approximately 472 adjudication-confirmed primary endpoints have been reached.
Section 9.8 Sample Size Calculation was revised following the planned sample size re-
estimation using blinded data and the updated sample size calculation is described in
Section 9.8.2.  
Appendix 5 Pre-defined potassium values for the management of hyperkalemia were updated 
to correct an inconsistency.  Hyperkalemia values that warrant corrective action include serum 
potassium greater than 5.3 and less than 5.5 mmol/L (mEq/L); serum potassium greater than 
or equal to 5.5 and less than 6.0 mmol/L (mEq/L).
Appendix 6 Investigational Plan
 
nd to reflect the additional exclusion criteria 
for patients participating in the pulmonary ultrasound assessment.  
Other minor updates and corrections were also included.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol No. CLCZ696G2301
Amendment 2 (25-Apr-2017)
Amendment rationale
 
 
 
  
 
 
 
    
The amendment also removes the targeted adverse event data collection, and provides 
additional guidance for co-administering LCZ696 with atorvastatin or other statins.  Further, 
in order to achieve the target dose in the early phase post AMI, for patients who have not 
titrated to the target dose level 3 by week 4, an unscheduled dose titration visit on or about 
week 6 is also recommended.   Finally, some minor changes were also made to clarify the 
valsartan bridging procedure on day 1 post randomization, and to correct typographical errors 
and inconsistencies in the protocol. There is no impact of this amendment on the study 
population or the main analysis of the study results.
Changes to the protocol
 
 
Section 3 Investigational plan was updated to clarify the one-day valsartan bridging procedure 
Section 4.1 Inclusion criteria

Inclusion criteria #3 was updated to clarify that patients with clinical presentation 
thought to be related to Takotsubo cardiomyopathy are also not eligible.

Inclusion criteria #4 was updated to add diuretics, vasodilators, vasopressors and/or 
inotropes as intravenous treatment required for pulmonary congestion. A footnote was 
also added clarifying the index MI with LV systolic dysfunction and/or pulmonary 
congestion.
Section 4.2 the following exclusion criteria were updated or added

Exclusion criteria #13 was updated to permit equivalent plasma potassium value.

Exclusion criteria #25 regarding women of child bearing potential and the use of 
highly effective contraception was updated to allow local regulations to take 
precedence when it deviates from the contraception methods listed in the protocol; the 
local regulations will be described in the ICF. 


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
 
Section 5.5.4 Instructions for prescribing and taking study drug was updated to clarify the 
valsartan bridging procedure.
Section 5.5.7 Concomitant medications was updated to provide additional guidance when co-
administering LCZ696 with atorvastatin or other statins. 
Table 6-1 Assessment schedule was updated as follows:

The use of the central laboratory for screening and study drug titration decisions was 
added if the use of the local laboratory is not possible or will take longer to obtain 
results than the central laboratory assessments.



The recommended unscheduled dose uptitration visit was added

More frequent pregnancy testing, if required by local regulatory authorities was added

 
  
Section 6.5.4 Laboratory evaluations was updated to allow equivalent plasma potassium and 
central laboratory assessments for screening and dose initiation and titration decisions. 
Section 6.5.6 Pregnancy and assessments of fertility was updated to allow more frequent 
pregnancy testing if required by local regulatory authorities.
Sections 6.6.4
Section 7.1 Adverse events were updated to remove the targeted collection of safety data so 
that all AEs will be collected.  Also, statin related adverse events were added to the list of AEs 
of special interest.
Section 7.4 Liver safety monitoring was updated to include acute heart failure episodes as an 
underlying cause for events of liver enzyme elevation.
Sections 9.6.6
.
Section 17, Appendix 5 Treatment guidelines for hyperkalemia was updated to allow serum or 
equivalent plasma potassium values.
Section 18, Appendix 6
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. The changes 
herein do NOT affect the trial specific ICF.


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Protocol No. CLCZ696G2301
Amendment 1 (29-Jun-2016)
Amendment rationale 
The purpose of this amendment is to refine the recommendations for alternative treatment to 
ensure sufficient RAS blockade in the event a patient needs to discontinue the study drug due 
to intolerable adverse events. The amendment also clarifies the acceptable methods of 
contraception for women of child bearing potential. Additional minor changes were also made 
to correct typographical errors and inconsistencies in the protocol.  None of these changes will 
have an impact on the study population, endpoints, or the analysis of the study results.
Changes to the protocol
Section 5.5.6 Rescue medications was updated to provide guidance on the alternative open-
label treatment of RAS blockade in the event a patient needs to discontinue study drug at the 
investigator’s discretion due to intolerable adverse events, despite the dose reduction or 
temporary interruption/re-challenge of study medication.  
Section 4.2 Exclusion criteria #25 was changed to clarify that women physiologically capable 
of becoming pregnant are excluded unless they are using highly effective methods of 
contraception not basic methods of contraception.  The methods of contraception currently 
described in the protocol are highly effective, however, the wording was modified to comply 
with the current Novartis guidelines for the prevention of pregnancy.
Additional minor changes were made to correct inconsistencies and typographical errors in 
the protocol.  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. The changes 
herein do NOT affect the trial specific ICF.


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Protocol No. CLCZ696G2301
Protocol summary 
Protocol number
CLCZ696G2301
Title
A multi-center, randomized, double-blind, active-controlled, parallel-group 
Phase 3 study to evaluate the efficacy and safety of LCZ696 compared to 
ramipril on morbidity and mortality in high risk patients following an acute 
myocardial infarction 
Brief title
PARADISE-MI:  Prospective ARNI versus ACE inhibitor trial to DetermIne 
Superiority in reducing heart failure Events after Myocardial Infarction
Sponsor and Clinical 
Phase
Novartis; Phase III
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this study is to evaluate the efficacy and safety of 
LCZ696 compared to ramipril, in reducing the occurrence of cardiovascular 
(CV) death, heart failure (HF) hospitalization and outpatient HF (time-to-first 
event analysis) in post-AMI patients with evidence of left ventricular (LV) 
systolic dysfunction and/or pulmonary congestion, without a known prior 
history of chronic HF.   
This is an event-driven study which is a well-established study design for 
long-term cardiovascular outcome trials in post-acute myocardial infarction 
(AMI) patients. While the composite of CV death or HF hospitalization is a 
well-established mortality and morbidity endpoint, the addition of the 
outpatient HF component, which in this study represents the confirmed 
diagnosis of new onset symptomatic HF, aims to capture the clinically 
important outpatient event that contributes to the totality of HF morbidity 
following an AMI presenting as either inpatient (i.e., HF hospitalization) or 
outpatient (i.e., outpatient HF) events.   
Ramipril is chosen as an active comparator of the study representing the 
guideline-recommended standard-of-care angiotensin converting enzyme 
(ACE) inhibitors shown to improve survival and reduce HF morbidity in 
high-risk post-AMI patients.
Primary Objective(s) 
To demonstrate that LCZ696 is superior to ramipril in delaying the time-to-
first occurrence of the composite endpoint of CV death, HF hospitalization 
or outpatient HF* in patients with LV systolic dysfunction and/or pulmonary 
congestion following an AMI.
(*The outpatient HF endpoint event is defined as an adjudicated event of 
clinical development of symptomatic HF (either urgent/unscheduled or non-
urgent) in the outpatient setting with symptoms and signs requiring 
initiation/intensification of intravenous or qualifying oral HF treatment.)
Secondary Objectives

To demonstrate the superiority of LCZ696, compared to ramipril, in 
delaying the time-to-first occurrence of CV death or HF hospitalization 

To demonstrate the superiority of LCZ696, compared to ramipril, in 
delaying the new onset of symptomatic HF defined as time-to-first 
occurrence of HF hospitalization or outpatient HF

To demonstrate the superiority of LCZ696, compared to ramipril,  in 
delaying the time-to-first occurrence of CV death, non-fatal 
spontaneous MI or non-fatal stroke 


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
To demonstrate the superiority of LCZ696, compared to ramipril, in 
reducing the rate of the composite endpoint of CV death and total (first 
and recurrent) hospitalizations  due to HF, non-fatal spontaneous MI or 
non-fatal stroke   

To demonstrate the superiority of LCZ696, compared to ramipril, in 
delaying the time to all-cause mortality

To evaluate the safety and tolerability of LCZ696 compared to ramipril
Study design
This study is a multicenter, randomized, double-blind, active controlled, 
event-driven phase III clinical trial designed to evaluate the efficacy and 
safety of LCZ696 compared to ramipril when added to standard therapy in 
post-AMI patients with LV systolic dysfunction and/or pulmonary congestion 
over a period of approximately 43 months.
The study is event-driven and will continue until the requirement of total 
confirmed endpoint events, i.e., at least 708 first primary composite 
endpoint events and at least 592 first CV death or HF hospitalization 
events, has been achieved.
Population
Approximately 5,650 male and female high risk patients ≥ 18 years of age 
who have sustained a spontaneous acute myocardial infarction (ST 
segment elevation MI (STEMI) or non-ST segment elevation MI (NSTEMI) 
between 12 hours to 7 days prior to randomization) with evidence of LV 
systolic dysfunction and/or pulmonary congestion associated with index MI.  
In addition, patients have to have at least one predefined risk factor and 
without known prior history of chronic HF.  
Key Inclusion criteria
1.
Written informed consent must be obtained before any assessment is 
performed. 
2.
Male or female patients ≥ 18 years of age. 
3.
Diagnosis of spontaneous AMI based on the universal myocardial 
infarction (MI) definition* with randomization to occur between 12 hours 
and 7 days after index event presentation**.  
Spontaneous AMI is defined when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischemia due to 
primary coronary event. Under these conditions, the following criteria 
have to be met for the diagnosis of spontaneous AMI:

Detection of rise and/or fall of cardiac enzymes (cardiac troponin, 
cTn or the MB fraction of creatinine kinase, CKMB) with at least 
one value above the 99th percentile of the upper reference limit 
(URL) or the local laboratory MI diagnosis cut-off value, together 
with evidence of myocardial ischemia with at least one of the 
following:
•
Ischemic discomfort or other ischemia symptom(s)
•
Electrocardiogram (ECG) characteristics of STEMI or 
NSTEMI including new or presumably new significant ST-
segment-T wave (ST-T) changes
•
Newly developed pathological Q waves or left bundle 
branch block (LBBB) in the ECG
(*Patients with a spontaneous MI event determined to be secondary to 
another medical condition such as anemia, hypotension, or an 
arrhythmia OR thought to be caused by coronary vasospasm with 
documented normal coronary arteries are not eligible; patients with 
clinical presentation thought to be related to Takotsubo cardiomyopathy 
are also not eligible)  


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(**Index MI presentation is the time of patient presentation at either the 
ER/ED, ICU/CCU or hospital ward etc., for the treatment of the index 
MI.)
4. Evidence of LV systolic dysfunction and/orǂ pulmonary congestion 
requiring intravenous treatment associated with the index MI event 
defined as:

Left ventricular ejection fraction (LVEF) ≤ 40% assessed locally by 
echocardiography, magnetic resonance imaging, cardiac CT, 
radionuclide or contrast ventriculography after index MI 
presentation and prior to randomization.
(These examinations may be performed as part of patient standard-of-
care. In case multiple LVEF measurements have been performed during 
index event, the last one performed prior to randomization should be 
considered as the qualifying measurement), and/orǂ

Pulmonary congestion requiring intravenous treatment (diuretics, 
vasodilators, vasopressors and/or inotropes) during the index 
hospitalization supported by clinical assessment (worst Killip class, 
II or above) or radiological findings.  Radiological evidence of 
pulmonary congestion is defined as pulmonary venous congestion 
with interstitial or alveolar edema and must be supported by at 
least one chest X-ray or CT scan. 
(ǂ denotes that patients with either LVEF ≤40%, or pulmonary 
congestion requiring IV treatment, or both will qualify for this inclusion 
criterion)
5.
At least one of the following 8 risk factors: 

Age ≥ 70 years

eGFR <60 mL/min/1.73 m2 based on Modification of Diet in Renal 
Disease (MDRD) formula at screening visit

Type I or II diabetes mellitus

Documented history of prior MI supported by ECG changes and/or 
elevation of cardiac enzymes consistent with MI diagnosis.

Atrial fibrillation as noted by ECG, associated with index MI

LVEF < 30% associated with index MI
(In case multiple LVEF measurements have been performed during 
index event, the last one performed prior to randomization should 
be considered as the qualifying measurement.)

Worst Killip class III or IV associated with index MI requiring 
intravenous treatment

STEMI without reperfusion therapy within the first 24 hours after 
presentation
6.
Hemodynamically stable defined as: 

Systolic blood pressure (SBP) ≥ 100 mmHg at randomization for 
patients who received ACE inhibitor/angiotensin receptor blocker 
(ARB) during the last 24 hours prior to randomization  (ACE 
inhibitor/ARB Yes patients)

SBP ≥ 110 mmHg at randomization for patients who did not receive 
ACE inhibitor/ARB during the last 24 hours prior to randomization 
(ACE inhibitor/ARB No patients)

No intravenous treatment with diuretics, vasodilators, vasopressors 
and/or inotropes during the last 24 hours prior to randomization.


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Key Exclusion criteria
1.
Known history of chronic HF prior to randomization
2.
Cardiogenic shock within the last 24 hours prior to randomization
3.
Persistent clinical HF at the time of randomization 
4.
Coronary artery bypass graft (CABG) performed or planned for index 
MI
5.
Clinically significant right ventricular MI as index MI
6.
Symptomatic hypotension at screening or randomization
7.
Patients with a known history of angioedema
8.
Stroke or transient ischemic attack within one month prior to 
randomization
9.
Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy
11. Open-heart surgery performed within one month prior to randomization 
or planned cardiac surgery within the 3 months after randomization
12. eGFR < 30 ml/min/1.73 m2 as measured by the Modification of Diet in 
Renal Disease (MDRD) formula at screening
13. Serum potassium > 5.2 mmol /L (or equivalent plasma potassium 
value) at randomization
14. Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL 
or increased ammonia levels, if performed), or history of cirrhosis with 
evidence of portal hypertension such as esophageal varices
15. Previous use of LCZ696 or EntrestoTM
16. Use of other investigational drugs within 30 days prior to screening
17. History of hypersensitivity to the study drugs or drugs of similar 
chemical classes
18. Known intolerance or contraindications to study drugs or drugs of 
similar chemical classes including ACE inhibitors, ARB or NEP 
inhibitors
19. Patients taking medications prohibited by the protocol that cannot be 
discontinued for the duration of the study
20. History of malignancy of any organ system (other than localized basal 
cell carcinoma of the skin) within the past 3 years with a life expectancy 
of less than 1 year
21. Any surgical or medical condition which might significantly alter the 
absorption, distribution, metabolism, or extraction of study drug at 
investigators’ discretion
22. History or evidence of drug or alcohol abuse within the last 12 months
23. Patients considered unsuitable for the study, including patients with 
psychiatric, behavioral or cognitive disorders, sufficient to interfere with 
the patient’s ability to understand and comply with the protocol 
instructions or follow-up procedures
24. 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 
25. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing of investigational drug
 
 


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27.
 
 
Study treatment
LCZ696*
50 mg (dose level 1), 100 mg (dose level 2) and 200 mg (dose level 3) 
twice daily
(* LCZ696 dose levels 1, 2 and 3 are equivalent to sacubitril/valsartan 
24/26 mg, 49/51 mg and 97/103 mg, respectively)
Ramipril 
1.25 mg (dose level 1), 2.5 mg (dose level 2), and 5 mg (dose level 3) twice 
daily
Valsartan (VAL489)** 
40 mg (dose level V1) and 80 mg (dose level V2) twice daily for one day
(** Patients who are randomized to LCZ696 and received ACE inhibitors in 
last 36 hours prior to randomization will be given a valsartan bridging in a 
blinded manner for one day with two doses at dose level V1 or V2: 40 or 80 
mg twice daily, prior to beginning the double-blind LCZ696 treatment)
Efficacy assessments

CV death, 

Heart failure hospitalization 

Outpatient heart failure

Non-fatal spontaneous MI 

Non-fatal stroke

All-cause mortality
Key safety 
assessments

All adverse events (AE)s

All serious adverse events (SAEs) 

Sitting systolic blood pressure (SBP), sitting diastolic blood pressure 
(DBP), and heart rate 

Laboratory values (including monitoring for hyperkalemia, renal 
dysfunction)

Angioedema surveillance
Other assessments


 


 



 

 


 





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
Data analysis
The primary efficacy variable is time to first occurrence of CV death, HF 
hospitalization or outpatient HF. 
The secondary efficacy variables are:

Time to first occurrence of CV death or HF hospitalization

Time to first occurrence of HF hospitalization or outpatient HF 
(censoring will occur at the time of all-cause death)

Time to first occurrence of CV death,  non-fatal spontaneous MI or non-
fatal stroke

Cumulative number of events, including HF hospitalization, 
hospitalization due to non-fatal spontaneous MI, hospitalization due to 
non-fatal stroke and CV death. 

Time to all-cause mortality
Time-to-event is computed as the number of days from randomization to 
the start date of the endpoint event (first occurrence).
The primary endpoint will be analyzed using a Cox proportional hazards 
model stratified by STEMI/NSTEMI, with Treatment, PCI use at baseline 
and region included as factors in the model. The hazard ratio for LCZ696 
vs. ramipril, the associated 2-sided 95% confidence interval and the 1-
sided and 2-sided p-values will be presented from the analysis.
The primary endpoint and the first four secondary endpoints will be 
included in a hierarchical statistical testing strategy to control the familywise 
type I error rate at the 1-sided 2.5% level (in the strong sense). 
Two interim analyses are planned to assess efficacy.  The first interim 
analysis for efficacy is planned when approximately two-thirds of the target 
number of primary adjudicated events has been obtained. The second 
interim analysis for efficacy is planned to include primary events with onset 
date prior to 01-Mar-2020 (estimated start of COVID-19 impact 
globally).Sample size calculation: The sample size and power calculations 
described below are based on the study design prior to protocol 
amendment 4 when only one interim analysis had been planned. With the 
planned addition of a second efficacy interim analysis to include 80% of the 
target 708 primary events (see Section 9.7), there will be a small impact on 
power (approximately 0.1% power loss for the primary endpoint). 
A sample size of 5,650 patients, randomized to LCZ696: ramipril using a 
1:1 allocation ratio, has been chosen with the aim to obtain at least 708 first 
primary events and at least 592 first CV death or HF hospitalization events 
in this event-driven study.  Seven hundred eight primary events will provide 
80% power assuming a true Relative Risk Reduction (RRR) of 19% (i.e. a 
hazard ratio of 0.81) for LCZ696 vs. ramipril with statistical testing at the 
overall 2.5% 1-sided type I error rate (with strong control of the FWER).  
Five hundred ninety two first CV death or HF hospitalization events will 
provide 77.5% nominal power assuming a true RRR of 20% (for the intent-
to-treat analysis) for this secondary endpoint for the same type I error rate. 
These calculations assume a 37 month recruitment period and 
approximately 4 month follow-up of the last randomized patient for 
endpoints to accrue in the field.  An additional 1-2 months are expected 
through to the last patient last visit.
Key words
Spontaneous AMI, HF hospitalization, outpatient HF, LV systolic 
dysfunction, pulmonary congestion, STEMI, NSTEMI, randomized clinical 
trial, LCZ696, ramipril, echocardiography 


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1
Introduction
1.1
Background 
Acute myocardial infarction (AMI) is one of the common reasons for cardiac hospitalization 
and its annual incidence in US, EU-5, Japan and China is currently estimated at 2.5 million 
per year. In the US alone, approximately 683,000 patients were discharged from hospitals in 
2009 with a diagnosis of acute coronary syndrome (O’Gara, et al 2013). Although the 
community incidence rates for ST elevation myocardial infarction (STEMI) have declined 
over the past decade, those for non-ST-elevation myocardial infarction (NSTEMI) have 
increased. The overall incidence rate of AMI is expected to continuously increase in the next 
decades due to an ageing population and global rise in diabetes (Mozaffarian, et al 2015).
The in-hospital mortality of post-AMI patients has decreased in several parts of the world as a 
result of more frequent use of reperfusion strategies.  Due to increasing numbers of post-AMI 
survivors, the prevalence of developing heart failure (HF), a frequent complication following 
an AMI, has increased worldwide (Jhund and McMurray 2009; Sulo, et al 2016). For example, 
of 63,853 patients discharged alive from their first AMI without a diagnosis of HF during 
2001-2009 in The Cardiovascular Disease in Norway Registry (CVDNOR), 12.6% of patients 
developed HF during a median follow-up time of 3.2 years and nearly half of these cases 
occurred within 1 year from the index myocardial infarction (MI) discharge (Sulo, et al 2016). 
In addition, high-risk patients with left ventricular ejection fraction (LVEF) ≤ 40% following 
an AMI representing approximately 1/4 to 1/3 of the overall post-AMI patient population, are 
known to have significantly greater risk of HF morbidity and mortality (Miller, et al 2012; van 
Diepen, et al 2015; Vasaiwala, et al 2012). In the VALIANT study of high-risk post-AMI 
patients (LVEF ≤ 40% and/or transient HF signs with no prior history of chronic HF) who 
received percutaneous coronary intervention (PCI), approximately 20% of these patients 
experienced cardiovascular (CV) death or HF hospitalization over the approximate 2-year 
follow-up period (Pfeffer, et al 2003; Novartis data analyses on file). These real-world 
registry and controlled clinical trial data underscore the need for additional therapeutic 
approaches to reduce HF-related morbidity and mortality in post-AMI patients.
There are several mechanisms contributing to an unfavorable long-term prognosis in post-
AMI patients. The most notable mechanism underlying the significantly greater risk of HF 
morbidity events following an AMI is pathological cardiac remodeling resulting from the loss 
of myocardium and maladaptive changes in the surviving myocardium. This remodeling 
process with changes in left ventricular (LV) geometry, size, and function is induced by 
altered myocardial loading conditions and dysregulated neurohumoral system (Pfeffer and 
Braunwald, et al 1990; Udelson and Konstam, et al 2002; White, et al 1987). 
Factors triggering cardiac remodeling are activated within hours after an AMI. As supported 
by multiple clinical outcome studies conducted in the 1990s, early inhibition of the Renin 
Angiotensin System (RAS) with angiotensin converting enzyme (ACE) inhibitors has shown 
to reverse pathological remodeling, improve survival, and reduce HF hospitalization in post-
AMI patients with LV systolic dysfunction and/or HF (AIRE Study Investigators, 1993; 
GISSI-12 Study Investigators, 1994; ISIS-12 Collaborative Group 1995;  Kober, et al 1995; 


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Pfeffer et al 1992). As a consequence, guidelines recommend early initiation of ACE 
inhibitors after an AMI in patients with LV systolic dysfunction and/or HF for indefinite use 
(IA recommendation) (Anderson, et al 2007; Antman, et al 2008;  Roffi, et al 2015;  Steg, et al 
2012). Despite this progress and a number of other evidence-based pharmacotherapies (β 
blockers, mineralocorticoid antagonists, etc.), the prognosis of high risk post-AMI patients 
with LV dysfunction and/or HF remains poor. Novel preventive strategies to reduce the risk 
for CV mortality and the clinical development of HF are clearly warranted.
Several lines of evidence have suggested that increasing natriuretic peptides in addition to 
RAS inhibition in post-AMI patients may offer greater benefits over the RAS inhibition alone. 
The potential mechanisms may include but are not limited to the anti-hypertrophic, anti-
fibrotic, anti-ischemic, anti-inflammatory and sympatholytic effects of natriuretic peptides 
(Braunwald, 2015; D’Souza, et al 2004; Molkentin, 2003).  In a small study of 24 anterior 
wall STEMI patients, the recombinant form of human BNP, nesiritide, given early after index 
MI presentation for 72 hours was well tolerated and associated with improved LVEF and 
reduced ventricular remodeling (i.e., smaller LV end-systolic volume) after 1 month (Chen, et 
al, 2009). A larger clinical study in Japanese STEMI patients (N=569) demonstrated that 
intravenous administration of atrial natriuretic peptide for 3 days after reperfusion treatment 
reduced infarct size and improved LVEF at 6-12 months (Kitakaze, et al 2007).
Entresto™ (sacubitril/valsartan, LCZ696) is a combination of neprilysin inhibitor and 
angiotensin II type 1 receptor blocker, providing concomitant neprilysin inhibition and 
angiotensin type 1 receptor blockade. Upon oral administration, LCZ696 delivers systemic 
exposure of sacubitril, a neprilysin inhibitor prodrug, and valsartan, an angiotensin receptor 
blocker (ARB). Sacubitril is then further metabolized by esterases to the active metabolite, 
sacubitrilat (LBQ657), which inhibits the degradation of natriuretic peptides and therefore 
enhances the effects of their biological activity. The efficacy and safety of LCZ696 titrated to 
a target dose of 200 mg twice daily in chronic HF patients with reduced ejection fraction 
(HFrEF) (LVEF ≤40%) was evaluated in the PARADIGM-HF study (N=8,442) and 
demonstrated that LCZ696 significantly reduced the primary composite endpoint of CV death 
or HF hospitalization by 20%, as compared to enalapril (McMurray, et al 2014). 
Given these positive results for the use of LCZ696 in the HFrEF patient population, and the 
improvement in LVEF, reduction in infarct size and ventricular remodeling observed in the 
STEMI patient population all of which suggest that increasing natriuretic peptides in addition 
to RAS inhibition may offer greater benefit in the post-AMI patient population, we 
hypothesize that early and sustained treatment with LCZ696 in high-risk patients with LV 
systolic dysfunction and/or pulmonary congestion following an AMI with no known prior 
history of chronic HF will be superior to the guideline recommended first-line treatment with 
ACE inhibitor as measured by a reduction in the composite endpoint of CV death, HF 
hospitalization or outpatient HF.
1.2
Purpose 
The purpose of this study is to evaluate the efficacy and safety of LCZ696 titrated to a target 
dose of 200 mg twice daily, compared to ramipril titrated to a target dose of 5 mg twice daily, 
in addition to conventional post-AMI treatment, in reducing the occurrence of composite 
endpoint of CV death, HF hospitalization and outpatient HF (time-to-first event analysis) in 


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post-AMI patients with evidence of LV systolic dysfunction and/or pulmonary congestion, 
with no known prior history of chronic HF.
2
Study objectives and endpoints
2.1
Primary objective(s)
To demonstrate that LCZ696 is superior to ramipril in delaying the time-to-first occurrence of 
the composite endpoint of CV death, HF hospitalization or outpatient HF* in patients with LV 
systolic dysfunction and/or pulmonary congestion following an AMI
(*The outpatient HF endpoint event is defined as an adjudicated event of clinical development 
of symptomatic HF (either urgent/unscheduled or non-urgent) in the outpatient setting with 
symptoms and signs requiring initiation/intensification of intravenous or qualifying oral HF 
treatment.  See Section 6.4.1 for full definition)
2.2
Secondary objective(s)

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time-to-
first occurrence of CV death or HF hospitalization 

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to 
new onset of symptomatic HF defined as time-to-first occurrence of HF hospitalization or 
outpatient HF

To demonstrate the superiority of LCZ696 compared to ramipril, in delaying the time-to-
first occurrence of CV death, non-fatal spontaneous MI or non-fatal stroke 

To demonstrate the superiority of LCZ696, compared to ramipril, in reducing the rate of 
the composite endpoint of CV death and total (first and recurrent) hospitalizations  due to 
HF, non-fatal spontaneous MI or non-fatal stroke 

To demonstrate the superiority of LCZ696, compared to ramipril, in delaying the time to 
all-cause mortality

To evaluate the safety and tolerability of LCZ696 compared to ramipril 
(All secondary efficacy hypotheses except all-cause mortality will be included in a statistical 
testing strategy to control the familywise type I error rate) (Section 9.5)
  
 
 
 
 
 
 
 


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3
Investigational plan
3.1
Study design
Figure 3-1
Study design
This study is a multicenter, randomized, double-blind, active controlled, event-driven phase 
III clinical trial designed to evaluate the efficacy and safety of LCZ696 compared to ramipril 


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when added to standard therapy in post-AMI patients with LV systolic dysfunction and/or 
pulmonary congestion.  Potential study candidates will consist of high-risk patients who have 
sustained a spontaneous acute myocardial infarction (STEMI or NSTEMI) with evidence of 
LV systolic dysfunction defined by LVEF ≤ 40% and/or pulmonary congestion (worst Killip 
class ≥ II or radiological findings requiring intravenous treatment).  In addition, patients must 
have at least one risk factor (age 70 yrs; diabetes; estimated glomerular filtration rate (eGFR) 
< 60 ml/min; history of prior MI; occurrence of atrial fibrillation during index hospitalization; 
LVEF < 30% or Killip class III or IV associated with the index MI, or diagnosis of STEMI 
without reperfusion therapy within the first 24 hours of the index MI) and should not have 
known prior history of chronic HF.  Study candidates must also be hemodynamically stable 
defined as systolic blood pressure (SBP) ≥ 100 mmHg if on ACE inhibitors or ARBs or SBP 
≥ 110 mmHg if not on ACE inhibitors or ARBs at time of randomization, must not have 
received intravenous diuretics, vasodilators, vasopressors or inotropes in the last 24 hours 
prior to randomization, and be considered clinically stable in the opinion of the investigator.
After assessing eligibility during the screening period, consenting patients who meet the study 
inclusion and exclusion criteria will be randomized 1:1 to receive LCZ696 titrated to a target 
dose of 200 mg twice daily or ramipril titrated to a target dose of 5 mg twice daily in a 
double-blind manner for the duration of the study.  In addition, in order to minimize the 
potential risk of angioedema, patients who were previously treated with ACE inhibitors 
receiving the last dose of that agent during the last 36 hours prior to randomization will 
receive a valsartan bridging for one day. To achieve this, those who are subsequently 
randomized to LCZ696 will receive two doses of valsartan in a blinded manner prior to 
beginning double-blind LCZ696 treatment. Patients randomized to ramipril will receive two 
doses of ramipril and two doses of valsartan placebo in a blinded manner prior to beginning 
double-blind ramipril and LCZ696 placebo treatment.  Randomization must occur no earlier 
than 12 hours and no more than 7 days after index MI presentation.    
A screening period, or epoch, of no more than 7 days after index MI presentation will be used 
to determine if patients qualify to enter the double-blind treatment phase of the study. Patients 
may be randomized on the same day that they are consented and screened.
Eligible patients will be randomized 1:1 to receive LCZ696 titrated to a  target dose of 200 
mg twice daily or ramipril titrated to a target dose of 5 mg twice daily.  Three dose levels of 
study medication will be administered in a stepwise titration (Table 3-1).  The goal of 
treatment is to ensure that each patient receives the target dose or maximal tolerated dose of 
study medication (Figure 3-2).  


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Table 3-1
Study drug dose levels during treatment epoch
Dose Level
LCZ696 Treatment Arm*
Ramipril Treatment Arm
1
50 mg b.i.d.†
1.25 mg b.i.d.
2
100 mg b.i.d.†
2.5 mg b.i.d.
3
200 mg b.i.d.
5 mg b.i.d.
* LCZ696 dosing is based on the total amount of both components of sacubitril/valsartan; dose levels 
1, 2 and 3 are equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, respectively.  
† Patients who are randomized to LCZ696 and received ACE inhibitors in the 36 hours prior to 
randomization will be given a bridging valsartan dose in a blinded manner for one day (two doses at 
either dose level V1 or V2: 40 or 80 mg b.i.d.) prior to beginning double-blind LCZ696 treatment.
Figure 3-2
Study drug initiation and up-titration in PARADISE-MI
The starting dose level of the study drugs will be determined based on the patient’s clinical 
condition and taking into consideration their prior standard background therapy.  Patients who 
did not receive an ACE inhibitor or ARB in the last 24 hours prior to randomization (ACE 
inhibitor/ARB No patients) will start at dose level 1. Patients who did receive an ACE 
inhibitor or ARB in the last 24 hours prior to randomization (ACE inhibitor/ARB Yes patients) 
will start at dose level 1, or at investigator’s discretion, dose level 2, after taking into 
consideration the patients’ prior dose level of ACE inhibitor/ARB therapy (Table 3-2) and 
clinical condition (SBP, renal function, etc.).


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Table 3-2
Total daily doses of commonly used ACE inhibitors and ARBs 
corresponding to dose level 2 of study drug 
ACE inhibitor
Dose
ARB
Dose
Benazepril
20 mg
Azilsartan
40 mg
Captopril
100 mg
Candesartan
16 mg
Cilazapril
2.5 mg
Eprosartan
400 mg
Enalapril
10 mg
Irbesartan
150 mg
Fosinopril
20 mg
Losartan
50 mg
Imidapril
10 mg
Olmesartan
10 mg
Lisinopril
10 mg
Telmisartan
40 mg
Moxepril
7.5 mg
Valsartan
160 mg
Perindopril
4 mg
Quinapril
20 mg
Ramipril
5 mg
Trandolapril
2 mg
Zofenopril
30 mg
ACE inhibitor/ARB No patients (no treatment with ACE inhibitor/ARB therapy during the 24 
hours prior to randomization):

Start at dose level 1, if SBP is ≥ 110 mmHg 
ACE inhibitor/ARB Yes patients (treated with ACE inhibitor/ARB therapy during the 24 
hours prior to randomization): 

Start at dose level 1, if SBP is ≥ 100 mmHg OR

At investigator’s discretion, patients may also start at dose level 2, taking into 
consideration patient’s prior dose level of ACE inhibitor/ARB therapy (Table 3-2) and 
clinical condition (SBP, renal function, etc.).
In order to minimize the potential risk of angioedema, patients who are randomized to 
LCZ696 but who were previously treated with an ACE inhibitor during the 36 hours prior to 
randomization will receive valsartan bridging for one day before beginning the double-blind 
LCZ696 treatment. Two doses of blinded valsartan (dose level V1, valsartan 40 mg or dose 
level V2 valsartan 80 mg) will be available.  As outlined above (Figure 3-2), the dose level of 
the 1-day valsartan bridging will also be determined based on the patient’s prior dose level of 
ACE inhibitor therapy and clinical condition at the investigator’s discretion (Figure 3-2). On 
day 1, patients randomized to ramipril will receive two doses of ramipril and two doses of 
valsartan placebo in a blinded manner prior to beginning double-blind ramipril and LCZ696 
placebo treatment.
Following initiation of study drug, patients should be uptitrated to the next dose level no 
earlier than 24 hours after the initial dose of study drug.  The aim is to achieve the target dose 
level 3 within 2 weeks after randomization; however, slower up-titration will be permitted if 
necessary to manage patient safety and tolerability.  For patients who have not been uptitrated 
to dose level 3 by week 4, an unscheduled dose titration visit on or about week 6 should be 
considered to evaluate whether uptitration to the target dose, dose level 3, can be implemented. 


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In addition, investigators should document the reasons for not achieving target study drug 
dose level 3 during the Week 2 to Week 8 visits.  
Patients that cannot tolerate dose level 3 will be allowed to stay at level 1 or 2 as maintenance 
dose. Study drug dose level adjustments should be based on overall safety and tolerability 
with special focus on a) symptomatic hypotension, b) any clinically significant decrease in 
eGFR/increase in creatinine (Cr) and c) hyperkalemia (Table 3-3). Treatment guidelines for 
blood pressure management and hyperkalemia are provided in Appendix 4 and Appendix 5, 
respectively.  Every attempt should be made to maintain patients on the target study drug dose 
(dose level 3) or maximally tolerated dose levels throughout the trial. If the patient does not 
tolerate the target study drug dose level the investigator should consider, if appropriate, 
adjusting non-disease-modifying background medications (e.g., diuretics, nitrates or calcium 
channel blockers) to rectify the situation before considering down-titration to the next lower 
study drug dose level.
Table 3-3
Safety monitoring criteria that must be met for dose uptitration
Parameter 
Criteria
Blood pressure
SBP ≥ 100 mmHg
Renal function
eGFR ≥ 30 mL/min/1.73m2 and creatinine increase  < 
0.5 mg/dl from baseline 
Serum potassium 
(or equivalent plasma potassium value)
K < 5.5 mmol/L (mEq/L) 
AEs or conditions
No postural symptoms or any AEs that preclude up-
titration according to the investigator’s judgment
 
 
 
  
  
  
This is an event-driven trial, the study will continue until a total of at least 708 first confirmed 
primary triple composite endpoint events and at least 592 confirmed double composite events 
of first CV death or HF hospitalization (i.e., first secondary endpoint) have been achieved. 
Approximately 5,650 randomized post-AMI patients will be required to accrue the necessary 
number of confirmed endpoints. Once randomized, all patients will be followed until the total 
numbers of required confirmed endpoint events have been achieved and final follow-up has 
been performed. 
It is anticipated that the total trial duration will be approximately 43 months, with a projected 
recruitment period of approximately 37 months, followed by approximately 4 months of 
follow-up after the last patient is enrolled to accrue the needed number of endpoints, the 
closeout period is expected to last an additional 1-2 months. The overall estimated mean 
follow-up time will be approximately 19 months for the study.  Although these are the 


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estimated timelines, they may change according to the rate of randomization and rates of 
occurrence of the primary and first secondary endpoints.
3.2
Rationale for study design
This phase III outcome study in post-AMI patients is designed as a multicenter, randomized, 
double-blind, active-controlled, event-driven study in order to assess the efficacy and safety of 
LCZ696 when added to standard therapy for high-risk post-AMI patients with left ventricular 
systolic dysfunction and/or pulmonary congestion. Patients entering the study will be 
randomized to either LCZ696 or ramipril and are required to receive standard-of-care 
background therapy according to regional or local guidelines / institutional standards 
throughout the study. Once randomized, all patients will be followed until the total required 
numbers of confirmed endpoint events have accrued. The study design reflects prior pivotal, 
long-term, cardiovascular outcome trials in post-AMI patients.  
The primary endpoint of this study is a composite of CV death, HF hospitalization or 
outpatient HF in patients with left ventricular systolic dysfunction and/or pulmonary 
congestion following an AMI who do not have known prior history of chronic HF. While the 
composite of CV death or HF hospitalization is a well-established mortality and morbidity 
endpoint, the addition of the outpatient HF component, which in this study represents the 
confirmed diagnosis of new onset symptomatic HF, aims to capture the clinically important 
outpatient event that contributes to the totality of HF morbidity following an AMI presenting 
as either inpatient (i.e., HF hospitalization) or outpatient (i.e., outpatient HF) events.   The 
diagnostic criteria for adjudication of HF symptoms and signs are identical whether the 
patient is seen in an inpatient or outpatient setting.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The selection of LCZ696 200 mg given orally twice daily as the target dose for this study was 
based primarily on the superior efficacy and safety results of LCZ696 200 mg compared to 
enalapril 10 mg each given twice daily in the PARADIGM-HF study, in which  60% of the 
HFrEF patients enrolled had an ischemic etiology and 43% had prior MI.  LCZ696 200 mg 
twice daily delivers similar valsartan exposure (assessed by AUC) as valsartan 160 mg twice 
daily, which was demonstrated in the VALIANT study to be as effective as standard-of-care 
ACE inhibitor in patients with AMI complicated by LV systolic dysfunction and/or HF. 
Further, biomarker analysis and modeling indicate that this dose of LCZ696 delivers 
approximately 90% of its maximal neprilysin (NEP) inhibition. The twice daily dosing 
schedule is considered necessary for sustained NEP inhibition over a 24-hour period and it is 
also anticipated to reduce the incidence of hypotension, compared to a once daily regimen, 
particularly in elderly patients.  
3.4
Rationale for choice of comparator
Major clinical trials have established ACE inhibitors as the standard-of-care for RAS 
blockade and ACE inhibitors are recommended by treatment guidelines as the first-line 
therapy for post-AMI patients with LV systolic dysfunction and/or HF. The primary objective 
of study CLCZ696G2301 is to demonstrate superiority of LCZ696 over an ACE inhibitor in 


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reducing CV mortality and HF morbidity in post-AMI patients with LV systolic dysfunction 
and/or pulmonary congestion. Ramipril is one of the most commonly used ACE inhibitors in 
post-AMI patients and is selected as the active comparator of this study. In the AIRE study, 
ramipril at target dose of 5 mg twice daily compared to placebo demonstrated a significant 
27% relative reduction in mortality (p=0.002; principally CV death), also 26% and 23% 
reductions in the risks of HF hospitalization and progression to severe/resistant HF, 
respectively (AIRE Investigators 1993).  Ramipril in the same daily dose was subsequently 
shown to reduce cardiovascular mortality in a broader population of patients at cardiovascular 
risk (The HOPE Investigators, 2000).
3.5
Purpose and timing of interim analyses/design adaptations
Two interim analyses (IAs) are planned to assess efficacy. The cut-off time for the first IA is 
planned to be when approximately two-thirds of the target number of primary adjudicated 
events (i.e. approximately 472 first CV death, HF hospitalization or outpatient HF events) 
have occurred. The analysis cut-off time for the second IA is planned to be 01-Mar-2020 
(estimated start of COVID-19 impact globally). All primary events that occurred prior to 
01-Mar-2020, will be included in the second IA. It is estimated that the second IA will include 
approximately 80% of the target number of 708 Clinical Event Committee (CEC)-confirmed 
primary events.
3.6
Risks and benefits 
The risk to patients participating in the study will be minimized by compliance with the 
inclusion/exclusion criteria and close clinical monitoring.  Patients will be instructed not to 
take any RAS blockade medications (ACE inhibitor or ARB) from the day they start study 
drug to avoid excess RAS blockade. The risk of discontinuation of concomitant ACE 
inhibitors or ARBs will be minimal as the study treatment will be reflective of the typical 
dosing schedule of most ACE inhibitors and ARBs. All patients will be required to continue 
receiving the rest of their standard of care background CV medications.  In addition, for 
patients randomized to LCZ696 who received ACE inhibitors in the last 36 hours prior to 
randomization, a one day bridging period with 2 doses of valsartan before starting LCZ696 
treatment is instituted to minimize the risk of angioedema (Section 3.1).
In women of child-bearing potential, a possible risk of developmental toxicity cannot be 
excluded. Women of child-bearing potential should therefore use a highly effective method of 
contraception during dosing. If there is any question that the patient will not reliably comply, 
they should not be entered in the study.   
Since this is a long-term outcome study, participating patients will benefit from careful 
monitoring and follow-up during the entire study duration regardless of whether they are 
receiving the study medication. 
4
Population
The study population will consist of male and female patients age 18 years or older with a 
diagnosis of acute spontaneous MI and evidence of left ventricular (LV) systolic dysfunction 
and/or pulmonary congestion associated with the index MI. Patients will be randomized 


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between 12 hours and 7 days following the index acute MI.  At the time of randomization, 
patients should be hemodynamically stable and without persistent clinical HF. The goal is to 
randomize approximately 5,650 patients in approximately 500 centers worldwide. 
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed. 
2. Male or female patients ≥ 18 years of age. 
3. Diagnosis of spontaneous AMI based on the universal MI definition* with randomization 
to occur between 12 hours and 7 days after index event presentation**.  
Spontaneous AMI is defined when there is evidence of myocardial necrosis in a clinical 
setting consistent with myocardial ischemia due to primary coronary event. Under these 
conditions, the following criteria have to be met for the diagnosis of spontaneous AMI:

Detection of rise and/or fall of cardiac enzymes (cardiac troponin, cTn or the MB 
fraction of creatinine kinase, CKMB) with at least one value above the 99th percentile 
of the upper reference limit (URL) or the local laboratory MI diagnosis cut-off value, 
together with evidence of myocardial ischemia with at least one of the following:

Ischemic discomfort or other ischemia symptom(s)

Electrocardiogram (ECG) characteristics of STEMI or NSTEMI including new or 
presumably new significant ST-segment-T wave (ST-T) changes

Newly developed pathological Q waves or left bundle branch block in the ECG
(* Patients with a spontaneous MI event determined to be secondary to another medical 
condition such as anemia, hypotension, or an arrhythmia OR thought to be caused by 
coronary vasospasm with documented normal coronary arteries are not eligible; patients 
with clinical presentation thought to be related to Takotsubo cardiomyopathy are also not 
eligible)
      (** Index MI presentation is the time of patient presentation at either the emergency 
room/emergency department (ER/ED), intensive care unit/coronary care unit (ICU/CCU) 
or hospital ward etc., for the treatment of the index MI.)
4. Evidence of LV systolic dysfunction and/orǂ pulmonary congestion requiring intravenous 
treatment associated with the index MI event defined as:

LVEF ≤40% assessed locally by echocardiography, magnetic resonance imaging, 
cardiac CT, radionuclide or contrast ventriculography after index MI presentation and 
prior to randomization.
(These examinations may be performed as part of patient standard-of-care. In case 
multiple LVEF measurements have been performed during index event, the last one 
performed prior to randomization should be considered as the qualifying 
measurement), and/or ǂ

Pulmonary congestion requiring intravenous treatment with diuretics, vasodilators, 
vasopressors and/or inotropes during the index hospitalization supported by clinical 
assessment (worst Killip class, II or above; see Appendix 3 for Killip class definition) 
or radiological findings.  Radiological evidence of pulmonary congestion is defined as 


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pulmonary venous congestion with interstitial or alveolar edema and must be 
supported by at least one chest X-ray or CT scan. 
(ǂ denotes that patients with either LVEF ≤40%, or pulmonary congestion requiring IV 
treatment, or both will qualify for this inclusion criterion)
5. At least one of the following 8 risk factors: 

Age ≥ 70 years

eGFR <60 mL/min/1.73 m2 based on MDRD formula at screening visit

Type I or II diabetes mellitus

Documented history of prior MI supported by ECG changes and/or elevation of 
cardiac enzymes consistent with MI diagnosis.

Atrial fibrillation as noted by ECG, associated with index MI

LVEF <30% associated with index MI
(If multiple LVEF measurements have been performed during index event, the last 
one performed prior to randomization should be considered as the qualifying 
measurement.)

Worst Killip class III or IV associated with index MI requiring intravenous treatment

STEMI without reperfusion therapy within the first 24 hours after presentation
6. Hemodynamically stable defined as: 

SBP ≥ 100 mmHg at randomization for patients who received ACE inhibitor/ARB 
during the last 24 hours prior to randomization  (ACE inhibitor/ARB Yes patients)

SBP ≥ 110 mmHg at randomization for patients who did not receive ACE 
inhibitor/ARB during the last 24 hours prior to randomization (ACE inhibitor/ARB 
No patients)

No intravenous treatment with diuretics, vasodilators, vasopressors and/or inotropes 
during the last 24 hours prior to randomization.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Known history of chronic HF prior to randomization
2. Cardiogenic shock within the last 24 hours prior to randomization
3. Persistent clinical HF at the time of randomization 
4. Coronary artery bypass graft (CABG) performed or planned for index MI
5. Clinically significant right ventricular MI as index MI
6. Symptomatic hypotension at screening or randomization
7. Patients with a known history of angioedema
8. Stroke or transient ischemic attack within one month prior to randomization
9. Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy


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11. Open-heart surgery performed within one month prior to randomization or planned cardiac 
surgery within the 3 months after randomization
12. eGFR < 30 ml/min/1.73 m2 as measured by the Modification of Diet in Renal Disease 
(MDRD) formula at screening
13. Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at randomization
14. Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL or increased 
ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension 
such as esophageal varices
15. Previous use of LCZ696 or EntrestoTM
16. Use of other investigational drugs within 30 days prior to screening
17. History of hypersensitivity to the study drugs or drugs of similar chemical classes
18. Known intolerance or contraindications to study drugs or drugs of similar chemical classes 
including ACE inhibitors, ARB or NEP inhibitors
19. Patients taking medications prohibited by the protocol that cannot be discontinued for the 
duration of the study
20. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin) within the past 3 years with a life expectancy of less than 1year.
21. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or extraction of study drug at investigators’ discretion.
22. History or evidence of drug or alcohol abuse within the last 12 months
23. Patients considered unsuitable for the study, including patients with psychiatric, 
behavioral or cognitive disorders, sufficient to interfere with the patient’s ability to 
understand and comply with the protocol instructions or follow-up procedures
24. 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
25. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of investigational drug and for 7 days off of study drug.  Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to Visit 1). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient 

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
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
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment

Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment is she 
considered not of child bearing potential
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF.
26.
 
27.
 
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
All eligible patients will be randomized 1:1 to either LCZ696 titrated to a target dose of 200 
mg twice daily or ramipril titrated to a target dose of 5 mg twice daily in a double-blind 
manner for the duration of the study. In addition, patients will continue to receive optimal 
standard of care background therapy to treat the index MI event and co-morbid conditions, as 
considered appropriate by the investigator and in accordance with the local/institutional 
guidelines, with the exception of an ACE inhibitor or ARB as this will be replaced by study 
drug. The use of an open label ACE inhibitor or an ARB in addition to randomized study drug 
is strictly prohibited. 
The following study drugs will be provided:

LCZ696 50 mg, 100 mg and 200 mg tablets, and matching placebo (LCZ696 doses are 
equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, respectively)

Ramipril 1.25 mg, 2.5 mg, and 5 mg capsules, and matching placebo

Valsartan (VAL489) 40 mg and 80 mg tablets, and matching placebo (two doses for 1 day 
in a subset of randomized patients) (Section 3.1)
All study medications will be supplied in bottles or blister cards. Sufficient medication will be 
provided for the treatment according to study protocol, including additional medication to 
allow for delayed visits. Medication labels will be in the local language and comply with the 
legal requirements of the country. They will include storage conditions for the drug and the 
medication number, but no information about the patient.


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5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
Patients will be assigned to one of the following two treatment arms in a ratio of 1:1 at Visit 
101.

LCZ696 at dose levels 1-3 (50, 100 and 200 mg twice daily)

Ramipril at dose levels 1-3 (1.25, 2.5 and 5 mg twice daily)
5.3
Treatment assignment and randomization 
At Visit 101 all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified by region and type of index MI (STEMI or NSTEMI).
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Randomization Group.
5.4
Treatment blinding
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone involved in the study with the following exceptions:
1. The independent and unblinded statistician, programmer and data personnel who are 
involved in preparing safety and efficacy interim analysis reports for the Data 
Monitoring Committee (DMC). These personnel will not be involved in any other 
trial conduct related activities. 
2. DMC members.


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
The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, labeling, schedule of administration, appearance, taste 
and odor.

A double-dummy design is used because the identity of the study drug cannot be disguised, 
as the drug products are visibly different.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9), at the time 
of an interim analysis by the DMC and at the conclusion of the study.
For any patient who was intentionally unblinded by the investigator (treatment code has been 
broken as per study process) the patient must permanently discontinue the study treatment; 
whereas the appropriate personnel from the site and Novartis will assess whether study drug 
should be discontinued in instances where a patient is inadvertently unblinded for any reason.
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. 
Upon signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 
 and subsequent 
patients/subjects are assigned consecutive numbers (e.g. the second patient is assigned patient 
number  the third patient is assigned patient number ). The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the patient to register 
them into the IRT. For studies using eCRFs, only the assigned patient number must be entered 
in the field labeled “Patient ID” on the electronic data capture (EDC) data entry screen (e.g. 
enter 
 etc.). Once assigned to a patient, the patient number will not be reused. 
If the patient fails to be randomized for any reason, the IRT must be notified within 2 days 
that the patient was not randomized. The reason for not being randomized will be entered on 
the Screening Log, and the screening eCRFs should also be completed.
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the two treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number. 


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5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis country 
pharma organization (CPO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at each study visit or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Novartis will supply the investigators with all study medications required for the course of the 
study. Patients will be provided with medication packs containing study drug corresponding 
to their assigned treatment arm and dose level, sufficient to last until the next scheduled visit. 
In order to adequately blind the study, patients will be required to take a total of two pills, 
(one tablet from the LCZ696/LCZ696 matching placebo pack and one capsule from the 
ramipril/ramipril matching placebo pack) twice a day for the duration of the study. 
For patients who were previously treated with an ACE inhibitor receiving the last dose of that 
agent within 36 hours prior to randomization, a valsartan bridging for one day will be 
administered in a blinded manner. To achieve this, on day 1, those patients who are 
subsequently randomized to LCZ696 will receive two doses of ramipril placebo and two 
doses of valsartan in a blinded manner prior to beginning double-blind LCZ696 plus ramipril 
placebo treatment. Patients randomized to ramipril on day 1 will receive two doses of ramipril 
and two doses of valsartan placebo in a blinded manner prior to beginning double-blind 
ramipril plus LCZ696 placebo treatment.


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Patients who were not previously treated with an ACE inhibitor, or who received the last dose 
of that agent greater than 36 hours prior to randomization, will immediately start on double-
blind LCZ696 or ramipril without valsartan bridging.   
Table 5-1 summarizes the study drug that will be taken during the treatment epoch.
Table 5-1
Study drug dispensed during the treatment epoch by study visit
Study 
visitc
Dose 
level
LCZ696
Ramipril
Valsartanb
101
1a
50 mg or matching 
placebo b.i.d.
1.25 mg or matching 
placebo b.i.d.
40 mg or matching 
placebo b.i.d. 
101a/102
2
100 mg or matching 
placebo b.i.d.
2.5 mg or matching 
placebo b.i.d.
80 mg or matching 
placebo b.i.d.
103
3
200 mg or matching 
placebo b.i.d.
5 mg or matching 
placebo b.i.d.
a At Investigator’s discretion, dose level 2 can be administered at Visit 101 for the [ACE inhibitor/ARB: 
Yes] patients.
b For patients who were previously treated with ACE inhibitor receiving the last dose within 36 hours 
prior to randomization; 
If randomized to LCZ696, they will receive a valsartan bridging for one day before beginning the 
double-blind LCZ696 treatment. 

Two doses of blinded valsartan dose level V1 (valsartan 40 mg) or dose level V2 (valsartan 80 
mg) will be available at Visit 101.  

At investigator’s discretion dose level V1 or V2 can be administered for one day followed by 
active LCZ696; these patients will also receive ramipril matching placebo from Visit 101 
onwards. 
If randomized to ramipril, they will receive active ramipril, and two doses of valsartan matching placebo 
for one day followed by active ramipril and LCZ696 matching placebo.
c If the study drug is up-titrated during the index hospitalization, increase to the next dose level can 
occur prior to next study visit if tolerable but should be no early than 24 hours; slower up-titration will 
also be permitted if necessary to manage patient safety and tolerability.  
Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 
AM) and their evening study drug dose at approximately 20:00 (8 PM). The study drugs 
should be taken with water, with or without food. If the patient misses taking any study drug 
dose, he/she should take it as soon as possible, unless it is almost time for the following 
scheduled dose. In this case, the patient should skip the missed dose and return back to his/her 
regular study drug administration schedule.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record case report form (CRF). All kits of 
study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.


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5.5.5
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose level 
adjustments and/or temporary interruptions of study treatment are permitted in order to keep 
the patient on study drug. The following guidelines should be followed: 
Every attempt should be made to maintain patients at the target study drug dose level 
throughout the trial. If the patient does not tolerate the target study drug dose level, the 
investigator can, if appropriate, adjust concomitant background medications for co-morbid 
conditions to rectify the situation, and if necessary down titrate to the next lower study drug 
dose level. For hypotension or dizziness, consideration should be given to adjusting the dose 
of diuretic and/or concomitant antihypertensive agents (e.g., calcium channel blockers) and 
non-antihypertensive agents that lower blood pressure (BP) (e.g., nitrates). It is important to 
note that dose adjustment of disease-modifying background therapy, e.g., β blockers, or 
mineralocorticoid (aldosterone) antagonists is discouraged under these circumstances.
Adjustment of study drug dose level
If in the investigator’s opinion down titration of study drug to a lower dose level is deemed 
necessary it should be done in accordance with the following instructions: 
During the treatment epoch, down titration of the study drug at any time during the study 
based on the judgment of the investigator will be allowed according to the safety and 
tolerability criteria defined in Appendix 4, and Appendix 5. If down titration is necessary, the 
patient should be down titrated to the next lower study drug dose level in the titration scheme. 
The patient may continue receiving the lower dose level for a recommended period of 1 to 4 
weeks before being re-challenged at the next higher dose level. For example, a patient who 
encounters tolerability problems at the target study drug dose level (i.e., dose level 3) should 
receive the study drug at dose level 2 for 1 to 4 weeks at the discretion of the investigator. 
Then, he/she should be re-challenged with up-titration back to dose level 3.
If the tolerability issues are not alleviated despite down titration by one dose level, the 
investigator may down titrate further to the next lower study drug dose level for 1 to 4 weeks, 
up to temporary discontinuation of the study drug. Again, once stable, the patient should be 
re-challenged with up titration to the next higher dose level every 1 to 4 weeks in an attempt 
to bring back the patient gradually to the target study drug dose level (i.e., dose level 3). The 
investigator may choose the next dose level for down- or up-titration according to his or her 
judgment. The IRT system should be contacted to register any changes in the patient’s study 
drug dose level, including in cases of temporary and permanent discontinuation of the study 
drug, and to obtain the medication numbers of the study drug supplies required for the new 
study drug dose level. In some instances, according to the safety and tolerability criteria and 
the investigator’s judgment, dose level 1 or 2 could be maintained if he/she considers that the 
patient’s condition would not allow any further up titration to the target dose level of study 
drug (i.e., dose level 3). In this case, it would be acceptable to maintain the patient at dose 
level 1 or level 2, whichever is the higher and tolerated dose level by the patient.
These changes must be recorded on the Dosage Administration Record CRF.


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Study drug restart after temporary treatment interruption
Study drug should be reintroduced in those patients who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator. Once the investigator considers the 
patient’s condition appropriate for receiving the study drug, the investigator should re-start the 
patient on the study drug at the most appropriate and allowable dose level per his/her medical 
judgment. If tolerated, the patient should be up-titrated one dose level every 1 to 4 weeks to 
the target dose level 3, as per the investigator’s judgment. Should the patient not tolerate the 
re-start study drug dose level, he/she may be down titrated again (if appropriate) or 
temporarily discontinue the study medication again and a new attempt to up titrate or 
reintroduce the study drug could be considered by the investigator as soon as medically 
justified in his/her judgment. 
The use of an open-label ACE inhibitor, ARB, commercially available Entresto™ or a direct 
renin inhibitor is strictly prohibited while patient is taking study drug. However, if for any 
reason a patient off study drug has started open-label treatment with an ACE inhibitor or 
Entresto™, it must be discontinued ≥36 hours prior to restarting study drug. For patients off 
study drug treated with an ARB or a direct renin inhibitor it must be discontinued prior to re-
initiation of study drug.
Reinitiation of study medications or any changes in concomitant medications must be 
recorded on the appropriate eCRFs.  
In case of pregnancy discovered during the screening epoch, the patient will be withdrawn 
from the study immediately. In case of pregnancy discovered during the treatment epoch, the 
patient should be instructed to temporarily discontinue study drug immediately. Study drug 
intake should be resumed as soon as possible after the completion of the pregnancy and 
lactation period. Meanwhile, the patient should continue to attend scheduled study visits. 
See Section 7.6 for further details on pregnancies and reporting guidelines
5.5.6
Rescue medication
The intent in this study is to ensure that, wherever possible, patients are treated with an 
evidence-based dose (or lower dose if the target dose is not tolerated) of RAS inhibitor. Some 
patients in the study may experience intolerable adverse effects thought to be due to study 
drug which could lead to discontinuation of study medication. If study drug discontinuation is 
considered despite dose reduction and/or temporary interruption as described in Section 5.5.5, 
substitution of open-label ACE inhibitor or ARB therapy is recommended, according to the 
following guidance, to ensure patients receive sufficient RAS blockade.
Hypotension, hyperkalemia, renal dysfunction and cough are likely to be common in the 
patients enrolled in the present study. Guidance on handling hypotension and hyperkalemia by 
correcting the underlying causes and/or adjusting the non-disease modifying background 
therapy is provided to investigators in Appendix 4, and Appendix 5, respectively. If these 
measures do not lead to resolution of the adverse event(s), the dose of study drug should then 
be down-titrated or temporarily withdrawn if needed, followed by re-challenge, as described 
in Section 5.5.5. If a patient experiences symptomatic hypotension (despite the above 
measures) and a study drug discontinuation is required open-label ACE inhibitor or ARB 
therapy should be administered and titrated to the guideline-recommended target doses if 


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tolerated. Similar principles (such as emphasizing dose reduction or discontinuation of non-
disease modifying drugs of NSAIDs and diuretics, etc., followed by dose adjustment of study 
drug) should also be exercised when handling the renal dysfunction adverse events.  
Cough is also likely to be a common adverse event in the patients enrolled in the present study 
because of concomitant lung disease and potentially pulmonary congestion. For patients who 
have to discontinue study drug per investigator’s assessment due to persistent and intolerable 
dry cough despite dose reduction or temporary interruption/re-challenge of study medication, 
it is recommended that patients are administered open-label valsartan (titrated to the guideline 
recommended target dose of 160 mg bid) or an alternative ARB if valsartan is not available.
Open-label ACE inhibitors or ARBs during the study can ONLY be given to patients if the 
study drug has been temporarily or permanently discontinued. If the patient is to be started on 
open-label ACE inhibitor the study drug must be stopped ≥ 36 hours prior to initiating ACE 
inhibitor. If reinitiating study drug, the open-label ACE inhibitor must be stopped ≥ 36 hours 
prior to resuming study drug. Open-label ARBs must also be stopped prior to resuming study 
drug.
Use of rescue medication must be recorded on the CV Concomitant medications/Significant 
nondrug therapies CRF.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
CV Medications
The patient should be on an optimal medical regimen of background medications to 
effectively treat the index MI event and comorbidities, such as hypertension, diabetes, 
dyslipidemia and atrial fibrillation, etc. Investigators should take into consideration the 
patient’s risk factors, such as age and comorbidities, and make every effort to control a 
patient’s BP, lipid and glucose levels in accordance with international and local treatment 
guidelines. 
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements and any other medications known to raise 
potassium levels should be used with caution while the patient is receiving the study drug due 
to the increased possibility of occurrence of hyperkalemia. The investigator is encouraged to 
assess patients’ potassium levels regularly, especially in those who are receiving these 
medications.


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Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of the occurrence of hypotension.
HMG-CoA reductase inhibitors
Caution is recommended when co-administering LCZ696 with atorvastatin or other statins 
because of the potential to raise its plasma level.  No meaningful increase in statin-related 
AEs was observed when LCZ696 was used concomitantly with statins in the PARADIGM-HF 
(Streefkerk H, et al. 2017) study.  No dose adjustments are currently proposed for atorvastatin 
or other statins when coadministered with sacubitril/valsartan, Investigators should treat their 
patients with statins based on their best clinical judgement and local treatment guidelines.  
Diligent monitoring and reporting of statin-related adverse events should also be performed.  
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-2 is NOT allowed after the start of study drug due 
to safety reasons, unless the actions specified are taken.   
Table 5-2
Prohibited medication
Medication
Action taken
Any ACE 
inhibitor
Discontinue study drug. The open label ACE inhibitor must be stopped for ≥36 hours 
prior to re-initiation of study drug
Any ARB
Discontinue study drug. The open label ARB must be stopped prior to re-initiation of 
study drug
Any direct 
renin 
inhibitor
Discontinue study drug. The open label direct renin inhibitor must be stopped prior to 
re-initiation of study drug
Entresto™*
Discontinue study drug. The open label Entresto™ must be stopped for ≥36 hours prior 
to re-initiation of study drug
*Commercially available sacubitril/valsartan
The concomitant use of open-label ACE inhibitor, ARBs, commercially available Entresto™ 
or a direct renin inhibitor is strictly prohibited while the patient is receiving study drug. If the 
addition of an ACE inhibitor, ARB, Entresto™ or direct renin inhibitor is necessary, then 
study drug must be temporarily discontinued. If the patient is to be started on open-label ACE 
inhibitor or Entresto™, the study drug must be stopped ≥36 hours prior to initiating ACE 
inhibitor or Entresto™. If study drug is to be re-started, the open-label ACE inhibitor or 
Entresto™ must also be stopped ≥ 36 hours prior to re-initiating study drug. ARBs or a direct 
renin inhibitor should be stopped prior to resuming study drug. 
5.5.9
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 


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the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
An assessment will be done by the appropriate site personnel and the Medical Lead (or 
designee) after a patient has been intentionally unblinded  and the patient must discontinue the 
study treatment; whereas the appropriate personnel from the site and Novartis will assess 
whether study drug should be discontinued in instances where a patient is inadvertently 
unblinded for any reason.
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment
The study will be completed when either the predefined target total number of adjudicated 
events has been obtained or a recommendation is made by the DMC to prematurely stop the 
study. At the end of the study, all patients will return for the final end of study (EOS) visit 
(Visit 199) and be asked to return the remaining study drug.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from study drug, or must refer them for appropriate ongoing care. A post trial 
access (PTA) program may also be initiated to allow for the investigational drug to be made 
available to qualified patients participating in the trial.  The PTA mechanism must comply 
with the local laws and regulations in the participating countries in order to be made available.
5.6.2
Discontinuation of Study Treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. However, 
study treatment discontinuation does not constitute withdrawal from the study, does not 
constitute withdrawal of consent and should not lead to the patient being withdrawn from the 
entire study.  Patients who have permanently discontinued study drug should be encouraged to 
attend all the protocol specified study visits and perform, at a minimum, AE/endpoint 
assessments as stipulated in the visit schedule (Table 6-1) and remain in follow-up for the 
duration of the trial.


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If they fail to return for these assessments for unknown reasons, every effort should be made 
to contact them. The investigator must also contact the IRT to register the patient’s 
discontinuation from study treatment and record it on the Dosage Administration Record CRF. 
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 
study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits: 

new / concomitant treatments 

adverse events (AE)/Serious Adverse Events (SAE) 
The emergence of the following circumstances will require permanent study drug 
discontinuation: 

Withdrawal of informed consent

Investigator thinks that continuation of study drug would be detrimental to the patient’s 
well-being

Suspected occurrence of clinically significant angioedema. A patient with any signs or 
symptoms of clinically significant angioedema should be thoroughly evaluated by the 
investigator
The emergence of the following circumstances will require temporary or permanent 
discontinuation of study drug (study drug may be restarted once these circumstances no 
longer exist): 

Use of an open label ACE inhibitor, ARB, Entresto™ (commercially available 
sacubitril/valsartan) or direct renin inhibitor

Any laboratory abnormalities that in the judgment of the investigator warrant 
discontinuation of study drug after taking into consideration the patient’s overall status

Pregnancy and post-pregnancy during lactation period (Section 7.7)
Study drug may be discontinued at the investigator’s discretion if any of the following occurs:

Any severe suspected drug-related AE

Any other protocol deviation that results in a significant risk to the patient’s safety
For any patient who was unblinded inadvertently for any reason, the appropriate personnel 
from the site and Novartis will assess whether study drug should be permanently discontinued.  
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  However, withdrawal of consent occurs only when a patient does not want to 
participate in the study anymore and does not want any further visits or assessments and does 
not want any further study related contacts and does not allow analysis of already obtained 
biologic material and does not allow further collection of personal data.
If a patient withdraws consent, the investigator must make every reasonable effort (e.g. 
telephone, email, letter) to determine the primary reason for this decision and record this 
information. Study treatment must be discontinued and no further assessments conducted, and 


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data that would have been collected at subsequent visits will be considered missing. All 
biological material that has not been analyzed at the time of withdrawal must not be used. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.  All efforts should be made to complete the assessments prior to 
study withdrawal.  A final evaluation at the time of the patient’s study withdrawal should be 
made as detailed in Table 6-1.  Novartis will continue to keep and use collected study 
information (including any data resulting from the analysis of a patient’s samples until their 
time of withdrawal) according to applicable law.
Patients can also refuse to participate in specific aspects of the study and/or take study 
medication at any time without withdrawing consent and permission should be requested of 
the patient to conduct follow-up visits or calls.  Investigators should make every effort to 
accommodate the needs of the patients to make it possible for them to continue to participate 
in the remaining aspects of the study.
This includes performing telephone visits to obtain 
health status and/or mortality and endpoint information for patients who are unable to or 
refuse to return for clinic visits.
5.6.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
contacting the patient, the patient’s family, friends and family physician as agreed in the 
informed consent and by documenting in the eSource/source documents steps taken to contact 
the subject, e.g. dates of telephone calls, registered letters, etc. A patient should not be 
considered lost to follow-up until just prior to database lock, after every effort to contact the 
patient has been exhausted.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient 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 investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Patients should be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study for any reason should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF.


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Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.
Patients who prematurely discontinue the investigational treatment remain in the study and 
should undergo all the assessments illustrated in Table 6-1. Patients can also refuse to 
participate in specific aspects of the study and/or take study medication at any time without 
withdrawing consent and permission should be requested of the patient to conduct follow-up 
visits or calls.  Investigators should make every effort to accommodate the needs of the 
patients to make it possible for them to continue to participate in the remaining aspects of the 
study. This includes performing telephone visits to obtain health status and/or mortality and 
endpoint information for patients who are unable to or refuse to return for clinic visits.
If a patient withdraws from participation in the study, refuses to return for study assessments 
or is unable to do so, every effort should be made to contact them or a knowledgeable 
informant by telephone and/or other measures to determine the patient’s survival status and 
endpoint information including heart failure hospitalization or outpatient heart failure events 
during the follow-up period.
Patients eligible to participate in this study must be randomized between 12 hours to 7 days 
after index AMI event presentation.  
Prospective study candidates will be identified either during the hospitalization for the index 
AMI or post discharge up to 7 days after the index MI presentation.  After identifying a 
potential patient, an informed consent form (ICF) must be signed before performing study-
related screening procedures that are not considered standard of care for AMI patients at that 
site.  Procedures that are part of a site’s standard of care for an individual with AMI may pre-
date the signed ICF.  The AE and SAE reporting period will begin at the time the ICF is 
signed. Screening will continue until the patient has been deemed eligible for randomization 
into the study up to 7 days after the index MI.  Screening and randomization can occur on the 
same day. 
Visit 101 will be considered the reference visit for all study visits during the treatment epoch. 
Regardless of the occurrence of any unscheduled visits, scheduled visits should be performed 
within the specified timeframe in relation to Visit 101 as outlined in Table 6-1. If a visit is 
completed earlier than scheduled or postponed, it should not result in the next visit being 
brought forward or postponed.
Visits are planned to occur at weeks 1, 2, 4 (month 1), month 2, month 4, and then every 4 
months until study end.
      


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Table 6-1
Assessment schedule
Epoch 
Screen
Treatment
Visit
1
101 102 103 10416 105 106 107 108 109 110
111
112
113
114
11517
11617
11717
199 and 
PSD
Day
1
7
14
28
61 122 243 365 486 608
730
851
973
1095
1216
1338
1460
EOS
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
156
173
190
208
EOS
Month
1
2
4
8
12
16
20
24
28
32
36
40
44
48
EOS
Obtain informed consent
X
Inclusion/exclusion criteria
X
X
Medical History – Protocol 
Solicited Events
X
Relevant Medical 
History/Current Medical 
Conditions/ Demography
X
Medical History Possibly 
Contributing to Liver 
Dysfunction1
X
History/Smoking
History/Alcohol History
X
12-lead ECG assessment2
S
Cardiac enzymes2
X
Chest X-ray or CT scan2,3
S
Evaluation of left ventricular 
systolic dysfunction2
X
Record Killip Class2,3
S
X


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Epoch 
Screen
Treatment
Visit
1
101 102 103 10416 105 106 107 108 109 110
111
112
113
114
11517
11617
11717
199 and 
PSD
Day
1
7
14
28
61 122 243 365 486 608
730
851
973
1095
1216
1338
1460
EOS
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
156
173
190
208
EOS
Month
1
2
4
8
12
16
20
24
28
32
36
40
44
48
EOS
Risk factor assessment
X
X
Qualifying AMI Event
X
Index AMI Hospitalization 
Summary
X
Physical exam2,4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Height2
X
Weight2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (pulse and BP)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAEs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete laboratory 
evaluation7
X
X
X
X
X
X
X
X
Abbreviated laboratory 
evaluation8
X
X
X
X
X
X
X
X
X
X
Local laboratory evaluation2,9
S
S
S
S
S
Endpoint assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Angioedema assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit Contact Information
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Epoch 
Screen
Treatment
Visit
1
101 102 103 10416 105 106 107 108 109 110
111
112
113
114
11517
11617
11717
199 and 
PSD
Day
1
7
14
28
61 122 243 365 486 608
730
851
973
1095
1216
1338
1460
EOS
Week
0
1
2
4
8
17
34
52
69
86
104
121
138
156
173
190
208
EOS
Month
1
2
4
8
12
16
20
24
28
32
36
40
44
48
EOS
Serum/urine pregnancy 
testing2,11
S
S
S
S
S
S
S
Dispense Study Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening disposition
X
Study Completion form
X
TD = Study treatment discontinuation; PSD = Premature patient discontinuation; EOS = End of study
X = assessment to be recorded on clinical data base
S = assessment to be recorded on eSource/source documentation only
1Collected retrospectively for patients who experience protocol defined liver events (See Appendix 2).
2Assessments typically performed as standard of care for index AMI according to local guidelines. Procedures that are part of a site’s standard of care for 
an individual with AMI may pre-date the signed ICF.  Local laboratory evaluations done as standard of care should not predate randomization by >72 
hours.  Vitals, weight, and physical exam assessments should be on the same day as visit 1 if they predate the signed ICF. 
3Pulmonary congestion is assessed by worst Killip class AND/OR chest x-ray or CT scan findings during index hospitalization.  
4Complete physical examinations are required at Visit 1 and yearly (Visits 108, 111, 114, 117, etc.) thereafter up until Visit 199 (EOS). Short physical 
examinations are required at all interim visits.
5 CV medications (e.g., β-blockers, aldosterone antagonists, anti-hypertensives, lipid lowering drugs, antiplatelet agents, etc.) and classes of non-
cardiovascular medications will be collected. 
6 All adverse events and all serious adverse events will be collected.  


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7 Complete laboratory evaluations will be collected and sent to the central lab at all specified visits for all patients. Complete laboratory evaluation will be 
performed at visits 101, 104, 106, and annually (Visit 108, 111, 114, 117, etc.). 
8 Abbreviated laboratory evaluations includes: blood urea nitrogen (BUN), serum creatinine, serum potassium and eGFR and will be collected and sent to 
the central lab at all specified visits for all patients. An abbreviated laboratory evaluation will be performed at all interval visits except annual visits (i.e., 
visit 108, 111, 114, 117, etc.).
9 Local laboratories for serum potassium (or equivalent plasma potassium value), creatinine and eGFR are permitted to help guide dosing decisions prior 
to initial dosing and prior to each dose titration step until target dose is achieved (Visits 1, 101, 102, 103 and potentially 104; additional visits may be 
added as necessary until target dose level is achieved and/or during dose adjustments throughout the study).  If screening (Visit 1) and randomization 
(Visit 101) occur on the same day, only one laboratory assessment will be required.  If local laboratory assessments are not possible or it will take longer 
to receive results than through the central laboratory assessment, the central laboratory may be used instead.  
11 Serum and urine pregnancy tests will be performed locally. Serum pregnancy test (not required for post-menopausal women) to be performed at Visit 
1. Urine pregnancy tests at visits 101 and annual (not required for post-menopausal women) or more frequently if required by local regulatory authorities.  
If screening (Visit 1) and randomization (Visit 101) occur on the same day, only serum pregnancy test will be required.  If serum pregnancy test is 
positive during the screening and on a confirmatory serum β-hCG test, the patient must not be randomized and must be discontinued from the trial. After 
randomization (Visit 101) a positive urine pregnancy test requires immediate interruption of study drug and confirmation by serum pregnancy test. If 
positive upon confirmation test, the patient must interrupt study drug until after the pregnancy and lactation period.
 
14 For patient who at the end of the study are completing visit 199 on or before month 8 (visit 107 as per protocol schedule) 
16 For patients who have not been titrated to dose level 3 by week 4, an unscheduled dose titration visit on or about week 6 should be considered to 
evaluate whether titration to the target dose, dose level 3, can be initiated.
17 Protocol visits will continue to occur every 4 months until the number of required study endpoints are met for end of study (EOS). If additional visits are 
required between visit 117/month 48 and EOS visit, patients must continue to complete scheduled visits every 4 months (3 visits per treatment year) 
increasing the protocol visit number by +1 at each subsequent visit (visit 118, visit 119, etc.).  The assessments to be completed at the 3 visits per 
treatment-year should follow the assessments described in visit 115, 116, and 117 respectively. Example: visit 118 has the same assessments as visit 
115, visit 119 has the same assessments as visit 116, and visit 120 has the same assessments as visit 117


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6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the eSource/source data.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients at least 
include year of birth, age, sex, race, and ethnicity. A detailed medical history (including CV 
and other conditions relevant to the study population to be enrolled) and current medical 
conditions present before the signing of informed consent, including the presentation and 
management of index MI event will also be recorded.
6.3
Treatment exposure and compliance
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient or care giver. This information should be 
captured in the eSource/source document at each visit. The investigator and/or study 
personnel should counsel the patient if compliance is below 80% at any time during the study. 
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
The duration of randomized treatment exposure will be calculated based upon the start and 
stop dates of study drug recorded in the CRF. 
6.4
Efficacy
6.4.1
Efficacy assessment 1
The primary efficacy endpoint is defined as the time to the first confirmed occurrence of CV 
death, heart failure hospitalization* or outpatient heart failure**.
* Heart failure hospitalization also includes the development of new symptomatic heart 
failure during an ongoing hospitalization including the index AMI hospitalization.  
** Outpatient heart failure is defined as:

An urgent/unscheduled visit to an ED, acute/urgent care facility or outpatient clinic or a 
non-urgent office/practice or study visit for a primary diagnosis of HF that does not 
require an overnight hospital stay.

Patients must exhibit at least one documented new HF symptom with objective evidence 
of clinical HF consisting of at least 2 physical examination findings or one physical 
examination findings and at least one laboratory criteria.

The event requires initiation or intensification of treatment specifically for HF. Such 
treatment can include administration of intravenous agent (e.g., diuretic, vasodilator, 
vasopressor, or inotrope) or mechanical or circulatory intervention for HF,  
OR initiation of oral loop diuretic treatment, or intensification of oral maintenance loop 
diuretics for the diagnosis of HF, over a sustained period (i.e., initiation or doubling of 


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total daily dose through a period of ≥ 4 weeks), which is confirmed at a subsequent 
outpatient visit
6.4.2
Efficacy assessment 2
The secondary endpoints are: 

Time-to-first occurrence of CV death or HF hospitalization (days)

Time-to-first occurrence of HF hospitalization or outpatient HF (days)

Time-to-first occurrence of CV death, non-fatal spontaneous MI or nonfatal stroke (days)

The cumulative number of composite events, including hospitalization due to HF, 
hospitalization due to non-fatal spontaneous MI, hospitalization due to non-fatal stroke 
and CV death. This endpoint is based on the total number of recurrent composite 
endpoints (count) and patient-specific follow-up time from randomization to end of 
study/death (days).

Time to all-cause mortality (days)
A blinded central Clinical Endpoint Committee (CEC) will be responsible for adjudicating 
and classifying all death events (CV vs. non-CV) and for determining whether pre-specified 
endpoint criteria are met for the primary and secondary non-fatal endpoint events.  The CEC 
will also be responsible for adjudicating and classifying all investigator-reported outpatient 
HF events as the clinical development of HF under an outpatient setting (urgent/unscheduled 
or non-urgent) with symptoms and signs requiring initiation/intensification of intravenous or 
qualifying oral HF treatment. The diagnostic criteria for HF symptoms and signs will be 
identical whether the patient is seen in an inpatient or outpatient setting. The detailed 
definitions of the endpoints, required documentation and the adjudication process will be 
provided to all sites in a separate endpoint manual.
6.4.3
Appropriateness of efficacy assessments 
The composite of CV death or HF hospitalization is a well-established mortality and 
morbidity endpoint. The addition of the outpatient HF component here aims to capture the 
clinically important outpatient symptomatic HF event that contributes to the totality of HF 
morbidity following an AMI presenting as either inpatient (i.e., HF hospitalization) or 
outpatient (i.e., outpatient HF) events. The clinical significance of HF events in the outpatient 
setting has been increasingly recognized by medical communities and health authorities 
(Hicks, et al 2014). Outpatient HF events reported in randomized chronic HF trials, of which 
the definition is analogous to the outpatient HF event proposed for CLCZ696G2301 study, 
have been shown to be associated with significantly increased risks of (CV) mortality. 
Furthermore, the outpatient HF events are also modifiable events that are equally sensitive to 
the evidence-based HF therapeutics as are the mortality and composite CV death/HF 
hospitalization endpoints, which underscores the similar pathology contributing to these 
events (Skali, et al 2014; Okumura, et al 2016).
6.5
Safety 
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety 


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profile of the study drugs. Such information may include diagnostic procedure reports, 
discharge summaries, autopsy reports, and other relevant information that may help in 
assessing the reported AE. All additional information will be de-identified prior to collection 
by Novartis or its agents.  
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will include the examination of general appearance and vital signs (BP 
[SBP and diastolic blood pressure (DBP)] and pulse). A short physical exam will be 
conducted at all visits starting from Visit 101 except where a complete physical examination 
is required (see Table 6-1). 
Information from all physical examinations must be included in the eSource/source 
documentation at the study site. Significant findings that are present prior to signing informed 
consent must be included in the Medical History part of the CRF. Significant findings made 
after signing the informed consent which meet the definition of an AE must be recorded on 
the AE section of the CRF.
6.5.2
Vital signs 
Vital signs include BP and pulse measurements. BP will be measured in the sitting position 
after 5 minutes of rest using an automated validated device (e.g., OMRON) or a standard 
sphygmomanometer with an appropriately sized cuff on the non-dominant arm. Guidelines for 
the management of BP are provided in Appendix 4.
6.5.3
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] or pound [lb] in 
indoor clothing, but without shoes) will be measured.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of most specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
Complete central laboratory evaluations (hematology and blood chemistry) for the assessment 
of safety in this study will be performed at Visits 101, 104, 106, 108, 111, 114, 117, annually 
thereafter, and end of study (199). Abbreviated laboratory central evaluations will be 
performed at all interim visits as indicated in Table 6-1.
In addition to the required central laboratory assessments, a local laboratory may be used for 
the assessment of potassium, creatinine and eGFR during the screening period and dose 
titration period as indicated in Table 6-1. The results from the local laboratory will be allowed 


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to make decisions regarding randomization, study drug administration and dose titration/dose 
level adjustments, and will be recorded in the eSource/source documents at the study sites. In 
addition, local laboratory assessments of potassium, creatinine and eGFR may be performed 
on an as-needed basis to monitor tolerability to study drug and dose adjustments at scheduled 
or unscheduled visits during the treatment epoch.  If local laboratory assessments are not 
possible or it will take longer to receive results than through the central laboratory assessment, 
the central laboratory may be used instead of local labs to make decisions regarding the study 
drug dosing.  
Laboratory values that exceed the boundaries of a notable laboratory abnormality should be 
assessed for AEs and additional evaluations should be performed, as judged appropriate by 
the investigator. If the laboratory abnormality induces clinical signs or symptoms, results in a 
dose adjustment of the study medications, is suspected to be study drug-related or requires 
therapeutic intervention, then the diagnosis or medical condition must be entered on the AE 
CRF. If the laboratory abnormality is the primary reason for an unforeseen hospitalization or 
otherwise fulfills the seriousness category of an AE, then the procedure for rapid notification 
of SAEs must be followed. If the laboratory abnormality leads to study drug discontinuation 
(temporarily or permanently), the patient must be followed until the abnormality resolves or 
until it is judged to be permanent. The investigation may include continued monitoring by 
repeat laboratory testing or by performing additional laboratory tests as deemed necessary by 
the investigator or the Novartis medical monitor.
Table 6-2
Routine laboratory examinations
Hematology 
Biochemistry 
Hematocrit
Alanine aminotransferase (ALT)
Hemoglobin
Albumin (Alb)
Platelet count
Alkaline phosphatase (ALP)
Red blood cell count (RBC)
Aspartate aminotransferase (AST)
White blood cell count (WBC)
Blood urea nitrogen (BUN)*
WBC differential
Calcium
Red blood cell distribution width (RDW)
Chloride
Mean corpuscular volume (MCV)
Creatinine*
Mean corpuscular hemoglobin
Glucose
concentration (MCHC)
Hemoglobin A1C
Lipid profile (total cholesterol, LDL, and HDL)
Phosphate
Potassium*
Sodium
Total bilirubin (TBL)
Fractionated bilirubin (if total bilirubin >2x ULN)
Total protein
Uric acid
*Laboratory assessments of BUN, serum creatinine and serum potassium for the abbreviated central 
laboratory evaluation at visits where the complete laboratory evaluation is not performed; eGFR is 
derived from serum creatinine values following MDRD formula


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6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count (RBC), red blood cell distribution width (RDW), 
mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), 
white blood count (WBC) with differential, and platelet count will be measured.
6.5.4.2
Clinical chemistry
Blood urea nitrogen (BUN), creatinine, total bilirubin, fractioned bilirubin (if total 
bilirubin >2x upper limit of normal (ULN)), Aspartate aminotransferase (AST), Alanine 
aminotransferase (ALT), alkaline phosphatase, sodium, glucose, hemoglobin A1C, lipid 
profile, phosphate, potassium, chloride, calcium, total protein, albumin, and uric acid will be 
measured. Potassium, BUN and creatinine will be obtained at study visits where abbreviated 
central laboratory evaluations are scheduled.
6.5.4.3
eGFR
Estimated GFR will be calculated by the central or local laboratory using the following 
MDRD formula (Stevens et al. 2006): 
Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154
× (age in years)-0.203 × (0.742 if female) × (1.212 if black), where SCr is the serum creatinine 
value.
For the calculation of eGFR using local laboratory data, serum creatinine in the above formula 
will be replaced with plasma creatinine when serum creatinine is not available from local labs.
6.5.4.4
Urinalysis
No urinalysis will be performed. 
6.5.5
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed locally in association with the index MI and 
recorded at Visit 1. Interpretation of the tracing must be made by a qualified physician and the 
ECG interpretation and the person interpreting the ECG must be recorded in the 
eSource/source documents at the study sites. The ECG tracing should be labeled with the 
study and patient number, date, and kept in the eSource/source documents at the study site. 
Clinically significant abnormalities should also be recorded on the Medical History/AE CRF 
page as appropriate.
6.5.6
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
performed locally at Visit 1. A urine dip-stick pregnancy test will be performed locally on an 
annual basis, or more frequently if required by local regulatory authorities. The urine dip-stick 
pregnancy test is not required for post-menopausal women. A positive urine pregnancy test 
requires immediate interruption of study drug and confirmation by serum pregnancy test. If 
positive upon confirmation test, the patient must interrupt study drug until after the pregnancy 
and lactation period.


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6.5.7
Angioedema 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway 
compromise. A patient with any signs or symptoms of clinically significant angioedema 
should be thoroughly evaluated by the investigator and study medication must be permanently 
discontinued.
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an 
Angioedema-like event form (provided by Novartis) to summarize the event, its treatment, 
and its ultimate outcome.  This report along with the requisite medical documentation must be 
submitted to Novartis as soon as possible. Follow-up reports must be communicated to 
Novartis as soon as new information regarding the event becomes available. All hospital 
records related to the event must be communicated to Novartis.
The investigator may be also be contacted by Novartis regarding AEs that may resemble an 
angioedema-like event. A list of terms that are considered “angioedema-like” (e.g., periorbital 
swelling) will be provided to sites in a manual. The investigator or his/her delegated staff 
must complete the required forms and provide the required medical records for all such events, 
regardless of whether the investigator views the event in question as angioedema or not.
All angioedema reports will be forwarded to an Angioedema Adjudication Committee by 
Novartis for independent adjudications. 
Information regarding this committee is outlined in Section 8.5. Details on the procedures for 
reporting angioedema events will be provided to investigators in a manual.
6.5.8
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
 
 
 
 
 
 
 


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7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.  
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
Adverse events of special interest (angioedema, hyperkalemia, hypotension, renal impairment, 
cognitive impairment, hepatotoxicity, hypersensitivity, malignancy, pregnancy and exposure 
during breast feeding, statin-related adverse events), along with all other AE and SAEs will be 
summarized and sent to the DMC for periodic safety reviews during the trial. The occurrence 
of adverse events must be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.


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Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment: 

Yes

No
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

treatment dosage increased/reduced

treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB 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 has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s eSource/source documents; however, if the AE meets the criteria of an SAE, it 
must be reported to Novartis.


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7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day 


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period after the last study visit should only be reported to Novartis if the investigator suspects 
a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
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.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Protocol specific unblinding rules for SUSARs that are also 
efficacy endpoints
In studies such as this one, where the efficacy endpoints potentially meet the requirements for 
SUSAR reporting, the integrity of the study may be compromised if the endpoints are 
systematically unblinded for expedited reporting to competent authorities/relevant ECs and 
investigators. In such cases, regulations allow an exemption from SUSAR unblinding and 
expediting aimed at ensuring the validity of an outcome study (EU Guidance 2011/C 172/01; 
FDA Guidance 2012). Therefore, the following rules for unblinding SUSARs during the study 
period will be applied.
7.3.1
Primary and secondary endpoints
The primary and secondary endpoints (CV death, HF hospitalization, outpatient HF, non-fatal 
spontaneous MI, and non-fatal stroke) will not be unblinded even if they meet the definition 
of a SUSAR.  Novartis will not expedite a report to competent authorities/relevant ECs and 


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will not issue an investigator notification (IN). However, non-CV death, a secondary endpoint 
for the study, will be unblinded if it meets the criteria for a SUSAR. 
If specifically requested by a local Health Authority, pre-specified endpoints that also meet 
criteria for SUSARs will be expedited to this Health Authority as blinded reports.  
Investigator notifications will not be issued for these events.
7.3.2
Adverse events that are commonly seen in the study population
Investigators will report AEs or SAEs that are commonly seen in the study population but 
they will not be unblinded and will not be reported as SUSARs to regulatory agencies, ECs, or 
investigators during the study. 
In clinical trials evaluating treatments for high morbidity and/or high mortality disease states, 
SAEs that are known consequences of the underlying disease or condition under investigation, 
or events common in the study population, are anticipated to occur with some frequency 
during the course of the trial, regardless of drug exposure. While the investigator must still 
report all SAEs and all the targeted non-serious AEs during and after the first two weeks after 
randomization, respectively, as outlined in Section 7.1  SUSARS considered consistent with 
the following SAE Preferred Terms (PT) will not be unblinded and reported in an expedited 
timeframe to regulatory agencies, ECs or investigators during the course of the study.  These 
events will be presented in the clinical study report at the end of the study.
abdominal pain, acute coronary syndrome, acute pulmonary oedema, anaemia, angina 
pectoris *, anxiety, arthralgia, asthenia, azotaemia, back pain, blood creatinine *, 
blood pressure *, blood urea nitrogen *, bronchitis *, cardiac arrest, cardiac 
arrhythmias (all Preferred Terms presenting any type of arrhythmia excluding
electrocardiogram QT interval abnormal, electrocardiogram QT prolonged, long QT 
syndrome, torsade de pointes), cardiac asthma, cardiac catheterization, cardiac failure 
*, cardiac output *, cardiac pacemaker *, cardiac resynchronization therapy, cardiac 
surgery (including coronary artery bypass grafting), cardiac tamponade, cardiogenic 
shock, cardiorenal syndrome, cerebrovascular accident, chest pain, chronic obstructive 
pulmonary disease, confusional state, constipation, cor pulmonale *, cough *, 
creatinine renal clearance  *, delirium, diarrhea, dizziness, dyspnea *, ejection fraction 
*, fatigue, generalized oedema, glomerular filtration rate  *, gout, headache, heart 
transplant, hepatic congestion, hyperglycemia, hyperkalemia, hyperlipidemia, 
hypertension *, hyperuricaemia, hypoglycemia, hypokalemia, hypernatremia, 
hypotension *, implantable defibrillator *, influenza *, insomnia, intra-aortic balloon 
pump, loss of consciousness, muscle spasm, musculoskeletal pain, myocardial 
infarction*, nasopharyngitis, nausea, oedema, oedema due to cardiac disease, oedema 
peripheral, osteoarthritis, pain in extremity, percutaneous coronary intervention, 
pericardial effusion, pleural effusion, pneumonia *,
presyncope, pulmonary 
hypertension, pulmonary oedema, renal failure *, renal impairment, respiratory 
distress *, respiratory failure *, respiratory tract infection *, stroke*, syncope, transient 
ischemic attack, urinary tract infection, valve insufficiency*, valve stenosis*, 
ventricular failure *, ventricular assist device, vomiting, weight increased
*More than 1 preferred term can contain this term.


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
If specifically requested by a local Health Authority, pre-specified AEs commonly 
observed in the study population (see above) that also meet the criteria for SUSARs will 
be expedited to the requesting Health Authority as blinded reports without issuing INs, or

Pre-specified AEs commonly observed in the study population that occur in patients under 
the jurisdiction of the requesting Health Authority will be expedited to the Health 
Authority as unblinded reports; INs will be issued for these events.
 
 
 
7.4
Liver safety monitoring
Liver Function Test (LFT) elevations, including both aspartate transaminase (AST) and 
alanine transaminase (ALT), are common in patients following an AMI.  In a study with a 
total of 1,783 patients presenting with STEMI, 59.1% patients with Killip class II had AST 
increase greater than 3x ULN and 5.1% had ALT increase greater than 3x ULN.  For patients 
with liver enzyme increase, AST and ALT levels in majority of them return to baseline within 
2 weeks (Lofthus, et al. 2012).
Evaluation of LFT elevations should focus on the potential drug-induced LFT changes. As 
described by Lofthus et al, any LFT elevations during the first 2 weeks post-AMI are very 
likely caused by the underlying disease. Therefore, AST and/or ALT elevations within 2 week 
post-AMI will not be reported as SAEs unless investigators suspect the liver transaminase 
change is due to the investigational drug. A similar consideration is also applicable to the 
recurrent MI or acute heart failure events during the trial.
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Liver events, which cannot be solely explained by apparent AMI (either index or recurrent 
spontaneous MI event) or acute heart failure episodes as the underlying cause, are divided into 
two categories:

LFT increases without associated symptoms which will require repeated assessments of 
the abnormal laboratory parameter 

Liver events (i.e., significant LFT increases or liver-toxicity related symptoms with or 
without LFT increases), which will require close observation, follow-up monitoring and 
completion of the standard base liver CRF pages
Please refer to Appendix 2 Table 14-1 for complete definitions of liver laboratory triggers and 
liver events. 
Every liver laboratory trigger of liver event without apparent AMI (either index or recurrent 
MI event) as the underlying cause and as defined in Appendix 2 Table 14-1 should be 


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followed up by the investigator or designated personnel at the trial site as summarized below. 
Detailed information is outlined in Appendix 2 Table 14-2.
For the liver laboratory trigger: 

Repeating the LFT within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For significant LFT increases or liver-toxicity related symptoms with or without LFT 
increases:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
It is the investigator’s responsibility to investigate the potential occurrence of these events.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.  In addition, independent assessments of the biochemical Hy’s 
law cases (defined as ALT or AST > 3x ULN and total bilirubin > 2x ULN) reported during 
the study will be performed by an external liver safety expert.
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) 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 
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Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (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
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
7.7
Monitoring of safety data by the Data Monitoring Committee
An external independent Data Monitoring Committee (DMC) (Section 8.4) will be appointed 
to monitor the safety of study participants and to ensure that the program is being conducted 
with highest scientific and ethical standards. This DMC will review the endpoint and SAE/AE 
of special interest data throughout the trial in an unblinded manner. Should the DMC make 
recommendations on the conduct of the trial that are considered to have significant bearing on 
the benefit-risk of the trial, these will be communicated by Novartis to HAs, ECs and 
investigators within an appropriate timeframe and implement any additional actions required.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to GCP, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 


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monitoring of each site’s data may be performed by a centralized Novartis Clinical Research 
Associate (CRA) organization.  Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain eSource/source documents for each patient in the study, 
consisting of case and visit notes (hospital or clinic medical records) containing demographic 
and medical information, laboratory data, electrocardiograms, and the results of any other 
tests or assessments. All information on CRFs must be traceable to these eSource/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 eSource/source documents to 
confirm their consistency with the CRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the eSource/source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in eSource/source documents about the 
identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Oracle 
Clinical/Remote Data Capture (OC/RDC) system. Designated investigator site staff will not 
be given access to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis staff or Clinical Research Organization (CRO) working on behalf of Novartis review 
the data entered into the CRFs by investigational staff for completeness and accuracy and 
instruct the site personnel to make any required corrections or additions. Queries are sent to 
the investigational site using an electronic data query. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. If the electronic query system 
is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete 
and sign the faxed copy and fax it back to Novartis staff that will make the correction to the 
database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
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Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee
An external data monitoring committee (DMC) independent of Novartis will be appointed to 
monitor the study conduct and to review the results of the interim analyses for safety on a 
regular basis and determine if it is safe to continue the study according to the protocol. In 
addition, they will review the results from two interim analyses to allow for early stopping 
due to overwhelming efficacy. Any major recommendation from the DMC will be 
communicated to the Executive Committee and must be reviewed and ratified by the 
Executive Committee in consultation with Novartis prior to its enactment.
The membership of the DMC and the responsibilities of the DMC and Novartis will be 
defined in a separate document entitled the “Data Monitoring Committee Charter”. The DMC 
Charter will include information about data flow, purpose and timing of DMC meetings, 
guidance in the decision making process, communication strategy, procedures for ensuring 
confidentiality, procedures to address conflicts of interest and statistical monitoring guidelines.
8.5
Adjudication Committee
Clinical Endpoint Committee
All clinical events, which could potentially fulfill the criteria for the primary, secondary, or 
other selected endpoints will be assessed during the study and reported to a blinded central 
Clinical Endpoint Committee (CEC) for adjudication.  The CEC will be responsible for 
adjudicating and classifying all death events (CV vs. non-CV) and for determining whether 
pre-specified endpoint criteria are met for selected non-fatal events.  The detailed definitions 
of the endpoints, required documentation and the adjudication process will be provided to all 
sites in a separate endpoint manual.
Angioedema Adjudication Committee
All angioedema or angioedema-like events will be assessed during the study and reported a 
blinded angioedema adjudication committee for adjudication. If such an event occurs, the 


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investigator will complete an Adjudication Questionnaire for an Angioedema-like Event form 
(provided by Novartis). Details on the process of reporting angioedema and angioedema like 
events are outlined in a manual provided to investigators.
Submission of an angioedema report is not a substitution for the submission of an SAE report. 
If an angioedema-like event satisfies the definition of an SAE, the investigator must submit an 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event.
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites.
9
Data analysis 
The analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. Additional details of the statistical analyses will be documented in 
a Statistical Analysis Plan (SAP).  
In the event that the study is stopped early for efficacy at the second interim analysis, or the 
study is terminated early by the sponsor due to prolonged COVID-19 impact, the main and 
supportive analyses for efficacy endpoints described in this section will be performed using 
the same analysis cut-off date as the second interim analysis (i.e., 01-Mar-2020). 
Section 9.4.4 provides information about the currently planned sensitivity analyses for the 
primary endpoint. Additional sensitivity and supportive analyses for the COVID-19 impact 
will be added if deemed necessary. Details of the additional analyses will be specified in the 
SAP prior to database lock.
9.1
Analysis sets
The following analysis populations will be defined for statistical analysis:

Randomized (RAN) set – All patients who received a randomization number, regardless 
of receiving trial medication.

Safety set (SAF) - All patients who received at least one dose of study drug. Of note, the 
statement that a patient had no adverse events also constitutes a safety assessment. 
Patients will be analyzed according to treatment received. 

Full analysis set (FAS) – All patients in the RAN population who were not mis-
randomized patients*.  Following the intent-to-treat (ITT) principle, patients are analyzed 
according to the treatment they have been assigned to at the randomization. 

The Per-protocol set (PPS) will be a subset of the FAS which will consist of the patients 
who do not have major deviations. Major protocol deviations will be pre-specified prior to 
unblinding.
* Mis-randomized patients are those who were not qualified for randomization and who did 
not take study drug, but have been inadvertently randomized into the study.
Subjects without valid written informed consent will be excluded from all analysis sets.


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9.2
Patient demographics and other baseline characteristics
Summary tables will be provided by treatment group for demographic characteristics:  
including age, age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years), sex, race, 
ethnicity, weight, height, body mass index (BMI) and baseline characteristics: including but 
not limited to information about the index MI event, (STEMI/NSTEMI; PCI/medical 
management; LVEF; Killip class, BP, renal function etc.), medical history and CV risk factors,   
and category of prior CV medications. 
Continuous variables will be summarized using n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized using frequency and 
percentage.
The FAS will be the patient population for the above analyses.
9.3
Treatments 
The overall duration on the randomized study drug will be summarized by treatment group 
using mean, standard deviation, median, minimum, and maximum. Additionally, the number 
and percentage of patients will be summarized by treatment group for duration category. 
Mean doses and dose levels will be summarized by treatment group and visit.  A Kaplan-
Meier plot of time to discontinuation of study medication will be provided.  A summary table 
by treatment group will be provided to display the number of patients who discontinued study 
medication and the number of patients who subsequently received the following medications 
during the study: ACE inhibitors, ARB, and Entresto™, (sacubitril/valsartan). 
The duration of randomized study drug will also be calculated excluding temporary treatment 
discontinuations. 
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date respectively, will be summarized by therapeutic class, preferred term, and 
treatment group for the safety set. 
The number and percentage of patients on different CV background medications (e.g., aspirin, 
P2Y12 inhibitors, β-blockers, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, 
statins, and diuretics, etc.) will be tabulated by treatment at baseline and during the treatment 
epoch.
The SAF will be used for the summaries of exposure data and the summaries of concomitant 
medications unless otherwise specified.
9.4
Analysis of the primary variable(s)
All patients in the Full Analysis Set (FAS) will be included in the primary analysis. 
9.4.1
Variable(s)
The primary efficacy variable is time to first occurrence of a confirmed composite endpoint of 
cardiovascular death, HF hospitalization or outpatient HF. The confirmation of the primary 
composite events will be based on an adjudication process by an independent CEC. 


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Note that deaths which cannot be classified by the adjudication committee as CV or non-CV 
death (for example due to lack of information), will be counted as a CV death for the purpose 
of the primary endpoint. 
Time-to-event is computed as the number of days from randomization to the start date of the 
primary endpoint event (first occurrence). A patient without an event will be censored at the 
last date the endpoint status was completely known* or at the time of death from non-CV 
causes (i.e. any death which is confirmed to be a non-CV death by the CEC). 
* This date could include the date of withdrawal of informed consent or date of the patient’s 
last visit prior to the cut-off date of the analysis (whichever occurred first).
9.4.2
Statistical model, hypothesis, and method of analysis
The following null hypothesis versus the alternative will be tested at the 1-sided 2.5% type I 
error rate. 
H0 : λ2/λ1 ≥ 1 (i.e., the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is greater than or equal to the hazard rate in the ramipril group (λ1)) versus
H1 : λ2/λ1 < 1 (i.e. the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is less than the hazard rate in the ramipril group (λ1))
λ2/λ1 is called the hazard ratio of LCZ696 relative to ramipril.
The time-to-first confirmed primary endpoint will be analyzed using a Cox proportional 
hazards model stratified by STEMI/NSTEMI, with Treatment, PCI use at baseline and region 
included as factors in the model. The hazard ratio for LCZ696 vs. ramipril, the associated 2-
sided 95% confidence interval and the 1-sided and 2-sided p-values will be presented from the 
analysis.
The Kaplan-Meier estimates of the cumulative event rate (1-survival function) for each 
treatment (and strata) will be plotted.
Supportive Analysis
The composition of the first confirmed composite primary efficacy endpoint will be 
summarized by treatment group descriptively. The time to reach the first of each individual 
component will be analysed using the same methodology as the described for the primary 
endpoint.  Note that for the components CV death and HF hospitalization, all events observed 
will be included in the individual component analyses and not just those which were counted 
as a ‘first event’ in the primary composite endpoint.  In addition to the standard censoring 
mechanism described in Section 9.4.3, for the analysis of time to outpatient HF, patients will 
be censored at the time of HF hospitalization or CV death. For the analysis of time to first HF 
hospitalization, patients will be censored at the time of CV death.  
An ‘on-treatment’ analysis will also be performed for the primary endpoint whereby events 
that occurred more than 28 days after permanent study treatment discontinuation will be 
excluded from the analysis.  For patients without events before or at 28 days after treatment 
withdrawal, the censoring date will be the minimum of the date of permanent study treatment 
discontinuation + 28 days and the date of standard censoring for the endpoint.


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Subgroup analysis
Subgroup analyses will be performed for the FAS only. 
Displays of treatment effects by subgroup categories (defined as marginal groupings) will be 
provided for descriptive purposes. 
The estimated hazard ratio, and 2-sided 95% confidence interval, will be provided for each 
individual subgroup using a Cox’s proportional hazards model stratified by STEMI/NSTEMI 
and including terms for treatment, region and PCI use at baseline in the model. The p-value 
associated with the interaction term will be calculated from a Cox’s proportional hazards 
model, stratified by STEMI/NSTEMI, including treatment, PCI use at baseline, region, 
subgroup, and treatment-by-subgroup as fixed-effect factors. Since no adjustment for multiple 
comparisons will be made, findings should be interpreted with caution.  Additionally, the 
frequency and percentage of patients reaching primary composite endpoint will be presented 
by treatment group for each of the subgroups listed below:

Age group (< 65 vs ≥ 65 years; < 75 vs ≥ 75 years)

Gender

Race

Region

STEMI vs. NSTEMI (for this analysis, do not stratify by STEMI/NSTEMI, but include as 
a factor in the model)

Baseline LVEF (by ≤40% and >40%) 

Killip class (I vs. ≥ II)

Infarct location (anterior, inferior, and other)

PCI use at baseline (PCI use versus medical management after index MI) 

Time from the index MI presentation to randomization (two subgroups cut by the median 
time)

Baseline SBP (three groups: ≤110 mmHg; >110 mmHg and ≤140 mmHg; >140 mmHg) 

Baseline eGFR (<60 vs ≥ 60 mL/min/1.73 m2)

History of diabetes (yes/no)

Atrial Fibrillation associated with index MI at baseline (yes/no) 

Prior history of MI 

History of hypertension (yes/no)

Prior ACEi or ARB use (yes/no) 

Use of β-blocker at baseline (yes/no)

Use of mineralocorticoid antagonists at baseline (yes/no) 

Use of oral loop diuretics at baseline (yes/no)
9.4.3
Handling of missing values/censoring/discontinuations
For patients without a primary event prior to the analysis time point, the censoring date is 
defined as one of the following (whichever occurred first):


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
Date when the patient withdrew informed consent

Date of the patient’s last visit before analysis cut-off date (including telephone visit)

Date of death from non-CV causes (i.e. date of death which is confirmed as a non- CV 
death by the adjudication committee).
Note that every effort will be made to follow all patients until the end of the study, regardless 
of adherence to study treatment.
9.4.4
Sensitivity analyses
As a sensitivity analysis treatment groups will be compared for the primary efficacy variable 
using a stratified log-rank test with STEMI/NSTEMI as a stratification factor.
In the event that the study is stopped early for efficacy at the second interim analysis, or the 
study is terminated early by the sponsor due to prolonged COVID-19 impact, a sensitivity 
analysis will be performed using the primary analysis model as specified in Section 9.4.2, 
including all CEC-confirmed primary endpoint data accrued in the study. 
If the study is not stopped at the second interim analysis and continues to the end, a sensitivity 
analysis will be added using the primary analysis model including CEC-confirmed primary 
endpoint events that occurred prior to 01-Mar-2020 (estimated start of COVID-19 impact 
globally). Additional sensitivity analyses to understand and mitigate the potential impact of 
COVID-19 may be specified in the SAP prior to database lock.
9.5
Analysis of secondary variables
The Full Analysis Set (FAS) will be used for all secondary analyses.
The general strategies for the main and sensitivity analyses of the secondary efficacy 
endpoints will be similar to those of the primary efficacy endpoint (see Section 9 second and 
third paragraphs for general strategies, and Section 9.4.4 for sensitivity analyses). 
9.5.1
Efficacy variables
The secondary variables are defined as follows; the censoring mechanism will be the same as 
defined for the primary endpoint unless indicated otherwise:
(1) Time from randomization to first occurrence of a confirmed composite of CV death or HF 
hospitalization
(2) Time from randomization to first occurrence of a confirmed composite of HF 
hospitalization or outpatient HF (censoring will occur at the time of all-cause death)
(3) Time from randomization to first occurrence of a confirmed composite of CV death, non-
fatal spontaneous MI or non-fatal stroke
(4) The cumulative number of composite events, including hospitalization due to HF, 
hospitalization due to non-fatal spontaneous MI, hospitalization due to non-fatal stroke and 
CV death. This endpoint is based on the total number of composite endpoints (count) and the 
patient-specific follow-up time from randomization to the last date the status of the patient 
was known (which could be the date of withdrawal from the study, the last visit prior to 
analysis cut off or the date of death).


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(5) Time from randomization to all-cause mortality - patients without a death will be censored 
at the date of withdrawal from the study or the last day known to be alive (which may be 
established via telephone contact or the last visit prior to analysis cut off).
The secondary endpoints will be analyzed in order to compare LCZ696 vs ramipril using the 
ITT approach (i.e. estimation of the treatment effect under the ‘treatment policy’). Endpoints 
(1), (2), (3), and (5) will be analyzed using the same statistical analysis methods as specified 
for the primary analysis.  
Secondary endpoint (4) will be analyzed using a negative binomial regression model with a 
Weibull baseline intensity function to allow flexibility if the baseline intensity is non-constant 
(Lawless, 1987).  Treatment, STEMI/NSTEMI, PCI use at baseline and region will be 
included in the model as fixed effects.  The relative rate ratio will be presented for LCZ696 vs 
ramipril together with 2-sided 95% confidence interval and 1-sided p-value.  
Supportive analysis
It is recognized that at the time of the first onset of symptomatic HF event some patients may 
discontinue randomized treatment and may be prescribed an alternative treatment for HF 
which could be locally available Entresto TM (sacubitril/valsartan, LCZ696). For endpoints (1), 
(3), (4) and (5), the secondary analysis described above will estimate the treatment effect of 
LCZ696 vs ramipril including any effect of prescribed Entresto™ for ramipril patients who 
discontinued study drug and took Entresto™ as an alternative treatment. Hence, the following 
supportive analyses aim to estimate the pure treatment effect as though in a situation whereby 
Entresto™ was not an available treatment option for HFrEF. 
Endpoints (1), (3) and (5) will be analyzed using an inverse probability of censoring weighted 
(IPCW) Cox proportional hazards model (Robins and Finkelstein 2000)). In this analysis, the 
censoring mechanism will be the same as described for the primary analysis for patients who 
are not prescribed Entresto™. For patients who do, censoring will occur at the minimum of 
the last date the endpoint status was known, the time of death from non-CV causes or 28 days 
after study treatment discontinuation. To adjust for the potential informative censoring, 
patients with event times censored due to treatment switch will be dynamically replaced in the 
patient risk-set to be represented by patients in control arm with a matching prognostic profile 
by up-weighting such patients in the analysis set. The weights will be calculated using a 
logistic regression with clinical risk factors determinant of developing the endpoint as 
covariates in the model (both baseline and post-baseline). A weighted Cox proportional 
hazard model will be fitted to this modified risk set. The model will be stratified by 
STEMI/NSTEMI; region, PCI use at baseline will be included as covariates. The hazard ratio 
for LCZ696 vs. ramipril, the associated 2-sided 95% confidence interval and the 1-sided and 
2-sided p-values will be presented from the analysis. Further details on appropriate covariate 
adjustment and associated implementation will be prospectively provided in the statistical 
analysis plan.
Endpoint (4), the total number of confirmed hospitalizations for HF, MI and stroke (including 
CV death) will be redefined for the patients who are prescribed open label Entresto™ as the 
total number of composite endpoints from randomization up to 28 days after the time of study 
treatment discontinuation. The analysis methods will remain the same as specified above.


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Control of familywise type I error rate
The primary endpoint and the first four secondary efficacy endpoints will be included in a 
statistical testing strategy to control the familywise type I error rate at the 1-sided 2.5% level 
(in the strong sense). A hierarchical testing procedure will be employed whereby the primary 
hypothesis will be tested first, if rejected then the hypothesis associated with the first 
secondary endpoint will be tested and so on.  The order of testing of the composite endpoints 
will be as follows:

Primary endpoint

Time to first CV death or HF hospitalization

Time to first HF hospitalization or outpatient HF

Time to first CV death,  non-fatal spontaneous MI or non-fatal stroke

The total number of composite events (hospitalizations (including CV death) due to HF, 
non-fatal spontaneous MI or non-fatal stroke and CV death).      
 
 
 
 
 
 
 
 
 
 
 
  
 


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9.7
Interim analyses
One interim analysis for efficacy was initially planned. The cut-off time for the first interim 
analysis was planned to be when about two-thirds of the target number of 708 primary events 
were reported and adjudication-confirmed. Approximately 472 of adjudication-confirmed 
primary events (i.e., first CV deaths, HF hospitalizations, or outpatient HF events) were 
planned; 464 adjudication-confirmed primary events were included. In the first interim 
analysis, the analysis dataset was comprised of all patients who were randomized before the 
cutoff date. 
A second interim analysis for efficacy will be added in response to the potential impact from 
the COVID-19 pandemic, allowing the study to stop for overwhelming efficacy for the 
primary endpoint at one-sided alpha of 0.005. The second efficacy interim analysis will 
include all patients randomized prior to 01-Mar-2020 and all primary endpoint events that 
occurred prior to 01-Mar-2020, approximately 80% of the target 708 total primary endpoint 
events in the PARADISE-MI study. The data collected prior to 01-Mar-2020 are generally 
considered not impacted by the COVID-19 pandemic at the global level.  Accordingly, 
patients who do not have a primary endpoint event prior to 01-Mar-2020 will be included in 
the second IA as censored.
Generalized Haybittle-Peto boundaries will be adopted for the interim statistical comparisons 
between treatments. An alpha of 0.001 (1-sided) was spent at the first interim analysis, and an
alpha corresponding to the nominal level of 0.005 (1-sided) will be spent at the second interim 
analysis for the comparison of the primary endpoint. The rest of alpha (resulting in a nominal 
1-sided 0.0244, with the currently specified target number of primary events of 708 and the 
planned addition of a second interim analysis to include 80% of the target 708 primary events, 
based on East version 6.4) will be used at the final analysis. The alpha to be spent for the final 


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analysis will be updated according to the actual number of primary events included in the 
second IA and final analysis in case of deviation from the current specification. In the first 
interim analysis, as designed, the study could be stopped for superior efficacy only when both 
the primary endpoint and CV death were significant at an alpha level of 0.001 (1-sided).  In 
the second interim analysis, the study may be stopped for superior efficacy when the primary 
endpoint is significant at the alpha level of 0.005 (1-sided).  
If the study is stopped early for superior efficacy at the interim analysis, the secondary 
endpoints will be tested using the same hierarchical testing procedure as described in 
Section 9.5.1 for the same level of alpha (i.e. 1-sided alpha of 0.001 if stopped at the first 
interim analysis, or of 0.005 if stopped at the second interim analysis).  If the study continues, 
then secondary endpoints will be tested at the final analysis using the same 1-sided alpha as 
the primary endpoint (i.e., 1-sided alpha of 0.0244, which may be updated according to the 
actual number of primary events included in the second IA and final analysis in case of 
deviation from the current specification). 
In the event that the COVID-19 pandemic continues over a prolonged period of time, the 
sponsor may consider terminating the study early without performing the second interim 
analysis. In this case, the final analysis will include all primary endpoint events with onset 
date prior to 01-Mar-2020. The remaining alpha to be spent at the final analysis will be 
calculated based on the number of primary events included in the final analysis using the 
generalized Haybittle-Peto boundaries, and will be specified in the SAP prior to database lock. 
Interim analyses are also planned for the monitoring of safety data, and will be performed 
approximately every 6 months during the course of the study. Such safety analyses do not 
inflate the type I error for the primary efficacy hypothesis testing, and thus no adjustment for 
multiplicity is required.  
Interim analyses will be performed by an independent statistician (at a CRO or academic 
institution) who will not be involved in the trial conduct. The results will be reviewed by an 
independent DMC. The trial investigators, Novartis employees and other personnel who are 
involved in the conduct of the trial and in the analysis of the final trial results, or who have 
contact with study centers, will remain blinded to the treatment codes and interim analysis 
results until all monitoring decisions have been made and the database has been locked for 
final analysis. Full details of the interim analysis plan will be described in the DMC charter.
9.8
Sample size calculation
The sample size and power calculations described in the entire Section 9.8 are based on the 
study design prior to the protocol amendment 4 when only one efficacy interim analysis had 
been planned. With the planned addition of a second efficacy interim analysis to include 80% 
of the target 708 primary events (see Section 9.7), there will be a small impact on power for 
the primary endpoint (approximately 0.1% power loss for the primary endpoint with a second 
interim analysis, compared to 80% power with only one planned interim analysis). 
The study was initially planned to randomize 4,650 patients to LCZ696:ramipril with a 1:1 
allocation ratio, with the aim to obtain at least 800 primary endpoint events and at least 633 
first CV death or HF hospitalization events. See details in Section 9.8.1. 


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Following the planned sample size re-estimation using blinded data, the study has been re-
designed to randomize 5,650 patient to LCZ696:ramipril with a 1:1 allocation ratio. This aims 
to obtain at least 708 confirmed first primary endpoint events and at least 592 first confirmed 
CV death or HF hospitalization events in this event-driven study. Seven hundred eight 
primary endpoint events will provide 80% power assuming a true Relative Risk Reduction 
(RRR) of 19% (i.e. a hazard ratio of 0.81) for LCZ696 vs ramipril with statistical testing at the 
overall 2.5% 1-sided type I error rate (with strong control of the FamilyWise error rate 
(FWER)). Five hundred ninety two first CV death or HF hospitalization events will provide 
77.5% nominal power assuming a true RRR of 20% (for the ITT analysis) for this double 
composite endpoint for the same type I error rate. See details in Section 9.8.2. 
9.8.1
Original sample size planning
A sample size of 4,650 patients, randomized to LCZ696:ramipril using a 1:1 allocation ratio, 
has been chosen with the aim to obtain at least 800 first primary events and at least 633 CV 
death or HF hospitalization events in this event-driven study.  Eight hundred primary events 
provide at least 80% power assuming a true Relative Risk Reduction (RRR) of 18% (i.e. a 
hazard ratio of 0.82) for LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-sided 
type I error rate (with strong control of the FWER).  Six hundred and thirty three CV death or 
first HF hospitalization events will provide at least 80% nominal power assuming a true RRR 
of 20% (for the intent-to-treat analysis) for the secondary endpoint for the same type I error 
rate.
Additional assumptions are described below.

0.5% per year lost to follow-up rate

Recruitment duration of 24 months, with approximately 8 months follow-up anticipated 
for last randomized patient (i.e. 32 months total study duration) and constant recruitment 
rate

One interim analysis is planned to allow for stopping for efficacy, using a Haybittle-Peto 
boundary, thus 2.49% 1-sided alpha will be available for the final analysis, see Section 9.7.
Cumulative event rates of CV death or HF hospitalization were estimated from selected 
patients from the VALIANT database (Pfeffer et al, 2003) who were considered to be 
representative of the target patient population of this study.  In the calculation, adjustments 
were made for expected differences between the sample of patients from VALIANT and the 
patients likely to be recruited in PARADISE-MI. In particular PCI use is expected to increase 
(2/3 PCI use vs. 1/3 in VALIANT), and a larger number of NSTEMI patients are expected 
(60% NSTEMI patients vs. approximately 30% in VALIANT). Following these adjustments, 
a further 10% reduction in hazard rate for other changes in standard of care was also included. 
The cumulative event rates for the primary endpoint were based on a further 15% increase in 
hazard rate in order to account for the third component of outpatient HF.  See Table 9-1 for 
the cumulative event rates assumed for the sample size calculation.
Table 9-1
Cumulative event rates assumed for the sample size calculation
Time period following 
randomization
CV death or HF 
hospitalization
CV death, HF hospitalization or outpatient HF
(assuming 15% increase in hazard rate compared 
to CV death or HF hospitalization)


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Time period following 
randomization
CV death or HF 
hospitalization
CV death, HF hospitalization or outpatient HF
(assuming 15% increase in hazard rate compared 
to CV death or HF hospitalization)
0-3 months
9.9%
11.3%
3-6 months
12.3%
14.0%
6-12 months
14.8%
16.8%
12-32 months
19.4%
21.9%
The sample size calculations were carried out using PASS 2008, citation software and 
applying the Lakatos method (Lakatos,1988) and confirmed using East version 6.3.
Sample size sensitivity
This is an event driven study and the assumption about the event rates for the primary 
endpoint is a key driver for the sample size calculation. In this regard there are two main areas 
of uncertainty:

The hazard rates calculated from the post-hoc analysis of VALIANT data as described 
above are thought to reflect the contemporary setting, however, there may have been other 
changes over time which are difficult to quantify and may decrease the event rates, hence 
for the final sample size calculation an additional 10% discount of the hazard rate was 
assumed.   

The hazard rates for the primary endpoint were calculated as 1.15 x the hazard rate for the 
secondary endpoint of CV death or HF hospitalization (i.e. assuming a 15% increase in 
hazard will be observed when adjudicated outpatient HF is included in the composite 
endpoint together with CV death and HF hospitalization). However, there is no adequate 
information available about the event rates of the primary triple composite endpoint which 
would be expected.
In order to understand the impact of the uncertainties described above, Table 9-2 provides the 
sample sizes estimated to achieve at least 800 primary events with different underlying 
assumptions.
Table 9-2
Total sample size required to achieve 800 primary events for different 
event rate assumptions
Increase in hazard 
rate when outpatient 
HF is included in 
primary composite 
endpoint
Discount of event rates for change in SoC
0%↓
10%↓
20%↓
20%↑
4066
4468
4968
15%↑
4224
4643
5167
10%↑
4395
4834
5382
Number of randomized patients required calculated using East version 6.3


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Power for secondary endpoints
Table 9-3 summarizes the nominal power for secondary endpoints which will be included in 
the statistical testing strategy. A 1-sided alpha of 2.5% has been used for the calculations.  All 
assumptions are based on exploratory analyses performed using VALIANT data (data on file).
Table 9-3
Summary of power to reject secondary hypotheses
Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(1) Time to first CV death or 
HF hospitalization
20% RRR
Expect 698 events1
84%
(2) Time to first HF 
hospitalization or outpatient 
HF
17% RRR
Expect 536 events2
58%
(3) Time to first composite of 
CV death, non-fatal MI or 
non-fatal stroke
15% RRR
Expect 680 events3
56%
(4) Total number of 
hospitalizations for HF, MI 
and stroke related reasons 
including CV death
17% reduction in rate 
ratio
Over-dispersion=9;
Rate of events on 
ramipril per year = 
0.2364
46%
1Event rates as per Table 9-1
2 Cumulative event rates for HF hospitalization of 6.5%, 8.2%, 9.9% and 12.8% were assumed for 0-
3m, 3-6m, 6-12m and 12-32m periods respectively. Then event rates were increased by a further 15% 
to account for outpatient HF.
3 Cumulative event rates of 8.5%, 10.9%, 14.0% and 18.6% were assumed
4 For the power calculation the rate was assumed to be constant over time 
The number of events were calculated for a sample size of 4,650 patients; 24 months recruitment and 
8 months minimum follow-up. 
HF = Heart Failure; RRR = Relative Risk Reduction
The power calculations were carried out using East Version 6.3.
Blinded sample size re-estimation
When approximately 1/2 of patients have been randomized and have reached the 3 month 
time point, the piecewise hazard rates for the primary endpoint and the double composite 
endpoint (CV death or HF hospitalization) will be estimated based on blinded data.  
The piecewise hazard rates estimated from the observed data will be compared to the original 
assumptions. If there is reason to believe that the original assumptions about event rates may 
not hold, the sample size will be re-estimated taking into consideration the new information. 
The duration of the trial and minimum follow-up will also be reconsidered as part of the 
calculation. This approach will allow flexibility to achieve the required number of events in 
an acceptable time frame.


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9.8.2
Blinded sample size re-estimation
Sample size re-estimation was planned and performed when approximately 1/2 of patients had 
been randomized and had reached the 3 month time point. The cumulative event rates and the 
corresponding piecewise hazard rates for the primary endpoint (first CV death, HF 
hospitalization or outpatient HF event) and the double composite endpoint (first CV death or 
HF hospitalization event) were estimated based on blinded data according to the plan. The 
estimated cumulative event rates based on the available blinded data were sizably lower than 
the originally assumed event rates for both the primary endpoint and the double composite 
endpoint (see Table 9-4 and Table 9-5 for the comparisons), which indicates that the original 
assumptions about the event rates may not hold. Therefore, in order to limit the impact in 
terms of a considerable increase in overall trial duration, sample size re-estimation was 
performed, taking into consideration the new information. The minimum follow-up was also 
reconsidered in the calculation.  
There are two points to be considered in the sample size re-estimation: the estimated lower 
event rates and a potentially higher hazard reduction in the primary endpoint. As shown in 
Table 9-4 and Table 9-5, the estimated event rates using blinded data are lower than the 
originally assumed event rates, for both the primary endpoint (see Table 9-4) and the double 
composite endpoint (see Table 9-5). An RRR of 19% is assumed for the primary endpoint in 
place of the original RRR of 18%. This change is based on the newly available efficacy data 
from the PIONEER-HF (CLCZ696BUS01) study in hospitalized patients with stabilized acute 
decompensated heart failure, which showed a 46% relative risk reduction (HR 0.54, 95% CI 
0.37, 0.79) in patients treated with sacubitril/valsartan for 8 weeks compared to enalapril for 
an exploratory composite of serious clinical endpoint of death, rehospitalization for heart 
failure, implantation of a left ventricular assist device, and inclusion on the list of patients 
eligible for heart transplantation (Velazquez, et al. 2019). The observed risk reduction on the 
composite endpoint from the PIONEER-HF study was primarily driven by rehospitalization. 
Given a similar underlined pathophysiological mechanism between HFrEF and post-AMI 
with left ventricular dysfunction, and also acute setting for both PIONEER-HF and 
PARADISE-MI studies, this new data indicated that the effect size may have previously been 
underestimated. 
Following the blinded sample size re-estimation, a sample size of 5,650 patients, randomized 
to LCZ696:ramipril using a 1:1 allocation ratio, has been chosen with the aim to obtain at 
least 708 first primary endpoint events and at least 592 first CV death or HF hospitalization 
events in this event-driven study. Seven hundred eight primary endpoint events will provide 
80% power assuming a true Relative Risk Reduction (RRR) of 19% (i.e. a hazard ratio of 0.81) 
for LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-sided type I error rate 
(with strong control of the FWER).  Five hundred ninety two first CV death or HF 
hospitalization events will provide 77.5% nominal power assuming a true RRR of 20% (for 
the ITT analysis) for this double composite endpoint for the same type I error rate.
Additional assumptions are described below.

0.5% per year lost to follow-up rate (same as the original protocol assumption)

Recruitment duration of 37 months, and approximately 4 months follow-up for the last 
randomized patient are assumed (i.e., approximately 41 months for endpoint accrual). 


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Constant recruitment rates are assumed in each of the following time period based on the 
observed PARADISE-MI study data and projection: (1) 0 to 10 months, with a total of 
463 patients randomized by month 10; (2) 10 to 24 months, with approximately a total of 
2400 patients randomized by month 24; (3) 24 to 37 months, with 250 patients 
randomized each month. 

One interim analysis is planned to allow for stopping for efficacy, using a Haybittle-Peto 
boundary, thus 2.49% 1-sided alpha will be available for the final analysis, see Section 9.7.

Cumulative event rates for the primary composite endpoint at 3, 6, 12, and 18 months 
were derived based on Kaplan-Meier estimates using blinded data from all randomized 
patients in the PARADISE-MI study at the time of sample size re-estimation. Constant 
piecewise hazard rates were then derived accordingly for the following time periods: 0 to 
3 months, 3 to 6 months, 6 to 12 months, and 12 to 41 months. The hazard rate for the 
time period of 12 to 41 months was derived through extrapolation of the 18 months 
cumulative event rate assuming a constant hazard rate during this time period. See 
Table 9-4 for the cumulative event rates (pooled) based on the originally assumed event 
rates from Table 9-1, as well as the estimated event rates from the blinded sample size re-
estimation. 
Table 9-4
Cumulative event rates (pooled) for the primary endpoint (first CV 
death, HF hospitalization or outpatient HF event)
Time from 
randomization
Cumulative event rate 
(original assumption)2
Cumulative event rate 
(estimated using blinded data) 
3 months
10.3%
7.2%
6 months
12.8%
8.6%
12 months
15.4%
11.0%
32 months1
20.1%
17.5%
1 32 months event rates were derived through extrapolation of the 18 months cumulative event rates, 
assuming constant monthly hazard rates from 12 to 32 months. The 18 months cumulative event rate 
was estimated to be 13.0% for the primary endpoint (first CV death, HF hospitalization or outpatient 
HF event).
2 Cumulative event rates (pooled) were derived according to the original assumption of the control 
group rates in Table 9-1.
Table 9-5
Cumulative event rates (pooled) for the double composite endpoint 
(first CV death or HF hospitalization event)
Time from 
randomization
Cumulative event rate 
(original assumption)2
Cumulative event rate 
(estimated using blinded data)
3 months
9.0%
6.0%
6 months
11.1%
7.5%
12 months
13.4%
9.6%
32 months1
17.6%
13.9%
1 32 months event rates were derived through extrapolation of the 18 months cumulative event rates, 
assuming constant monthly hazard rates from 12 to 32 months. The 18 months cumulative event rate 
was estimated to be 10.9% for the double composite endpoint (first CV death or HF hospitalization 
event).


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Time from 
randomization
Cumulative event rate 
(original assumption)2
Cumulative event rate 
(estimated using blinded data)
2 Cumulative event rates (pooled) were derived according to the original assumption of the control 
group rates from Table 9-1.
The sample size calculations were carried out using East version 6.4.
Power for secondary endpoints
Table 9-6 summarizes the nominal power for secondary endpoints which will be included in 
the statistical testing strategy. A 1-sided alpha of 2.5% has been used for the calculations.  All 
assumptions are based on the sample size re-estimation using blinded data.
Table 9-6
Summary of power to reject secondary endpoints’ null hypotheses
Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(1) Time to first CV death or 
HF hospitalization
20% RRR
Expect 592 events1
77.5%
(2) Time to first HF 
hospitalization or outpatient 
HF
17% RRR
Expect 566 events2
60.1%
(3) Time to first composite of 
CV death, non-fatal MI or 
non-fatal stroke
15% RRR
Expect 594 events3
50.8%
(4) Total number of
hospitalizations for HF, MI 
and stroke related reasons 
including CV death
17% reduction in rate 
ratio
Over-dispersion=6;
Rate of events per 
year (pooled) = 
0.1924
55.1%
1 Event rates as per Table 9-5, estimated using blinded data
2 Cumulative event rates (pooled) for the composite endpoint (first HF hospitalization or outpatient HF 
event) at 3, 6, 12, and 18 months were estimated to be 5.4%, 6.6%, 8.3% and 10.3%, respectively. 
Constant piecewise hazard rates were derived accordingly for the following time periods: 0 to 3 
months, 3 to 6 months, 6 to 12 months, and 12 to 41 months. The hazard rate for the time period of 12 
to 41 months was derived through extrapolation of the 18 months cumulative event rate.
3 Cumulative event rates (pooled) for the composite endpoint (first CV death, non-fatal MI or non-fatal 
stroke event) at 3, 6, 12, and 18 months were estimated to be 4.6%, 6.0%, 8.7% and 11.0%, 
respectively. Constant piecewise hazard rates were derived accordingly for the following time periods: 
0 to 3 months, 3 to 6 months, 6 to 12 months, and 12 to 41 months. The hazard rate for the time 
period of 12 to 41 months was derived through extrapolation of the 18 months cumulative event rate.
4 For the power calculation the rate was assumed to be constant over time 
The number of events were calculated for a sample size of 5,650 patients; 37 months recruitment and 
approximately 4 months minimum follow-up. 
HF = Heart Failure; RRR = Relative Risk Reduction
The power calculations were carried out using East Version 6.4.


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10
Ethical considerations
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the International Council for Harmonisation (ICH) Harmonized Tripartite 
Guidelines for Good Clinical Practice, with applicable local regulations (including European 
Directive 2001/20/EC, US CFR 21, and Japanese Ministry of Health, Labor, and Welfare), 
and with the ethical principles laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approved informed consent, or, if incapable of doing so, after such consent has 
been provided by a legally acceptable representative(s) of the patient. In cases where the 
patient’s representative gives consent, the patient must be informed about the study to the 
extent possible given his/her understanding. If the patient is capable of doing so, he/she must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the patient eSource/source documents.* 
[*] For Germany only, the first paragraph will read as follows: 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent. He/she should indicate 
assent by personally signing and dating the written informed consent document. Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient eSource/source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 


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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.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group 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.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 


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implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request
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FDA (2012) Guidance for Industry and Investigators: Safety reporting requirements for INDs 
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adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised 
trials. Lancet 2007;370:1483-93.
Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-
enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial 
infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 
1995;333:1670-6.
Lakatos E. Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics 
1988;44:229-41.
Lawless JF. Regression Methods for Poisson Process Data. Journal of the American Statistical 
Association 1987; 82:808-15.
Lofthus DM, Stevens SR, Armstrong PW, et al. Pattern of liver enzyme elevations in acute 
ST-elevation myocardial infarction. Coronary Artery Disease 2012, 23:22–30.
McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in 
heart failure. N Engl J Med 2014;371:993-1004.
Miller AL, Dib C, Li L et al.  Left Ventricular Ejection Fraction Assessment Among Patients 
With Acute Myocardial Infarction and Its Association With Hospital Quality of Care and 
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Molkentin JD. A friend within the heart: natriuretic peptide receptor signaling. J. of Clin. 
Invest. 2003;111:1275-7.
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O’Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management 
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Cardiol 2013;61:e78-140.
Okumura N, Jhund PS, Gong J, et al. Importance of Clinical Worsening of Heart Failure 
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Appendix 1: Clinically notable laboratory values and vital 
signs
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:
Hematology
Hematocrit
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Platelet count
>75% increase, >50% decrease
RBC Count
>50% increase, >20% decrease
WBC count
>50% increase, >50% decrease
Blood Chemistry
Alkaline phosphatase >100% increase 
ALT (SGPT)
>150% increase
AST (SGOT)
>150% increase 
BUN
>50% increase 
Calcium
>10% increase, >10% decrease 
Chloride
>10% increase, >10% decrease 
Creatinine
>50% increase 
Potassium
>20% increase, >20% decrease 
Total bilirubin
>100% increase 
Uric acid
>50% increase


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


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


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Appendix 3:  Killip Classification
Pulmonary congestion following the index MI event will be assessed as the worst Killip class 
between index MI presentation and randomization using the criteria outlined below:

Class 1 No rales, no 3rd heart sound 

Class 2 Rales in <1⁄2 lung field or presence of a 3rd heart sound 

Class 3 Rales in >1⁄2 lung field–pulmonary edema 

Class 4 Cardiogenic shock–determined clinically 


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Appendix 4: Guidelines for the management of blood 
pressure
Guidelines
1. Investigator should monitor BP closely
2. If symptomatic hypotension occurs:
a. Correct any treatable cause, e.g. hypovolemia
b. If hypotension persists, any non-disease modifying background antihypertensive drug 
such as diuretics, calcium channel blockers (CCBs), nitrates, and/or α-blockers, can 
be down-titrated or stopped first per investigator’s clinical judgement before down-
titration of the study drug is considered..
c. It is important to note that dose adjustment of disease-modifying background therapy, 
e.g., β blockers, or mineralocorticoid antagonists is discouraged under these 
circumstances, unless they are believed to be the most likely cause of hypotension.
If hypotension persists, the study drug should be down-titrated or even temporarily withdrawn. 
The dose re-challenge and medications adjust guidelines described in Section 5.5.5 should be 
adhered to as much as possible.


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Appendix 5: Treatment guidelines for hyperkalemia (serum 
potassium greater than 5.3 mmol/L [mEq/L])
General principles
Elevation of serum* potassium levels above the predefined values should be repeated and 
confirmed before any action is taken.
Any patient with a serum* potassium > 5.3 mmol/L (mEq/L) at any time after randomization 
requires the Investigator to confirm the serum potassium concentration in a non-hemolyzed 
sample via an immediate repeat lab sample to the clinic local lab, the study central lab or both.  
Regular, repeated checks of serum potassium concentration (beyond that prescribed in the 
protocol) should continue until it is clear that the serum potassium concentration is stable and 
not rising into the range of concern (≥ 5.5 and < 6.0 mmol/L [mEq/L]* ) or potential danger 
(≥ 6.0 mmol/L [mEq/L]*). 
Patients with elevated serum potassium value will be managed according to the corrective 
actions outlined below. Hyperkalemia should be followed until resolution.
Corrective action for management of hyperkalemia
Serum potassium greater than 5.3 and less than 5.5 mmol/L (mEq/L)* 

Confirm serum potassium concentration in a non-hemolyzed sample

Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
tomatoes, coffee, etc.) 

Correct metabolic acidosis if necessary. 

Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents:

Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 

Potassium supplements, e.g., potassium chloride

Salt substitutes 

Non-steroidal anti-inflammatory drugs (NSAIDs)

Cyclo-oxygenase-2 (COX-2) inhibitors

Trimethoprim and trimethoprim-containing combination products, such as Bactrim®
and Septra® (trimethoprim/sulfamethoxazole fixed combination)

Herbal Supplements:

For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily 
of the valley, Siberian ginseng, hawthorn berries


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
Assess patient for dehydration or any condition that could lead to dehydration (e.g., 
diarrhea, vomiting) and/or hypovolemia and initiate appropriate corrective measures of 
rehydration. 

Repeat serum potassium measurement within 3 to 5 days

If serum potassium remains > 5.3 and  5.5 mmol/L (mEq/L)*, regularly monitor serum 
potassium levels to ensure stability (suggested once monthly)

Consider down-titration of study drug, according to investigator’s medical judgment.
Serum potassium greater than or equal to  5.5 and less than 6.0 mmol/L (mEq/L)* 

Confirm serum potassium concentration in a non-hemolyzed sample 

Consider down-titration or temporarily discontinue background therapy of 
mineralocorticoid antagonists (if they are believed to be the most likely cause of 
hyperkalemia). 

Apply all measures outlined for serum potassium > 5.3 and    5.5 mmol/L* 

Repeat serum potassium measurement after 2-3 days

If serum potassium < 5.5 mmol/L*, consider resumption of study drug at lower dose with 
repeat serum potassium within 5 days
Serum potassium greater than or equal to 6.0 mmol/L (mEq/L)* 

Immediately discontinue study drug

Confirm serum potassium concentration in a non-hemolyzed sample

Urgently evaluate patient and treat hyperkalemia as clinically indicated 

Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L (mEq/L)* 
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee.
*Or equivalent plasma potassium value


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Summary of all amendments to the protocol: 
Date 
Amendment 
Summary 
29-Jun-2016 
Amendment 1 
The purpose of this amendment is to refine the recommendations 
for alternative treatment to ensure sufficient RAS blockade in the 
event a patient needs to discontinue the study drug due to 
intolerable adverse events. The amendment also clarifies the 
acceptable methods of contraception for women of child bearing 
potential. Additional minor changes were also made to correct 
typographical errors and inconsistencies in the protocol. None of 
these changes will have an impact on the study population, 
endpoints, or the analysis of the study results.  
 
The main changes in this amendment are: 
 
Section 5.5.6 Rescue medications was updated to provide guidance 
on the alternative open-label treatment of RAS blockade in the 
event a patient needs to discontinue study drug at the investigator’s 
discretion due to intolerable adverse events, despite the dose 
reduction or  temporary interruption/re-challenge of study 
medication. 
 
Section 4.2 Exclusion criteria #25 was changed to clarify that 
women physiologically capable of becoming pregnant are excluded 
unless they are using highly effective methods of contraception not 
basic methods of contraception. The methods of contraception 
currently described in the protocol are highly effective, however, the 
wording was modified to comply with the current Novartis guidelines 
for the prevention of pregnancy.  
 
Additional minor changes were made to correct inconsistencies and 
typographical errors in the protocol. 
 
Changes to specific sections of the protocol are shown in the track 
changes version of the protocol using strike through red font for 
deletions and red underlined for insertions. 
 
A copy of this amended protocol will be sent to the Institutional 
Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. The changes described in this amended protocol 
require IRB/IEC approval prior to implementation. The changes 
herein do NOT affect the trial specific ICF. 
 
25-Apr-2017 
Amendment 2 
 
 
 
 
 
 
 
 
 
 
 
The amendment also removes the targeted adverse event data 
collection, and provides additional guidance for co-administering 


LCZ696 with atorvastatin or other statins. Further, in order to 
achieve the target dose in the early phase post AMI, for patients 
who have not titrated to the target dose level 3 by week 4, an 
unscheduled dose titration visit on or about 
week 6 is also recommended. Finally, some minor changes were 
also made to clarify the valsartan bridging procedure on day 1 post 
randomization, and to correct typographical errors and 
inconsistencies in the protocol. There is no impact of this 
amendment on the study population or the main analysis of the 
study results. 
 
The main changes in this amendment are: 
 
 
 
 
 
 
 
 
 
 
 
Section 4.1 Inclusion criteria 
• 
Inclusion criteria #3 was updated to clarify that patients with 
clinical presentation thought to be related to Takotsubo 
cardiomyopathy are also not eligible. 
• 
Inclusion criteria #4 was updated to add diuretics, vasodilators, 
vasopressors and/or inotropes as intravenous treatment 
required for pulmonary congestion. A footnote was also added 
clarifying the index MI with LV systolic dysfunction and/or 
pulmonary congestion. 
 
Section 4.2 the following exclusion criteria were updated or added 
• 
Exclusion criteria #13 was updated to permit equivalent plasma 
potassium value. 
• 
Exclusion criteria #25 regarding women of child bearing 
potential and the use of highly effective contraception was 
updated to allow local regulations to take precedence when it 
deviates from the contraception methods listed in the protocol; 
the local regulations will be described in the ICF. 
• 
 
 
 
 
Section 5.5.4 Instructions for prescribing and taking study drug was 
updated to clarify the valsartan bridging procedure. 
 
Section 5.5.7 Concomitant medications was updated to provide 
additional guidance when coadministering LCZ696 with atorvastatin 
or other statins. 
 
Table 6-1 Assessment schedule was updated as follows: 
• 
The use of the central laboratory for screening and study drug 
titration decisions was added if the use of the local laboratory is 


not possible or will take longer to obtain results than the central 
laboratory assessments. 
• 
 
• 
 
• 
The recommended unscheduled dose uptitration visit was 
added 
• 
More frequent pregnancy testing, if required by local regulatory 
authorities was added 
• 
 
 
 
 
Section 6.5.4 Laboratory evaluations was updated to allow 
equivalent plasma potassium and central laboratory assessments 
for screening and dose initiation and titration decisions. 
 
Section 6.5.6 Pregnancy and assessments of fertility was updated 
to allow more frequent pregnancy testing if required by local 
regulatory authorities.  
 
 
  
 
Section 7.1 Adverse events were updated to remove the targeted 
collection of safety data so that all AEs will be collected. Also, statin 
related adverse events were added to the list of AEs of special 
interest.  
 
Section 7.4 Liver safety monitoring was updated to include acute 
heart failure episodes as an underlying cause for events of liver 
enzyme elevation. Sections  
 
 
 
Section 17, Appendix 5 Treatment guidelines for hyperkalemia was 
updated to allow serum or equivalent plasma potassium values. 
 
 
  
 
Changes to specific sections of the protocol are shown in the track 
changes version of the protocol using strike through red font for 
deletions and red underlined for insertions. 
 
A copy of this amended protocol will be sent to the Institutional 
Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. The changes described in this amended protocol 
require IRB/IEC approval prior to implementation. The changes 
herein do NOT affect the trial specific ICF. 
01-May-2019 
Amendment 3 
The purpose of this amendment is to increase the sample size from 
4,650 to 5,650 and adjust the assumption for the primary composite 
endpoint events of cardiovascular (CV) death, heart failure (HF) 
hospitalization, or outpatient HF treatment effect from 18% to 19%. 
These changes were made as an outcome of the per-protocol 
sample size re-estimation that was conducted when approximately 


½ of patients were randomized and reached the 3 month treatment 
time point as described in Section 9.8. At the time of this protocol 
amendment release, over 3,500 patients have been randomized.  
 
PARADISE-MI is an event-driven outcomes study. In the per 
protocol sample size re-estimation, the estimated cumulative event 
rates based on the available blinded data were lower than the 
originally assumed event rates. This indicated that the original 
assumptions may not hold. Therefore, in order to limit the impact in 
terms of considerable increase in overall trial duration, sample size 
re-estimation was performed and sample size increase became 
necessary. In addition, newly available efficacy data from the 
PIONEER-HF (CLCZ696BUS01) study showed a 46% relative risk 
reduction (RRR) (HR 0.54, 95% CI 0.37, 0.79) in patients treated 
with sacubitril/valsartan for 8 weeks compared to enalapril for an 
exploratory composite of serious clinical endpoint of death, 
rehospitalization for heart failure, implantation of a left ventricular 
assist device, and inclusion on the list of patients eligible for heart 
transplantation (Velazquez, et al. 2019). The observed risk 
reduction on the composite endpoint from the PIONEER-HF study 
was primarily driven by rehospitalization. Given a similar underlying 
pathophysiological mechanism between heart failure with reduced 
ejection fraction (HFrEF) and post- acute myocardial infarction 
(AMI) with left ventricular dysfunction, and also the acute setting for 
both PIONEER-HF and PARADISE-MI studies, this new data 
indicated that the initial hazard reduction assumption of the primary 
endpoint in PARADISE-MI may have been an underestimate. The 
increase in the sample size and the assumption for the treatment 
effect size maintain the statistical power of 80% for the primary 
composite endpoint.  
 
Additionally, Section 5.6.1 was updated to replace the described 
open-label extension study with a post-trial access program (PTA). 
The purpose of the PTA is to make the investigational drug 
available to qualified patients participating in the trial after the 
completion of the trial, in line with local laws and regulations.  
 
Lastly, the assessment schedule has been clarified in regard to 
additional visits. PARADISE-MI is an event-driven trial and patients 
will continue to be treated until the required number of endpoints is 
met and the maximum treatment period is expected to extend 
beyond month 32. Some minor changes are also made to clarify the 
entry criteria regarding risk factors, and to correct typographical 
errors and minor inconsistencies in the protocol. There is no impact 
of this amendment on the study population or the main analysis of 
the study results. 
 
The main changes in this amendment are: 
 
The described changes under the amendment rationale regarding 
the sample size re-estimation are implemented throughout the 
protocol. In addition, the following updates, clarifications, and 
omissions are included in this protocol amendment:  
 
Protocol Summary was updated to reflect the extended trial 
duration, updated sample size and endpoint event assumptions, to 


add clarity to Inclusion Criteria #5, 
 
  
 
In Figure 3-1, the duration of double-blind treatment epoch was 
expanded to reflect treatment until the number of required 
endpoints is met and patients return for the end of study (EOS) visit.  
 
Table 3-3 The renal function criteria was corrected to estimated 
globular filtration rate (eGFR)≥ 30 mL/min/1.73m2 and creatinine 
increase < 0.5 mg/dl from baseline as noted elsewhere in the 
protocol.  
 
Section 3.1 The estimated trial duration was updated from 32 
months to 43 months and the recruitment period was updated to 
approximately 37 months.  
 
Section 3.5 Estimated number of endpoints needed at the time of 
interim analysis was updated.  
 
Section 4 The number of centers with randomized patients was 
reduced from approximately 650 to approximately 500.  
 
Section 4.1 Inclusion Criteria #5 was updated to clarify that if 
multiple left ventricular ejection fraction (LVEF) measurements have 
been performed during index event, the last one performed prior to 
randomization should be considered as the qualifying 
measurement.  
 
Section 4.2 Exclusion Criteria #27 was added. 
 
 
 
 
  
 
Section 5.4, Section 5.5.9, and Section 5.6.2 were aligned to clarify 
that patients who are intentionally unblinded as per study process 
must permanently discontinue study treatment; whereas the 
appropriate personnel from the site and Novartis will assess 
whether study drug should be discontinued in instances where a 
patient is inadvertently unblinded for any reason.  
 
Section 5.6.1 Approach for the investigational drug to be made 
available to qualified patients participating in the trial was refined 
from an open-label extension study to a post-trial access (PTA) 
program and added that the mechanism for post-trial access to 
investigational drug must comply with the local laws and regulations 
in the participating countries in order to be made available.  
 
Section 5.6.3 Withdrawal of Informed Consent section was updated 
to align with new laws regarding personal data. 
 
Section 6 Language was added to specify that in addition to vital 
status, primary endpoint information should be collected for every 
patient.  
 


Table 6-1 was expanded to reflect patients’ continuation in the trial 
until the number of required events is met and patients are asked to 
return for the EOS and reflect assessments which are considered 
standard of care at time of screening and randomization.  
 
Section 6.5.4 Section was updated as per Table 6-1. 
 
Section 6.5.6 Section was updated to reflect that the patient must 
interrupt, rather than discontinue, study drug in case of pregnancy. 
Update is also reflected in Table 6-1.  
 
Section 9.3 Section was updated to align with the statistical analysis 
plan.  
 
Section 9.6.1 Secondary efficacy endpoint regarding changes in 
serum creatinine was clarified.  
 
Section 9.7 Section was updated to reflect that the interim analysis 
will be conducted when approximately 472 adjudication-confirmed 
primary endpoints have been reached. 
 
Section 9.8 Sample Size Calculation was revised following the 
planned sample size reestimation using blinded data and the 
updated sample size calculation is described in Section 9.8.2. 
 
Appendix 5 Pre-defined potassium values for the management of 
hyperkalemia were updated to correct an inconsistency. 
Hyperkalemia values that warrant corrective action include serum 
potassium greater than 5.3 and less than 5.5 mmol/L (mEq/L); 
serum potassium greater than or equal to 5.5 and less than 6.0 
mmol/L (mEq/L).  
 
 
 
 
 
 
 
Other minor updates and corrections were also included. 
 
Changes to specific sections of the protocol are shown in the track 
changes version of the protocol using strike through red font for 
deletions and red underlined for insertions. 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional 
Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. 
 
The changes described in this amended protocol require IRB/IEC 
and Health Authority approval according to local regulations prior to 
implementation. 
 
The changes herein affect the Informed Consent. Sites are required 
to update and submit for approval a revised Informed Consent that 


takes into account the changes described in this protocol 
amendment. 
06-Aug-2020 
Amendment 4 
The purpose of this amendment is to add a second interim analysis 
in response to the COVID-19 pandemic with the stopping boundary 
for the primary endpoint at one-sided alpha of 0.005.  
 
A novel coronavirus that had not previously been identified is 
causing clinical disease in humans (COVID-19). On 11-Mar-2020, 
the World Health Organization (WHO) characterized COVID-19 as 
a pandemic. As acknowledged by global Health Authorities in their 
guidance to the pharmaceutical industry, the COVID-19 pandemic 
has a global impact on the conduct of clinical trials of medicinal 
products. Challenges arising include at-risk patient populations, 
site closures, travel restrictions, shelter-in-place orders, 
interruptions to the supply chain for the investigational product, and 
other considerations if trial patients and site personnel become 
infected with COVID-19.  
 
The significant impact of COVID-19 on the safety of patients and 
study personnel has greatly impacted study conduct. We have 
already observed marked increase in missed visits, treatment 
interruption due to drug supply issues related to the pandemic and 
substantial reduction of HF hospitalization and outpatient HF 
events. This observation is consistent with the published data which 
showed a greater than 50% reduction in the occurrence of HF 
hospitalization during the COVID-19 pandemic (Hall, et al. 2020), 
adding to other serious challenges on the conduct of the 
PARADISE-MI study.  
 
Prior to 01-Mar-2020, timepoint before which clinical trial data has 
generally not been impacted by the COVID-19 pandemic at the 
global level, approximately 80% of the 708 target total number of 
the primary events in the PARADISE-MI study had been 
accumulated. Considering the advanced state and documented 
impact of the COVID pandemic on the conduct of the trial, the 
PARADISE-MI Executive Committee recommended adding a 
second interim analysis using the primary events accrued prior to 
01-Mar-2020 for the primary analysis. In case of early stopping, all 
additional endpoints occurring on or after 01-Mar-2020 until study 
close out will be included as a sensitivity analysis. In the event that 
the data accumulated prior to the adverse influence of the 
pandemic had already established convincing efficacy, as per the 
proposed second interim analysis criteria, it would represent the 
most reliable test of the study hypothesis.  
 
Novartis will continue monitoring the impact of the COVID-19 
pandemic, in the event that the COVID-19 pandemic continues over 
a prolonged period of time hampering the ability to complete the 
trial in a timely and appropriate fashion, Novartis may consider 
modifying the proposed interim analysis to be the final analysis and 
close out the study prematurely.  
 
There is no impact of this amendment on the study population or 
endpoints. If the trial continues after the interim analysis, the main 
analysis of the study result will remain as per the original protocol 
but additional sensitivity analyses will be performed to evaluate the 


potential impact of COVID-19 on the interpretation of data 
generated post 01-Mar-2020. The alpha for the final analysis will be 
adjusted accordingly to control the overall type 1 error (across the 2 
interim analyses and the final analysis) at 1-sided alpha of 0.025. 
 
The main changes in this amendment are: 
 
List of abbreviations was updated to include COVID-19.  
 
Previous Amendments were updated to include amendment 
finalization date as per current Novartis standard.  
 
Protocol Summary Data Analysis section, Section 3.5 Purpose and 
timing of interim analyses/design adaptations, and Section 8.4 Data 
Monitoring Committee were updated to reflect the introduction of a 
second interim analysis.  
 
Table 6-1 and Section 18 Appendix 6 Investigational Plan 
 
 
 
 Table 6-1 has 
also been updated to indicate echocardiograms performed as 
standard of care prior to consent are permitted.  
 
Section 9 has been updated to reflect the general data analysis 
strategies for the added second interim analysis and possible early 
termination by sponsor if needed due to COVID-19. 
 
Section 9.4.4 has been updated to define the approach for 
sensitivity analyses related to COVID-19.  
 
Section 9.5 has been updated to describe the general strategies for 
the main and sensitivity analyses relative to the secondary efficacy 
endpoints. 
 
 
  
 
Section 9.7 Interim Analysis was updated to describe the plan for 
the added efficacy interim analysis.  
 
Section 9.8 has been updated to discuss the impact on power for 
the primary endpoint in adding the second efficacy interim analysis.  
 
Section 12 was updated with the added reference. 
 
Other typographical corrections were also included. 
 
All changes to specific sections of the protocol are shown in the 
track changes version of the protocol using strike through red font 
for deletions and red underlined for insertions. 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional 
Review Board (IRBs)/Independent Ethics Committee (IECs) and 
Health Authorities. 


 
The changes described in this amended protocol may require 
IRB/IEC and Health Authority approval according to local 
regulations prior to implementation. The changes herein do NOT 
affect the trial specific model ICF. 
 

SAP_001.pdf: 
Clinical Development
LCZ696
CLCZ696G2301 / NCT02924727
A multi-center, randomized, double-blind, active-controlled, 
parallel group Phase 3 study to evaluate the efficacy and 
safety of LCZ696 compared to ramipril on morbidity and 
mortality in high risk patients following an acute 
myocardial infarction
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
12-Nov-2016
Number of pages:
39
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................11
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................12
2.2.1
Subgroups of interest.............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................15
2.3.2
Demographics and baseline characteristics...........................................15
2.3.3
Medical history......................................................................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant therapies..................................................................19
2.5
Analysis of the primary objective..........................................................................20
2.5.1
Primary endpoint...................................................................................21
2.5.2
Statistical hypothesis, model, and method of analysis..........................21
2.5.3
Handling of missing values/censoring/discontinuations.......................21
2.5.4
Supportive analyses...............................................................................22
2.5.5
Subgroup analysis .................................................................................22
2.6
Analysis of secondary efficacy objective(s) ..........................................................23
2.6.1
Secondary endpoints .............................................................................23
2.6.2
Statistical hypothesis, model, and method of analysis..........................24
2.6.3
Control of familywise type I error rate .................................................24
2.6.4
Handling of missing values/censoring/discontinuations.......................25
2.6.5
Supportive analysis ...............................................................................25
2.6.6
Subgroup analysis .................................................................................27
2.7
Safety analyses.......................................................................................................27
2.7.1
Adverse events (AEs)............................................................................27
2.7.2
Deaths....................................................................................................29
2.7.3
Laboratory data .....................................................................................29


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2.7.4
Other safety data ...................................................................................31
2.8
Pharmacokinetic endpoints....................................................................................31
2.9
PD and PK/PD analyses.........................................................................................31
.31
31
31
32
32
33
2.13
Interim analysis......................................................................................................34
3
Sample size calculation .....................................................................................................35
4
Change to protocol specified analyses ..............................................................................37
5
Appendix ...........................................................................................................................38
5.1
Imputation rules.....................................................................................................38
5.2
Statistical models...................................................................................................38
5.2.1
Primary analysis ....................................................................................38
5.2.2
Key secondary analysis .........................................................................38
5.3
Rule of exclusion criteria of analysis sets..............................................................38
6
Reference...........................................................................................................................39


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
bid
bis in diem/twice a day
CSR
Clinical Study report
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
o.d.
Once Daily
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
The statistical analysis plan (SAP) describes the detailed methodology and implementation of 
the planned statistical analyses outlined in the study protocol for CLCZ696G2301. The 
analyses following the SAP below will be used for clinical study reporting purposes while the 
same analysis plan will also be used for the planned interim efficacy analysis unless otherwise 
specified. 
It is important to note that this version of statistical analysis plan details the statistical 
methodology for the analyses planned and agreed to at the time of finalization of the 
CLCZ696G2301 protocol (Version 00 – original protocol). Any statistical analysis planned 
thereafter will be prospectively furnished with relevant details in subsequent versions as 
amendments and will be finalized before database lock (DBL) prior to the final analysis.
1.1
Study design
This is a multicenter, randomized, double-blind, active controlled, event-driven phase III 
clinical trial designed to evaluate the efficacy and safety of LCZ696 compared to ramipri l 
when added to standard therapy in post-AMI patients with LV systolic dysfunction and/or 
pulmonary congestion. 
The study population consists of high risk patients who have sustained a spontaneous acute 
myocardial infarction (ST segment elevation MI (STEMI) or non-ST segment elevation MI 
(NSTEMI) within the last 12 hours to 7 days prior to randomization) with evidence of LV 
systolic dysfunction and/or pulmonary congestion associated with index MI. In addition, 
patients need to have at least one predefined risk factor and without known prior history of 
chronic HF.
Figure 1-1
Study Design
As per the study design (Figure 1-1), a screening epoch of no more than 7 days after index MI 
presentation will be used to determine if patients qualify to enter the double-blind treatment 
phase of the study with respect to protocol specified inclusion/ exclusion criteria. 


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Eligible patients, stratified by type of MI (STEMI/ NSTEMI) and region, will be randomized 
1:1 to receive LCZ696 titrated to a target dose of 200 mg twice daily or ramipril titrated to a 
target dose of 5 mg twice daily. Patients may be randomized on the same day that they are 
consented and screened. To reduce the potential risk of angioedema, patients on ACEI during 
the last 36 hours prior to randomization will undergo a valsartan bridging treatment for 1 day 
in a blinded manner. 
Three dose levels of study medication will be administered in a stepwise titration (Table 1-1). 
Randomized patients are planned to start at dose level 1 while those who were on prior 
ARB/ACEI may start at dose level 2 at investigator’s discretion.  
Table 1-1
Study drug dose levels during treatment epoch
Dose Level
LCZ696 Treatment Arm*
Ramipril Treatment Arm
1
50 mg b.i.d.†
1.25 mg b.i.d.
2
100 mg b.i.d.†
2.5 mg b.i.d.
3
200 mg b.i.d.
5 mg b.i.d.
* LCZ696 dosing is based on the total amount of both components of sacubitril/valsartan; dose 
levels 1, 2 and 3 are equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, 
respectively.  
† Patients who are randomized to LCZ696 and received ACE inhibitors in the 36 hours prior to 
randomization will be given a bridging valsartan dose in a blinded manner for one day (two doses 
at either dose level V1 or V2: 40 or 80 mg b.i.d.) prior to beginning double-blind LCZ696 
treatment.
Patients can be up-titrated to the next dose level subject to satisfying pre-defined safety / 
tolerability criteria (SBP ≥ 100 mmHg, eGFR ≥ 30 mL/min/1.73m2 or serum creatinine 
increase < 0.5 mg/dl from baseline, serum potassium < 5.5 mmol/L (mEq/L)). The titration 
scheme aims to achieve the target dose within 2 weeks of randomization. 
The study is event-driven and will continue until both a total of 800 confirmed primary triple 
composite endpoint events and 633 confirmed double composite events of CV death or HF 
hospitalization (i.e., first secondary endpoint) have been achieved. Approximately 4,650 
randomized post-AMI patients are estimated to provide the necessary number of confirmed 
endpoints over a total study duration of 32 months with a projected patient recruitment period 
of 24 months. The overall estimated mean follow-up time will be 20 months for the study.
1.2
Study objectives and endpoints
Table 1-2
Objectives and related endpoints
Objective
Related endpoint and Definition
Analysis 
method
Primary objective
To demonstrate that LCZ696 is 
superior to ramipril in delaying the 
time-to-first occurrence of the 
composite endpoint of CV death, 
HF hospitalization or outpatient HF 
in patients with LV systolic 
dysfunction and/or pulmonary 
The primary efficacy endpoint is defined as 
the time to the first confirmed occurrence of 
CV death, heart failure hospitalization* or 
outpatient heart failure**.
* Heart failure hospitalization also includes the 
development of new symptomatic heart failure 
Section 2.5


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Objective
Related endpoint and Definition
Analysis 
method
congestion following an AMI
during an ongoing hospitalization including the 
index AMI hospitalization.
** Outpatient heart failure is defined as:

An urgent/unscheduled visit to an ED, 
acute/urgent care facility or outpatient clinic 
or a non-urgent office/practice or study visit 
for a primary diagnosis of HF that does not 
require an overnight hospital stay.

Patients must exhibit at least one documented 
new HF symptom with objective evidence of 
clinical HF consisting of at least 2 physical 
examination findings or one physical 
examination findings and at least one 
laboratory criterion.

The event requires initiation or intensification 
of treatment specifically for HF. Such 
treatment can include administration of 
intravenous agent (e.g., diuretic, vasodilator, 
vasopressor, or inotrope) or mechanical or 
circulatory intervention for HF, OR initiation 
of oral loop diuretic treatment, or 
intensification of oral maintenance loop 
diuretics for the diagnosis of HF, over a 
sustained period (i.e., initiation or doubling of 
total daily dose through a period of ≥ 4 
weeks), which is confirmed at a subsequent 
outpatient visit
Secondary objective
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
delaying the time-to-first occurrence 
of CV death or HF hospitalization
Time-to-first occurrence of CV death or HF 
hospitalization (days). 
Section 2.6
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
delaying the time to new onset of 
symptomatic HF defined as time-to-
first occurrence of HF 
hospitalization or outpatient HF
Time-to-first occurrence of HF hospitalization 
or outpatient HF (days)
Section 2.6
To demonstrate the superiority of 
LCZ696 compared to ramipril, in 
delaying the time-to-first occurrence 
of CV death, non-fatal spontaneous 
MI1 or non-fatal stroke
Time-to-first occurrence of CV death, non-
fatal spontaneous MI1 or non-fatal stroke
(days). 
Section 2.6
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
reducing the rate of the composite 
endpoint of CV death and total (first 
and recurrent) hospitalizations due 
to HF, non-fatal spontaneous MI1 or 
non-fatal stroke
Cumulative number of composite endpoint of 
CV death and total (first and recurrent) 
hospitalizations due to HF, non-fatal 
spontaneous MI1 or non-fatal stroke (count). 
Section 2.6


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Objective
Related endpoint and Definition
Analysis 
method
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
delaying the time to all-cause 
mortality
Time to all-cause mortality (days).
Section 2.6
To evaluate the safety and 
tolerability of LCZ696 compared to 
ramipril

Number and percentage of adverse 
events, serious adverse events, drug-
related discontinuations, etc.

Change from baseline in laboratory 
assessments and vital signs 
measurements
Section 2.7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objective
Related endpoint and Definition
Analysis 
method
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2
Statistical methods
The following section contains important information on detailed statistical methodology used 
for analysis and reporting purposes.


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2.1
Data analysis general information
Data will be analyzed by Novartis Biostatistics and Statistical Reporting department 
according to the statistical analysis section 9.1 of the study protocol using SAS 9.4, unless 
otherwise specified. Further details on planned statistical analyses and data-driven regression 
diagnostics will be presented in the following section and in CSR Appendix 16.1.9. The same 
analysis plan will also be used for planned interim efficacy analysis, as applicable.
In general, the continuous variables will be summarized descriptively by presenting n, mean, 
SD, median, quartiles, minimum and maximum while categorical variables will be 
summarized by presenting count and percentage of patients in each category. Graphical 
presentation of summary data will also be provided as applicable.
The randomization in this study will be stratified by region and type of M I (STEMI or 
NSTEMI). The stratification factors will be appropriately accounted for in the planned 
statistical analyses.
For planned interim efficacy, the analysis cutoff date will be determined as date when 2/3rd of 
target primary composite outcome i.e. approximately 540 primary composite outcomes will 
be reported and adjudication-confirmed. If the assumptions of the study design regarding 
event rate, accrual rate and drop-out rate remain valid, the final analysis cut-off date will be a 
predicted date when either a total of 800 confirmed primary triple composite and 633 
confirmed double composite events have been achieved, or study termination has been 
decided based on other study termination criteria.
2.1.1
General definitions 
Study treatment or drug
In future sections through this document, ‘study treatment’ or ‘study drug’ will be used to 
refer to investigational therapy assigned to a patient. Specifically, for the double-blind 
treatment phase, study treatment refers to LCZ696 or ramipril as assigned to a pati ent at 
randomization.
Screening epoch 
Screening epoch is defined as the period starting from date of signed of informed consent 
until date of randomization or decision on randomization.
Randomized treatment phase 
The randomized treatment phase begins at the time of randomization and ends with the last 
study drug intake or the death of the patient, whichever comes earlier. During the randomized 
treatment phase, patients will return for scheduled clinic visits. For all related safety analyses 
randomized treatment starts with the first intake of randomized, double-blind study drug. 
Temporary interruption of the study drug will not be counted as randomized treatment phase 
discontinuation.


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Post-treatment follow-up phase
The post-treatment follow-up phase (usually after premature permanent study drug 
discontinuation) begins after last study drug intake + 1 day and ends on the date last seen (or 
vital status confirmed by indirect contact).
Double-blind treatment phase
The double-blind treatment phase is the combination of the randomized treatment phase and 
the post-treatment follow-up phase.
Baseline and study day
For analysis purpose, baseline value for all variables is defined to be the last results obtained 
at or prior to randomization (or prior to 1st study drug intake for safety assessments). Most of 
variables will have their baseline at visit 101, unless otherwise specified. For assessments not 
performed at visit 101, the assessment at screening visit or most recent assessment prior to 
randomization will be used as baseline. 
 
Study day of any assessment refers to the number of days to the assessment relative to 
randomization (day 1), or relative to the 1st study drug intake for safety assessments. 
On-treatment data for an efficacy endpoint
The on-treatment data refers to any observation occurring while the patient is on-study 
medication or within 28 days inclusive of permanent treatment discontinuation excluding any 
observation occurring thereafter.
2.2
Analysis sets
The following analysis populations will be defined for statistical analysis:

Screened (SCR) set – All patients who have signed informed consent. The screened set 
includes only unique screened patients, i.e., in the case of re-screened patients only the 
chronologically last screening data is counted.

Randomized (RAN) set – All patients who received a randomization number, regardless 
of receiving trial medication.

Safety set (SAF) - All randomized patients who received at least one dose of study drug. 
Patients in the SAF will be analyzed according to treatment received. 

Full analysis set (FAS) – All patients in the RAN population who were not mis-
randomized patients*. Following the intent-to-treat (ITT) principle, patients in the FAS 
are analyzed according to the treatment they have been assigned to at the randomization. 

Per-protocol set (PPS) will be a subset of the FAS which will consist of the patients who 
do not have major deviations. Major protocol deviations will be pre-specified prior to 
unblinding.
* Mis-randomized patients are those who were not qualified for randomization and who did 
not take study drug, but have been inadvertently randomized into the study.


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A sample of rules leading to exclusion from specific analysis sets of patients violating 
protocol specified inclusion/ exclusion criteria and any other protocol deviations developed 
during the study has been provided in Appendix 5-5. The final list may be different from this 
which will be finalized and signed off before DBL.
2.2.1
Subgroups of interest
Subgroups will be formed to explore the consistency of treatment effects and safety pro filing 
on selected parameters between the subgroups and the overall population. In general, 
subgroups will be defined based on baseline information as defined in section 2.1. 
In Table 2-1, we have listed all subgroups defined for this study and the ways to derive them. 
Subsets of these subgroups will be used depending on the parameter under consideration. Also 
note that only important parameters or variables in these analyses will have subgroup analyses. 
The details about the parameters having subgroup analyses will be presented in the 
corresponding sections as appropriate. Also, additional subgroups may be formed later for 
regional or country-wise analyses as applicable.
Table 2-1
Specification of subgroups
Subgroup
Method of derivation
Disposition/ 
Background & 
Demographics / 
Exposure
Efficacy
Safety
Age groups:
(<65 vs. ≥65 years, 
<75 vs. ≥75 years)
Screening (derived)
X
X
X
Gender (male/ 
female)
Screening
X
X
X  
Race
Screening
X
X
X
Region*
Derived (pooled
countries or country), 
using
Screening 
X
X
X
Baseline LVEF (by 
quartiles)
Screening
X
Baseline LVEF ≤40% 
vs. > 40%
Screening
X
Worst Killip class (I 
vs. ≥ II)
Randomization
X
Type of MI (STEMI 
vs. NSTEMI)
Randomization 
X
X
X  
Infarct location 
(anterior, inferior, and 
other)
X
PCI use at baseline 
(PCI use versus 
medical management 
after index MI up to 
randomization)
X
X
  


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Subgroup
Method of derivation
Disposition/ 
Background & 
Demographics / 
Exposure
Efficacy
Safety
Time from the index 
MI presentation to 
randomization (< 
median, ≥median)
X
Baseline SBP (three 
groups: ≤110 
mmHg; >110 mmHg 
and ≤140 
mmHg; >140 mmHg)
Randomization
X
Baseline eGFR (<60 
vs ≥ 60 mL/min/1.73 
m2)
Randomization
X
History of diabetes 
(yes/no)
X
Atrial Fibrillation 
associated with index 
MI at baseline 
(yes/no)
X
Prior history of MI
X
History of 
hypertension (yes/no)
Screening 
X
Prior ACEi or 
ARB use (yes/no) 
Randomization 
X
Use of β-blocker at 
baseline (yes/no)
X
Use of 
mineralocorticoid 
antagonists at 
baseline (yes/no) 
X
Use of oral loop 
diuretics at baseline 
(yes/no)
X
* North America: Canada, USA
Latin America (including Central America): Argentina, Peru, Brazil, Colombia,  Mexico
Western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, 
Portugal, Spain, Sweden, Switzerland, United Kingdom
Central Europe: Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, Turkey
Asia Pacific & Others: Australia, South Africa, Israel, China, India, Korea, Philippines, Singapore, Taiwan, 
Thailand


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Based on all patients in the screened set, number and percentage of patients screened 
successfully will be provided. In addition, screen failure patients will be summarized by 
primary reason for screen failure.  
The number and percentage of randomized patients included in different analysis sets (Section 
2.2) will be summarized based on the randomized patients. Patients with premature study 
discontinuation during the double-blind treatment epoch will be summarized by the primary 
reason of discontinuation for each randomized treatment group and overall based on all 
patients in randomized set (RAN).
In addition, the number and percentage of patients with protocol deviations as well as the 
criteria leading to exclusion from analysis sets will be provided for the patients in randomized 
set (RAN).  All the disposition data will also be listed at a patient level separately for 
screening phase disposition and double-blind treatment phase disposition.
2.3.2
Demographics and baseline characteristics
Following demographic and baseline characteristics will be summarized by randomized 
treatment group for all patients in full analysis set (FAS): 

Continuous variables
Age (in years), height (in meters), weight (in Kg.), body mass index (BMI) in Kg/m2, SBP 
(in mmHg), DBP (in mmHg), heart rate (in bpm), eGFR (in ml/min/1.73m2), time from 
index MI presentation to randomization

Categorical variables
Age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years), sex, race, ethnicity, region 
2.3.2.1
Characteristics and therapies associated with qualifying MI
Qualifying MI related characteristics, cardiovascular (CV) risk factors associated with 
qualifying MI and therapies used to manage qualifying MI will be summarized separately for 
all patients in the Full Analysis set (FAS) which includes: 

Disease characteristics
Location of infraction (anterior / inferior), type of MI (STEMI/ NSTEMI), number of 
diseased vessels, ejection fraction (EF) (in %), Killip class

CV risk factors/co-morbidity/past history at baseline
Age (<70, ≥70 years), screening eGFR (<60, ≥60 ml/min/1.73m2), diabetes (yes/no), 
history of prior MI (yes/ no), atrial fibrillation associated with qualifying MI (yes/ no), 
categories of EF (<30%, >=30%), worst Killip class (<III, ≥III), STEMI without 
reperfusion therapy within the first 24 hours after presentation (yes/no)

Therapies used to manage qualifying MI –
Use of reperfusion therapies (yes / no) –


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
use of PCI (yes/ no) (including procedures performed for qualifying MI both prior to 
and after randomization but before discharge)

type of stenting if PCI performed (bare metal/drug eluting stent)

use of antithrombotic therapy (yes/no) which includes aspirin, P2Y12 inhibitor, 
antithrombin agents, glycoprotein (GP) IIb/IIIa inhibitors

use of oral CV medications  including (but not limited to) ARB/ACE inhibitors, beta 
blockers, mineralocorticoid receptor antagonists (MRA), statins, oral anticoagulants, 
non-loop diuretics, loop diuretics, digitalis glycosides, oral nitrates and calcium 
channel blockers..

use of IV diuretics (yes/no), IV vasodilator (yes/no), IV vasopressors (yes/no), IV 
inotropes (yes/no)
In general, all continuous variables will be summarized by presenting descriptive statistics (n, 
mean, SD, Q1, Q3, median, minimum, maximum) and all categorical variables will be 
summarized by number and percentage of patients in each category. The summaries will be 
provided by randomized treatment group for all patients in Full Analysis set (FAS).
2.3.3
Medical history
Any condition entered on the relevant medical history / current medical conditions CRF will 
be coded using the most updated version of MedDRA dictionary. Medical history includes 
heart failure history and cardiovascular disease history, and other medical history in this study, 
which are collected at Visit 1 (Screening visit). The number and percentage of subjects with 
each medical condition will be provided by treatment group and system of organ class for the 
Full Analysis Set (FAS).
Patient disposition, demographic/ baseline and other disease characteristics will also be 
summarized similarly for the following subgroups:

Age group (<65 vs. ≥65 years), age group (<75 vs. ≥75 years)

Gender (male/female)

Region

Race

Type of MI (STEMI vs. NSTEMI)

PCI use at baseline (Yes vs. No)
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Overall treatment exposure
The duration of overall treatment exposure (in days) will be calculated as –
Last known date when the patient took study medication – Date of 1st intake of 
randomized study medication during double-blind treatment epoch + 1


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This includes days patient is off-treatment due to temporary treatment interruption.
The overall treatment exposure duration (in days) will be summarized by randomized 
treatment group using mean, standard deviation, median, minimum and maximum. 
Additionally, the treatment exposure duration will also be summarized categorically by 
presenting number and percentage of patients with exposure 

<2 weeks 

2 to < 4weeks 

4weeks to < 6months 

6months to < 1 year

1 year to < 2 years

>= 2 years 
Mean daily dose and mean dose level for each patient will be summarized by treatment group. 
Mean daily dose and mean daily dose level for each patient will be calculated as –
∑
(Number of days spent on Dose)X(Dose)


∑
(Number of days spent on Dose)


For mean daily dose calculation ‘Dose’ represents actual dose (in mg) administered at dose 
level ‘i’ according to Table 1-1, whereas for mean daily dose calculation ‘Dose’ represents the 
categorical dose level (0, 1, 2 or 3) administered at dose level ‘i’. Further, dose level ‘0’ refers 
to zero dose signifying treatment interruption. Mean daily dose and mean daily dose level 
calculated as above will be summarized by treatment groups for overall study duration. Mean 
doses and mean dose levels of study drug at each visit will also be summarized by treatment 
group and visit. Last dose and last dose level when patients are alive will also be summarized 
by treatment group.
Descriptive summary of number of days spent at each dose level as mentioned in Table 1-1
will be provided by treatment group. Also, number and percentage of randomized patients at 
each dose level will be summarized by visit and treatment group.  Time to first reach the dose 
at each dose level and time to first reach the target dose will be summarized for each treatment 
group during the double-blind treatment epoch. In addition, reasons for down-titrating 
treatment will be summarized by each treatment group for each dose level. 
Time to permanent discontinuation of study medication will be summarized according to the 
Kaplan-Meier analysis. A summary table by treatment group will be provided to display the 
number and percentage of patients who discontinued study medication by the primary reason 
for discontinuing and the number and percentage of patients who subsequently received the 
following medications during the study: ACE inhibitors, ARB, and Entresto™, 
(sacubitril/valsartan). Exposure durations, dosages and dose levels will be summarized by 
treatment group for these medications. The last doses and dose levels of study drugs for these 
switchers will also be summarized by treatment group.
Overall study drug exposure
Duration of overall study drug exposure is defined as the duration of treatment exposure (in 
days) excluding days of treatment interruption and is calculated as –


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(Last known date when the patient took study medication – Date of 1st intake of 
randomized study medication during double-blind treatment epoch + 1) – number of days 
of treatment interruption
The duration of study drug exposure (in days) will be summarized by randomized treatment  
group using mean, standard deviation, median, minimum and maximum. Additionally, the 
treatment exposure duration will also be summarized categorically by presenting number and 
percentage of patients with exposure 

<2 weeks 

2weeks to < 4weeks 

4weeks to < 6months 

6months to < 1 year

1 year to < 2 year

>=2 years 
Treatment and study drug exposure in subgroups
Both overall treatment exposure and overall study drug exposure will be summarized by the 
following subgroups -  

Age group (< 65 vs ≥ 65 years; < 75 vs ≥ 75 years)

Gender

Race

Region

Type of MI (STEMI vs. NSTEMI)
Overall study exposure (Follow-up duration)
Following the definition of double blind phase in section 2.1.1, for each patient duration of 
study exposure (in days) during double blind phase is calculated as total duration of on -
treatment randomized phase and post-randomized treatment phase where –
Duration of on-randomized treatment phase (in days) is calculated as –
Date of last study drug intake – randomization date + 1.
Duration of post-randomized treatment phase or off-treatment phase (in days) is calculated 
as –
min(Last date patient is known to be alive, Last visit date before analysis cutoff date) –
Last known date patient took randomized study medication + 1
Hence, overall study exposure duration (follow-up duration) = Duration of on-randomized 
treatment  phase + Duration of post-randomized treatment phase – 1.
Of note, for randomized patients not receiving double-blind randomized study medication, 
overall study exposure duration is calculated as –
min(Last date patient is known to be alive, Last visit date before analysis cu toff date) 
– randomization date + 1


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The duration of overall study exposure, on-treatment randomized phase and post-randomized 
treatment phase are summarized by randomized treatment group for all patients in FAS by 
providing descriptive statistics (n, mean, SD, Q1, Q3, median, minimum, maximum).
2.4.2
Prior, concomitant therapies
‘Prior medications’ are defined as drugs taken prior to first dose of double-blind study 
medication. Any medication which has been started during the double-blind treatment epoch 
including medications started prior to randomization but continued in the double-blind 
treatment epoch are identified as ‘Concomitant medications’.
Prior and Concomitant medications and significant non-drug therapies will be summarized 
separately by therapeutic class (by ATC code), preferred term, and treatment group for the 
safety set. The number and percentage of patients on following CV background medications 
during double-blind treatment epoch will be tabulated by randomized treatment group –

Aspirin

P2Y12 inhibitors

Antithrombin agents

Glycoprotein (GP) IIb/IIIa inhibitor

ARBs

ACE inhibitors

Beta Blockers

Mineralocorticoid Receptor Antagonists 

Statins

Diuretics (Loop/non-loop diuretics, summarized by IV/ oral diuretics)

Cardiac glycosides (Digoxin/digitalis glycoside)

Calcium channel blockers

Other vasodilators

Oral anticoagulants

Antiarrhythmic agents

Nitrates

Other lipid lowering agents
Apart from the CV medications listed above, reperfusion therapies used during post-
randomized treatment phase for managing index MI and any other post-randomization  MI 
will be summarized separately in a similar way as in section 2.3.2.1. The summaries of 
background medications and non-drug therapies will be provided for Safety set (SAF) and 
Full Analysis Set (FAS).
Analysis of dose intensity of RAS blockade during double-blind period
Dose intensity of RAS blockades during post-randomization phase will be captured in terms 
of mean total daily dose levels of blinded study drug and open label ARB/ACEIs used after 
study drug discontinuation. Mean total daily dose for each study medication is defined by 
average of different doses for the medications (including no or zero dose) weighted by 


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number of days patient is on that dose during the specified analysis period. The total daily 
dose of RAS blockades (high/low) are categorized based on the table 2-2 below.
Table 2-2
Definition of high and low RAAS blockade group based on total daily 
dose of commonly used ARB/ACEIs
ARBs
Low RAAS 
blockade 
group
High RAAS 
blockade 
group
ACEIs
Low RAAS 
blockade 
group
High RAAS 
blockade 
group
Azilsartan
<80 mg
≥80 mg
Enalapril
<10 mg
≥10 mg
Candesartan
<16 mg
≥16 mg
Benazepril
<20 mg
≥20 mg
Eprosartan
<400 mg
≥400 mg
Captopril
<100 mg
≥100 mg
Irbesartan
<150 mg
≥150 mg
Cilazapril
<2.5 mg
≥2.5 mg
Losartan
<50 mg
≥50 mg
Delapril
<30 mg
≥30 mg
Olmesartan
<10 mg
≥10 mg
Fosinopril
<20 mg
≥20 mg
Telmisartan
<40 mg
≥40 mg
Imidapril
<10 mg
≥10 mg
Valsartan
<160 mg
≥160 mg
Lisinopril
<10 mg
≥10 mg
Moexipril
<7.5 mg
≥7.5 mg
Perindopril
<4 mg
≥4 mg
Quinapril
<20 mg
≥20 mg
Ramipril
<5 mg
≥5 mg
Spirapril
<6 mg
≥6 mg
Temocapril
<2 mg
≥2 mg
Trandolapril
<2 mg
≥2 mg
Zofenopril
<30 mg
≥30 mg
For patients randomized to taking blinded LCZ696 (sacubitril/ valsartan) or patients taking 
open-label Entresto after permanent discontinuation of study drug, total mean daily dose is 
categorized into high/low dose level according to the dose of valsartan component. LCZ696 
dose levels 50mg bid (low), 100 mg bid (high), 200 mg bid (high) are equivalent to sacubitril/ 
valsartan 24/26 mg bid, 49/51 mg bid, 97/103 mg bid. Combined RAS blockade based on 
blinded study medication dose level and open label ARB/ACEI dose level will be considered 
to determine whether a patient is on high or low dose level of RAS blockade.
Overall mean total daily dose levels combining RAS blockades through study medication and 
open label ARB/ACEIs will be summarized for each treatment group by providing number 
and percentage of patients on high and low dose level during the first 12 months from 
randomization for the following patient populations -

FAS
FAS patients who discontinue study treatment during the first 12 months after 
randomization.  
2.5
Analysis of the primary objective
All patients in the Full Analysis Set (FAS) will be included in the primary analysis.


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2.5.1
Primary endpoint
The primary efficacy variable is time to first occurrence of a confirmed composite endpoint of 
cardiovascular death, HF hospitalization or outpatient HF. The confirmation of the primary 
composite events will be based on an adjudication process by an independent CEC. 
Note that deaths which cannot be classified by the adjudication committee as CV or non -CV 
death (for example due to lack of information), will be counted as a CV death for the purpose 
of the primary endpoint. 
Time-to-event is computed as the number of days from randomization to the date of the 
primary endpoint event (first occurrence). A patient without an event will be censored at the 
last date the endpoint status was completely known* or at the time of death from non-CV 
causes (i.e. any death which is confirmed to be a non-CV death by the CEC). 
* This date could include the date of withdrawal of informed consent, date of the patient’s last 
visit prior to the cut-off date of the analysis (whichever occurred first).
2.5.2
Statistical hypothesis, model, and method of analysis
The following null hypothesis versus the alternative will be tested at the 1-sided 2.5% type I 
error rate. 
H0 : λ2/λ1 ≥ 1 (i.e., the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is greater than or equal to the hazard rate in the ramipril group (λ1)) versus
H1 : λ2/λ1 < 1 (i.e. the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is less than the hazard rate in the ramipril group (λ1))
λ2/λ1 is called the hazard ratio of LCZ696 relative to ramipril.  
The time-to-first confirmed primary endpoint will be analyzed using a Cox proportional 
hazards model stratified by STEMI/NSTEMI, with treatment, PCI use at baseline and region 
included as factors in the model. This model allows the hazard rates to vary with time while 
the hazard ratio is assumed to be constant, i.e., independent of time, within each stratum. The 
hazard ratio for LCZ696 vs. ramipril, the associated 2-sided 95% confidence interval and the 
1-sided and 2-sided p-values will be presented from the analysis. 
The Kaplan-Meier estimates of the cumulative event rate (1-survival function) for each 
treatment (and strata) will be tabulated and will also be presented graphically.
2.5.3
Handling of missing values/censoring/discontinuations
For patients without a primary event prior to the analysis time point, the censoring date is 
defined as one of the following (whichever occurred first):

Date when the patient withdrew informed consent

Date of the patient’s last visit before analysis cut-off date (including telephone visit)

Date of death from non-CV causes (i.e. date of death which is confirmed as a non- CV 
death by the adjudication committee).
Note that every effort will be made to follow all patients until the end of the study, regardless 
of adherence to study treatment. The analysis methods specified is valid under the assumption 


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that the censoring mechanism is independent of the event generating process (non-informative 
censoring).
2.5.4
Supportive analyses
The composition of the first confirmed composite primary efficacy endpoint will be 
summarized by treatment group descriptively. The time to reach the first of each individual 
component will be analysed using the same methodology as the described for the primary 
endpoint. Note that for the components CV death and HF hospitalization, all events observed 
will be included in the individual component analyses and not just those which were counted 
as a ‘first event’ in the primary composite endpoint. In addition to the standard censoring 
mechanism described in Section 2.5.3, for the analysis of time to outpatient HF, patients will 
be censored at the time of HF hospitalization or CV death. For the analysis of time to first HF 
hospitalization, patients will be censored at the time of CV death.
An ‘on-treatment’ analysis (Section 2.1.1) will also be performed for the primary endpoint 
whereby events that occurred more than 28 days after permanent study treatment 
discontinuation will be excluded from the analysis. For patients without events before or at 28 
days after treatment withdrawal, the censoring date will be the minimum of the date of 
permanent study treatment discontinuation + 28 days and the date of standard censoring for 
the endpoint.
The primary analysis will also be repeated for per-protocol set (PPS) for assessing robustness 
of results to significant protocol deviations leading to exclusion from FAS.
Sensitivity analysis 
As a sensitivity analysis to the above proportional hazards analysis, treatment groups will be 
compared for the primary efficacy variable using a stratified log-rank test with 
STEMI/NSTEMI as a stratification factor.
2.5.5
Subgroup analysis
For primary endpoint and its components, subgroup analyses will be performed based on the 
pre-defined subgroups in section 2.2.1 for patients in FAS only. 
Displays of treatment effects by subgroup categories (defined as marginal groupings) will be 
provided for descriptive purposes. 
The estimated hazard ratio, and 2-sided 95% confidence interval, will be provided for each 
individual subgroup using a Cox’s proportional hazards model stratified by STEMI/NSTEMI 
with treatment, region and PCI use at baseline as fixed effects factor in the model, with t he 
exception for type of MI (STEMI/ NSTEMI) subgroup for which the analysis will not be 
stratified by STEMI/ NSTEMI.
For subgroups other than type of MI (STEMI vs. NSTEMI), the p-value associated with the 
test of treatment-by-subgroup interaction effect will be calculated from a Cox’s proportional 
hazards model, stratified by STEMI/NSTEMI, including treatment, PCI use at baseline, 
region, subgroup, and treatment-by-subgroup as fixed-effect factors. For STEMI vs. NSTEMI, 


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p-value for interaction term will be provided from a similar model but STEMI/NSTEMI only 
included as a fixed effect factor and not a stratifying factor.
Since no adjustment for multiple comparisons will be made, findings should be interpreted 
with caution.  Additionally, the frequency and percentage of patients reaching primary 
composite endpoint will be presented by treatment group for each of the subgroups listed in 
Section 2.2.1.
2.6
Analysis of secondary efficacy objective(s)
The Full Analysis Set (FAS) will be used for all secondary analyses.
2.6.1
Secondary endpoints
The secondary variables are as follows-
1. Time from randomization to first occurrence of a confirmed composite of CV death or HF 
hospitalization
2. Time from randomization to first occurrence of a confirmed composite of HF 
hospitalization or outpatient HF
3. Time from randomization to first occurrence of a confirmed composite of CV death, non-
fatal spontaneous MI or non-fatal stroke

Non-fatal spontaneous MI is defined as either Type 1 or Type 2 MI confirmed by 
the independent Clinical Event Committee
4. The cumulative number of composite events, including hospitalizations due to HF, 
hospitalizations due to non-fatal spontaneous MI, hospitalizations due to non-fatal stroke 
and CV death. 
5. Time from randomization to all-cause mortality
Censoring of secondary endpoints
The event generating process for the secondary endpoints will be censored following the 
mechanism below-

Endpoints (1) and (3) will be censored following a similar censoring mechanism followed 
for primary endpoint (Section 2.5.3). Event generating process for endpoint (4) will also 
be censored following the same mechanism as the follow up time is censored at last date 
the status of the patient was known (which could be the date of withdrawal from the study, 
the last visit prior to analysis cut off or the date of death). 

Endpoint (2) will be censored following the same mechanism with the exception that 
occurrence of death regardless of reason (CV / non-CV) constitutes a censoring for the 
endpoint.

Endpoint (5) will be censored at the earlier of 

date of withdrawal from the study or 

the last date till when patient was known to be alive (which may be obtained via 
telephone contact or the last visit prior to analysis cut off).


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2.6.2
Statistical hypothesis, model, and method of analysis
The secondary endpoints will be analyzed in order to compare LCZ696 vs ramipril using the 
ITT approach (i.e. estimation of the treatment effect under the ‘treatment policy’).
Analysis of time to event variables
The time to event endpoints (1), (2), (3), (5) will be analyzed using the same statistical 
analysis methods as specified for the primary analysis. Treatment groups will be descriptively 
compared by presenting number and percentage of patients with events while inferential 
comparisons between treatment groups will be provided based on estimated hazard ratio and 
95% CI. Both 1-sided and 2-sided p-values will be reported for treatment group comparison 
(LCZ696 vs. ramipril). Kaplan-Meier estimates of event rates will be tabulated for specific 
time points and will also be presented graphically.
Analysis of count variable
Secondary endpoint (4) will be analyzed using a negative binomial regression model with a 
Weibull baseline intensity function to allow flexibility if the baseline intensity is non-constant 
(Lawless, 1987). The regression model will consider the number of composite events as 
dependent variable with randomized treatment, STEMI/NSTEMI, PCI use at baseline and 
region as factors having fixed effects. Every event jump time, including the terminal event 
time, will be used to estimate the parameters specified in this model. For treatment group 
comparison LCZ696 vs ramipril, the relative rate ratio will be presented together with 2-sided 
95% confidence interval and 1-sided and 2-sided p-values from the fitted model.
For descriptive summary, unadjusted annualized incidence rate will be provided along with 
the model-based estimates and their 95% confidence intervals will be presented by treatment 
groups. Also, adjusted event rate functions over time will be graphically presented from the 
estimated Weibull intensity .
2.6.3
Control of familywise type I error rate
The primary endpoint and the first four secondary efficacy endpoints will be included in a 
statistical testing strategy to control the familywise type I error rate at the 1-sided 2.5% level 
(in the strong sense). A hierarchical testing procedure will be employed whereby the primary 
hypothesis will be tested first, if rejected then the hypothesis associated with the first 
secondary endpoint will be tested and so on.  The order of testing of the composite endpoints 
will be as follows:
1. Primary endpoint
2. Time to first CV death or HF hospitalization
3. Time to first HF hospitalization or outpatient HF
4. Time to first CV death,  non-fatal spontaneous MI or non-fatal stroke
5. The total number of composite events (hospitalizations (including CV death) due to HF, 
non-fatal spontaneous MI or non-fatal stroke and CV death).


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2.6.4
Handling of missing values/censoring/discontinuations
For each patient, the information on secondary endpoints censoring will be censored as 
defined earlier. The primary analysis methods are valid under the assumption that the 
censoring mechanism is independent of the event generating process (non-informaitve 
censoring). 
Sensitivity analyses have been proposed to assess robustness of the results to the potential 
violation of this assumption, wherever applicable.
2.6.5
Supportive analysis
It is recognized that at the time of the first onset of symptomatic HF event some patients may 
discontinue randomized treatment and may be prescribed an alternative treatment for HF 
which could be locally available EntrestoTM (sacubitril/valsartan, LCZ696). For the pre-
specified secondary endpoints (1), (3), (4) and (5), the analysis described in Section 2.7.2 will 
estimate the treatment effect of LCZ696 vs ramipril including any effect of prescribed 
Entresto™ for ramipril patients who discontinued study drug and took Entresto™ as an 
alternative treatment. Hence, the following supportive analyses aim to estimate the pure 
treatment effect as though in a situation whereby Entresto™ was not an available treatment 
option for HFrEF. In this regard, as a sensitivity analysis, inverse probability of censoring 
weighted (IPCW) Cox proportional hazards model (Robins and Finkelstein 2000) will be 
performed on the secondary endpoints (1), (3) and (5).  
Inverse probability of censoring weighted (IPCW) Cox proportional hazards 
model
In the IPCW analysis, the following censoring mechanism will be used for the event 
generating process for secondary endpoints:

For patients randomized to LCZ696 and patients randomized to ramipril but did not take 
open label Entresto upon diagnosis of HFrEF event will be censored according to the 
mechanism described for the secondary endpoints.

For patients randomized to ramipril who subsequently start taking open label Entresto, 
(defined as treatment switch), censoring will occur at the minimum of the last date the 
endpoint status was known, the time of death from non-CV causes, 28 days after study 
treatment discontinuation or start of open-label Entresto.
To adjust for the potential informative censoring, patients in the ramipril arm with event times 
censored due to treatment switch will be dynamically replaced in the patient risk-set by 
remaining uncensored patients in the ramipril arm with a matching prognostic profile by up-
weighting such patients in the analysis set. At a specific time, patients in the ramipril arm who 
have not switched to taking open label Entresto will be assigned a weight inversely 
proportional to the probability of not switching till that time (i.e., patients who do not switch, 
but have covariates implying a high probability of switching, get a larger weight in the 
analysis). 
Estimating IPC weights


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In order to predict these patient specific time-varying probabilities, the time scale is split into 
small intervals based on the visit schedules. In each interval the conditional probability of 
being switched given patient has not switched at any earlier interval is modelled using a 
logistic regression model with the following covariates–

Time independent (baseline) covariates:
Age (in years), baseline LVEF, baseline eGFR (ml/min/1.73m2), history of prior MI (yes/ 
no), history of diabetes (yes/ no), Atrial Fibrillation associated with qualifying MI (yes/ 
no), baseline Killip class, use of PCI for qualifying MI (yes/ no), use of ACEI/ARB in last 
24 hours prior to randomization (yes/ no),), use of IV treatment for qualifying MI (yes/ no)

Time dependent covariates:
Systolic BP (mmHg), Heart rate (bpm), eGFR (ml/min/1.73m2), *use of PCI or CABG 
(yes/ no), *use of ICD/CRT (yes / no)
(*procedures related to any post-randomization MI event)
Predicted probability of switching at a specific time for a patient will be obtained by 
multiplying individual conditional probabilities of switching in intervals prior to that time 
point. To minimize impact of extreme weights (e.g. patients not switched though having very 
high estimated probability to switch), the stabilized version of weights will be used which is 
defined as the ratio of predicted probabilities of not being switched by time t –

from the logistic regression with only baseline covariates

from the logistic regression with both baseline and post-baseline covariates
It is conceivable that the above logistic regression procedure of estimating weights may not 
converge due to reasons including (but not limited to) sparseness of switchers in the 
subpopulations implied by the selected covariates resulting into an infinite likelihood due to 
complete or quasi-complete separation or numerical difficulties in evaluating an overly 
complex likelihood function. Should such problems arise, the logistic regression model used 
to determine the IPC weights will be simplified by pooling pre-specified time intervals 
(thereby extending the time windows in which time-dependent covariates are assessed). If that 
still does not solve convergence problems, the model will be simplified by removing 
covariates.
All patients randomized to LCZ696 will be assigned a weight of 1 for all time intervals.
Estimation of treatment effect
Following the estimation of weights, a weighted Cox proportional hazard model will be fitted 
to the time to event endpoints (1), (3) and (5). The model will be stratified by 
STEMI/NSTEMI while treatment, region, PCI use at baseline will be included as fixed effects 
factors. The hazard ratio for LCZ696 vs. ramipril, the associated 2-sided 95% confidence 
interval and the 1-sided and 2-sided p-values will be presented from the analysis.
On-treatment analysis
Endpoint (4), the total number of confirmed hospitalizations for HF, MI and stroke (including 
CV death) will be redefined for the patients who are prescribed open label Entresto™ as the 
total number of composite endpoints from randomization up to 28 days after the time of study 
treatment discontinuation. The analysis methods will remain the same as specified above.


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2.6.6
Subgroup analysis
Subgroup analysis for the secondary endpoints (1), (2), (3) and (5) will also be performed 
similarly as described in Section 2.5.5 for the primary endpoint based on pre-defined 
subgroups (Section 2.2.1).
For secondary endpoint (4), subgroup analysis will be performed following a similar 
modeling as used for primary analysis of this endpoint (Section 2.6.2). Specifically, a negative 
binomial regression with Weibull baseline intensity function will be fitted within each 
subgroup with randomized treatment, STEMI/NSTEMI, PCI use at baseline and region as 
factors having fixed effects. P-value for treatment-subgroup interaction will be reported based 
on the same model but including factors for subgroup and treatment-subgroup interaction 
fitted to the overall population. Additionally, for descriptive purposes, exposure adjusted 
incidence rate and 95% CI for the secondary events will be reported by treatment group for 
each subgroup.
All the subgroup analyses for secondary endpoints will be performed for patients in FAS only.
2.7
Safety analyses
All safety analyses will be carried out for the Safety set (SAF).  
2.7.1
Adverse events (AEs)
In this study, all adverse events and all serious adverse events occurring through the first two 
weeks post-randomization will be collected and reported. After the first two weeks post-
randomization, the following targeted safety data will be collected and reported in this study:

all serious adverse events,

adverse events of special interest (angioedema, hyperkalemia, hypotension, renal 
impairment, cognitive impairment, hepatotoxicity, hypersensitivity, malignancy, 
pregnancy and exposure during breast feeding)

adverse events leading to a change in dose (down titration) or discontinuation of study 
drugs, and

all suspected non-serious adverse events
Any AE defined by the study protocol occurred during the study period will be included in 
AE summary tables by the specific treatment phase as described in Table 2-3, i.e., AEs/ SAEs 
occurred during screening and double blind period. Specifically, adverse events occurring 
during the randomized treatment phase will be summarized both as overall and also by 
following periods 

AEs/ SAEs from randomization up to 2 weeks

AEs/ SAEs from 2 weeks to permanent study drug discontinuation

AEs/ SAEs from permanent study drug discontinuation until end of study.


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Table 2-3
Allocation of AEs
Screening 
epoch 
(V1-V101)
Double-blind treatment epoch
Phase AE to be reported in
Randomization 
- EOT (V101-
EOT)
EOT – EOS 
(EOT- V199)
X
Reported by site from informed consent
X
Report AE in double-blind period
X
X2
Report as two separate AEs:
One with onset date X (X) during screening epoch 
and one with onset date X2 for DB
X, X2
Report as one AE: 
One with onset date X during DB
X
Report AE in post-EOT phase
X, X2
Report as one AE: 
One with onset date X after EOT
X
X2
Report as one AE in summaries for double-blind
treatment epoch. 
For other summaries, report as two separate AEs; 
One with onset date X before EOT and one with 
onset date X2 during post-EOT
X indicates onset date of an AE.
X2 stands for the same AE but with increased severity
The number (and proportion) of patients with treatment emergent adverse events (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 in the 
following ways:

by treatment, primary System Organ Class (SOC) and Preferred Term (PT).

by treatment, primary System Organ Class (SOC), Preferred Term (PT) and maximum 
severity.

by treatment, Standardized MedDRA Query (SMQ) and Preferred Term (PT)
according to the Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA 
version used for reporting will be described in the footnote
Within each reporting phase (Table 2-3), the following rules are applicable. 

If a subject reported more than one adverse event with the same preferred term, the 
adverse event with the maximum severity will be presented. 

If a subject reported more than one adverse event within the same primary system organ 
class, the subject will be counted only once with the maximum severity at the system 
organ class level, where applicable. 

Statistical analyses performed for the randomized treatment phase will include all post-
randomization AEs up to and including the analysis cut-off irrespective of whether patient 
was on or off study drug.


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
Separate summary of AEs will also be provided for double-blind treatment epoch in which  
separate incidence of same AE (or same episode with increased severity) during before 
and after end of treatment will be considered as separate AEs. 
The most common adverse events reported (≥ 1 % in any group for each preferred term in the 
SOC-PT table) will be presented in descending frequency according to its incidence in the 
LCZ696 group starting from the most common event. Separate summaries, for each reporting 
phase (Table 2-3), will be provided for study medication related adverse events, death, serious 
adverse event, other significant adverse events leading to study discontinuation and adverse 
events leading to dose adjustment / interruption.
For each reporting phase, incidence of AEs will also be listed at a patient level by randomized 
treatment group including outcome, severity and action taken with the AE. 
2.7.1.1
Adverse events of special interest / grouping of AEs
Specific AEs of interest will be summarized separately in addition to the above analysis. 
These specific AEs of interest are: angioedema, hyperkalemia, hypotension, renal impairment, 
cognitive impairment, hepatotoxicity, hypersensitivity, malignancy, pregnancy and exposure 
during breast feeding. Besides providing the crude percentages, annualized exposure adjusted 
incidence rates will also be provided by treatment group. 
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for these risks 
are stored (or alternatively "summarized") in the latest version of LCZ696 Case Retrieval 
Strategy.
In addition to above standard analyses, for double blind phase, analysis for time-to-first 
selected AEs by treatment group will be performed using Kaplan-Meier estimate. The 
annualized exposure duration adjusted event rates will also be provided. 
2.7.2
Deaths
Patients experiencing deaths during the study period will be reported separately for screening 
epoch and double-blind treatment epoch. Deaths occurring during double-blind treatment 
epoch will be summarized by actually received treatment group to present number and 
percentage of patients died by overall and adjudicated reason categories (CV/ non-CV). 
Separate listings will be provided for patients died during the study period with primary 
reason of death as confirmed by adjudication committee.
2.7.3
Laboratory data
Each laboratory parameter, evaluations will be summarized by visit and actually received 
treatment group by presenting summaries (n, mean, standard deviation, median, minimum and 
maximum) for actual and change from baseline values. The summary will be provided 
separately for biochemistry and hematology laboratory parameters. 
Shift tables based on the standard ranges for each laboratory parameters will be provided by 
treatment group at each visit to present incidence of transitions from a baseline high, normal 
or low laboratory value to a post-baseline high, normal or low value. 


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The number and percentage of patients with clinically notable laboratory results after baseline 
will be presented in accordance with Table 2-4. 
Table 2-4
Clinically notable laboratory values and vital signs
Hematology
Hematocrit
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Platelet count
>75% increase, >50% decrease
RBC Count
>50% increase, >20% decrease
WBC count
>50% increase, >50% decrease
Hematocrit
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Blood chemistry
Alkaline phosphatase
>100% increase 
ALT (SGPT)
>150% increase
AST (SGOT)
>150% increase 
BUN
>50% increase 
Calcium
>10% increase, >10% decrease 
Chloride
>10% increase, >10% decrease 
Creatinine
>50% increase 
Potassium
>20% increase, >20% decrease 
Total bilirubin
>100% increase 
Uric acid
>50% increase
Patients with liver enzymes (ALT/AST and CPK) falling within predefined categories of 
elevations and persistent elevations will be summarized by treatment group in accordance 
with the Table 2-5 for the following treatment phases –

Overall randomized treatment phase

from randomization up to first 2 weeks

from week 3 until end of study.
Descriptive summaries will be provided by presenting count and percentage of patients with 
each type of Liver event in addition to graphical summaries, as applicable.
Table 2-5
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 


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TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
2.7.4
Other safety data
2.7.4.1
Vital signs
Sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP) and Sitting pulse 
pressure (PP) will be descriptively summarized by presenting summaries (n, mean, standard 
deviation, median, minimum, maximum) of actual value and change from baseline values for 
each scheduled assessment visit and treatment group. 
2.8
Pharmacokinetic endpoints  
Not applicable
2.9
PD and PK/PD analyses
Not applicable
 
 
 
 
 
 
 
 
 


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2.13
Interim analysis
One interim analysis for efficacy is planned. The cut-off time for this interim analysis will be 
when about two-thirds of the target number of primary events have been reported and 
adjudication-confirmed, approximately 540 of adjudication-confirmed CV deaths, HF 
hospitalizations and outpatient HF events. In the interim analysis, the analysis dataset will 
comprise of all patients who were randomized before the cutoff date. Haybittle-Peto 
boundaries will be adopted for the interim statistical comparisons between treatments. An 
alpha of 0.1% (1-sided alpha) will be spent for the comparison of primary endpoint at the 
interim analysis and the rest of alpha (1-sided 2.49% for the current specified boundary, based 
on East version 6.3) will be utilized at the final analysis. In the interim analysis, the study may 
be stopped for superior efficacy only when both the primary endpoint and CV death are 
significant at level of 0.1% (1-sided).
If the study is stopped early for superior efficacy at the interim analysis, the secondary 
endpoints will be tested using the same hierarchical testing procedure as described in Section 
2.6.3 for the same level of alpha (i.e. 1-sided alpha 0.1%).  If the study continues, then 
secondary endpoints will be tested at the final analysis using 1-sided alpha of 2.49%.
Interim analyses are also planned for the monitoring of safety data, and will be performed 
approximately every 6 months during the course of the study. Such safety analyses do not 


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inflate the type I error for the primary efficacy hypothesis testing and thus no adjustment for 
multiplicity is required.  
Interim analyses will be performed by an independent statistician (at a CRO or academic 
institution) who will not be involved in the trial conduct. The results will be reviewed by an 
independent DMC. The trial investigators, Novartis employees and other personnel who are 
involved in the conduct of the trial and in the analysis of the final trial results, or who have 
contact with study centers, will remain blinded to the treatment codes and interim analysis 
results until all monitoring decisions have been made and the database has been locked for 
final analysis. Full details of the interim analysis plan will be described in the DMC charter.
3
Sample size calculation
A sample size of 4,650 patients, randomized to LCZ696:ramipril using a 1:1 allocation ratio, 
has been chosen with the aim to obtain at least 800 first primary events and at least 633 CV 
death or HF hospitalization events in this event-driven study.  Eight hundred primary events 
provide at least 80% power assuming a true Relative Risk Reduction (RRR) of 18% (i.e. a 
hazard ratio of 0.82) for LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-sided 
type I error rate (with strong control of the FWER).  Six hundred and thirty three CV death or 
first HF hospitalization events will provide at least 80% nominal power assuming a true RRR 
of 20% (for the intent-to-treat analysis) for the secondary endpoint for the same type I error 
rate.
Additional assumptions are described below.

0.5% per year lost to follow-up rate

Recruitment duration of 24 months, with approximately 8 months follow-up anticipated 
for last randomized patient (i.e. 32 months total study duration) and constant recruitment 
rate

One interim analysis is planned to allow for stopping for efficacy, using a Haybittle-Peto 
boundary, thus 2.49% 1-sided alpha will be available for the final analysis (Section 2.13).

Cumulative event rates of CV death or HF hospitalization were estimated from selected 
patients from the VALIANT database (Pfeffer et al, 2003) who were considered to be 
representative of the target patient population of this study.  In the calculation, adjustments 
were made for expected differences between the sample of patients from VALIANT and 
the patients likely to be recruited in PARADISE-MI. In particular PCI use is expected to 
increase (2/3 PCI use vs. 1/3 in VALIANT), and a larger number of NSTEMI patients are 
expected (60% NSTEMI patients vs. approximately 30% in VALIANT). Following these 
adjustments, a further 10% reduction in hazard rate for other changes in standard of care 
was also included. The cumulative event rates for the primary endpoint were based on a 
further 15% increase in hazard rate in order to account for the third component of 
outpatient HF (refer to Table 3-1 for the cumulative event rates assumed for the sample 
size calculation.
Table 3-1
Cumulative event rates assumed for the sample size calculation
Time period following 
randomization
CV death or HF 
hospitalization
CV death, HF hospitalization or outpatient HF
(assuming 15% increase in hazard rate compared 
to CV death or HF hospitalization)


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Time period following 
randomization
CV death or HF 
hospitalization
CV death, HF hospitalization or outpatient HF
(assuming 15% increase in hazard rate compared 
to CV death or HF hospitalization)
0-3 months
9.9%
11.3%
3-6 months
12.3%
14.0%
6-12 months
14.8%
16.8%
12-32 months
19.4%
21.9%
The sample size calculations were carried out using PASS 2008, citation software and 
applying the Lakatos method (Lakatos,1988) and confirmed using East version 6.3.
Sample size sensitivity
This is an event driven study and the assumption about the event rates for the primary 
endpoint is a key driver for the sample size calculation. In this regard there are two main areas 
of uncertainty:

The hazard rates calculated from the post-hoc analysis of VALIANT data as described 
above are thought to reflect the contemporary setting, however, there may have been other 
changes over time which are difficult to quantify and may decrease the event rates, hence 
for the final sample size calculation an additional 10% discount of the hazard rate was 
assumed.   

The hazard rates for the primary endpoint were calculated as 1.15 x the hazard rate for the 
secondary endpoint of CV death or HF hospitalization (i.e. assuming a 15% increase in 
hazard will be observed when adjudicated outpatient HF is included in the composite 
endpoint together with CV death and HF hospitalization). However, there is no adequate 
information available about the expected event rates of the primary triple composite 
endpoint.
In order to understand the impact of the uncertainties described above, Table 3-2 provides the 
sample sizes estimated to achieve at least 800 primary events with different underlying 
assumptions.
Table 3-2
Total sample size required to achieve 800 primary events for different 
event rate assumptions
Increase in hazard 
rate when outpatient 
HF is included in 
primary composite 
endpoint
Discount of event rates for change in SoC
0%↓
10%↓*
20%↓
20%↑
4066
4468
4968
15%↑*
4224
4643
5167
10%↑
4395
4834
5382
* Assumptions used for protocol specified study design
Number of randomized patients required calculated using East version 6.3


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Power for secondary endpoints
Table 3-3 summarizes the nominal power for secondary endpoints which will be included in 
the statistical testing strategy. A 1-sided alpha of 2.5% has been used for the calculations.  All 
assumptions are based on exploratory analyses performed using VALIANT data (data on file).
Table 3-3
Summary of power to reject secondary hypotheses 
Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(1) Time to first CV death or 
HF hospitalization
20% RRR
Expect 698 events1
84%
(2) Time to first HF 
hospitalization or outpatient 
HF
17% RRR
Expect 536 events2
58%
(3) Time to first composite of 
CV death, non-fatal MI or 
non-fatal stroke
15% RRR
Expect 680 events3
56%
(4) Total number of 
hospitalizations for HF, MI 
and stroke related reasons 
including CV death
17% reduction in rate 
ratio
Over-dispersion=9;
Rate of events on 
ramipril per year = 
0.2364
46%
1Event rates as per Table 3-1
2 Cumulative event rates for HF hospitalization of 6.5%, 8.2%, 9.9% and 12.8% were assumed for 0-3m, 3-6m, 6-
12m and 12-32m periods respectively. Then event rates were increased by a further 15% to account for outpatient 
HF.
3 Cumulative event rates of 8.5%, 10.9%, 14.0% and 18.6% were assumed
4 For the power calculation the rate was assumed to be constant over time 
The number of events were calculated for a sample size of 4,650 patients; 24 months recruitment and 8 months 
minimum follow-up. 
HF = Heart Failure; RRR = Relative Risk Reduction
The power calculations were carried out using East Version 6.3.
Blinded sample size re-estimation
When approximately 1/2 of patients have been randomized and have reached the 3 month 
time point, the piecewise hazard rates for the primary endpoint and the double composite 
endpoint (CV death or HF hospitalization) will be estimated based on blinded data.  
The piecewise hazard rates estimated from the observed data will be compared to the original 
assumptions. If there is reason to believe that the original assumptions about event rates may 
not hold, the sample size will be re-estimated taking into consideration the new information. 
The duration of the trial and minimum follow-up will also be reconsidered as part of the 
calculation. This approach will allow flexibility to achieve the required number of events in 
an acceptable time frame.
4
Change to protocol specified analyses
Not applicable


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5
Appendix
5.1
Imputation rules
The missing or partially missing AE start/end date and concomitant medication start/end date
will be imputed using the Novartis ADaM Governance Board (AGB) global standard 
approach. Details will be provided in the study Programming Datasets Specifications.
5.2
Statistical models
5.2.1
Primary analysis
See Section 2.5.2.
5.2.2
Key secondary analysis
Not applicable.
5.3
Rule of exclusion criteria of analysis sets 
Following tables present a sample of the rules for subject classification in the analysis sets 
based on protocol deviation specifications (Table 5-1) and non-protocol deviation 
classification criteria (Table 5-2). The PDs leading to exclusion of patients from analysis sets 
may be updated prospectively and will be finalized before DB lock.
Table 5-1
Protocol deviations that cause subjects to be excluded
Deviation ID
Description of Deviation
Exclusion in Analyses
INCL04
Spontaneous MI event secondary to other 
medical conditions such as anemia, 
hypotension, or an arrhythmia OR thought 
to be caused by coronary vasospasm with 
documented normal coronary arteries
Excluded from PP analysis
INCL05
Non-spontaneous MI
Excluded from PP analysis
INCL06
LVEF >40% after index MI presentation or 
prior to randomization without symptoms of 
pulmonary congestion 
Excluded from PP analysis
INCL07
Subject with no risk factors
Excluded from PP analysis
INCL11
Time from presentation to randomization < 
12 hours or  > 7 days
Excluded from PP analysis
EXCL01
Known history of chronic HF at 
randomization
Excluded from PP analysis
EXCL03
Persistent clinical HF at the time of 
randomization
Excluded from PP analysis
EXCL05
Clinically significant right ventricular MI as 
index MI
Excluded from PP analysis
EXCL15
Previous use of LCZ696 or EntrestoTM
Excluded from PP analysis
TRT03
Patients were misrandomized
Excluded from primary and PP analysis
OTH01
Treatment accidentally unblinded at site.
Excluded from primary and PP analysis
OTH03
Major GCP violation at site.
Excluded from primary and PP analysis


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Table 5-2
Subject classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
SCR
NA
NA
RAN
NA
Not randomized
FAS
TRT03, OTH01, OTH03
Not in RAN;
PPS
INCL04, INCL05, INCL06, 
INCL07, INCL11, EXCL01, 
EXCL03, EXCL05, EXCL15, 
TRT03, OTH01, OTH03
Not in FAS;
SAF
NA
No double-blind study drug taken
6
Reference
Lakatos E. Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics 
1988;44:229-41.
Lawless JF. Regression Methods for Poisson Process Data. Journal of the American Statistical 
Association 1987; 82:808-15.
Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial 
infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 
2003;349:1893-906.
Robins JM, Finkelstein DM. Correcting for Noncompliance and Dependent Censoring in an 
AIDS Clinical Trial with Inverse Probability of Censoring Weighted (IPCW) Log-Rank Tests. 
Biometrics 2000; 56:779-88.


Clinical Development
LCZ696
CLCZ696G2301
A multi-center, randomized, double-blind, active-controlled, 
parallel group Phase 3 study to evaluate the efficacy and 
safety of LCZ696 compared to ramipril on morbidity and 
mortality in high risk patients following an acute 
myocardial infarction
Statistical Analysis Plan (SAP) Amendment 2 
Author:
Trial Statistician, 
Document type:
SAP Documentation (clean)
Document status:
Final
Release date:
18-Mar-2021
Number of pages:
63
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
SAP version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
Amendment 
1
Prior 
to DB 
lock
Update 
introduction for 
this SAP 
amendment 1
Section 1 Introduction first and 
second paragraphs have been 
updated.
Section 
1
Change in study 
design as per 
study protocol up 
to v04
Updated text about the study 
duration, sample size (including 
sample size re-estimation in 
protocol v03), and interim 
analyses change as per study 
protocol v04
Section 
1.1, 2.1, 
2.14, 3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
1.2, 
2.13.1
Clarification for 
the definitions of 
non-fatal 
spontaneous MI 
and non-fatal 
stroke
Added clarification for non-fatal 
spontaneous MI/stroke definition 
in the Table 1-2 footnote 
Section 
1.2
 
 
 
 
Clarification for 
the grouping of 
Added text for clarification of 
the grouping of “NSTEMI” type 
of MI
Section 
2.1


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SAP version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
stratification 
factor type of MI 
Additional 
analyses due to 
mis-stratification
Added analyses for mis-
stratification by type of 
MI/region
Section 
2.1
Clarification for 
censoring methods 
for time-to-event 
variables
Added/modified censoring 
methods for time-to-event 
endpoints with a structure for 
more clarity
Section 
2.1, 
2.5.3, 
2.6.1
Changes as per 
study protocol v04 
for COVID-19 
impact
Added additional analyses for 
potential COVID-19 impact
Section 
2.1,
2.3.1,
2.5, 
2.5.4, 
2.6, 
2.6.5, 
2.10, 
2.11, 
2.13
Clarification of 
baseline definition
Updated baseline definition 
Section 
2.1.1
Adding rules for 
unscheduled visit
Added rules for use of 
unscheduled visit
Section 
2.1.1
Change as per 
study protocol v02
Text added about the exclusion 
of subjects without a valid 
informed consent from all 
analyses sets
Section 
2.2
Update of the
derivation of 
subgroups due to 
refinement / 
feasibility / 
scientific reasons
Updated Table 2-1 definition and 
derivation of subgroups;
Updated Table 2-1 footnote for 
region classification to align 
with the LCZ project standard;
Added subgroup of number of 
CV risk factors in Table 2-1
Section 
2.2.1
Update of CV 
medication 
classification
Updated the classification of CV 
medications
Section 
2.4.2


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SAP version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
Clarification for 
hierarchical 
testing procedure
Clarified that the components of 
the primary endpoint are not part 
of the testing procedure
Section 
2.6.3
Adding an 
endpoint in the 
IPCW analysis
Added an endpoint ((2) time-to-
first event of CV death or HF 
hospitalization) in the IPCW 
analysis
Section 
2.6.5
Update AE 
summaries
Summaries of AEs have been 
updated
Section 
2.7.1
Update AEs of 
special interest 
terms
Updated AEs of special interest 
terms
Section 
2.7.1
Update RAAS 
blockade 
summaries
Summaries of RAAS blockade 
and open-label Entresto have 
been updated
Section 
2.4.2
Clarification of 
central lab data 
use
Clarified that central lab data 
will be used for the summary of 
lab results
Section 
2.7.3
Adding abnormal 
criteria for vital 
signs
Added abnormal criteria for vital 
signs
Section 
2.7.4
Update renal 
injury endpoint as 
per study protocol 
v03
Clarified the definition of renal 
injury endpoints as measured by 
serum creatinine change from 
baseline 
Section 
2.13.1
Adding 
imputation rules 
for dates
Updated imputation rules for 
various types of missing or 
partially missing dates
Section 
2.1, 5.1
Update of PD or 
non-PD criteria 
for exclusion from 
analysis sets
Updated the text and code for the 
PDs leading to exclusion from 
analysis sets in Table 5-1;
Updated the text for non-PDs in 
Table 5-2
Section 
5.3


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SAP version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
Amendment 
2
Prior 
to
DBL
Adding definition 
for initiation or 
intensification of 
antihyperglycemic 
medications per 
protocol 
requirement 
before DBL
Added the definition of initiation 
or intensification of 
antihyperglycemic medications
Sections 
1.2, 
2.13.1
Removing 
alternative 
definition of renal 
composite 
endpoint (not 
specified in 
protocol)
Deleted the alternative definition 
of renal composite endpoint
Sections 
1.2, 
2.13.1
 
 
 
 
 
 
 
  
 
 
 
Adding number of 
CV risk factors 
summary 
Added number of CV risk 
factors to the summary of CV 
risk factors
Section 
2.3.2.1
Clarification of 
definition for time 
to treatment 
discontinuation 
analysis
Update the text for “time to 
permanent discontinuation of 
study medication not due to 
death”  
Section 
2.4.1
Update of study 
exposure 
summary
Updated study exposure 
summary 
Section 
2.4.1
Clarification of 
definition of CV 
death endpoint
Added text for the CV death 
endpoint definition
Section 
2.5.1
Adding analysis 
cut-off date
Analysis cut-off date 
Sections 
2.1, 


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SAP version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
2.5.3, 
2.6, 2.13
Adding supportive 
analyses for 
primary endpoint 
Added alternative definitions for 
primary endpoint as supportive 
analyses
Section 
2.5.4
Adding a 
sensitivity 
analysis for 
primary endpoint
Added a Bayesian sensitivity 
analysis with robust prior to 
combine potentially COVID-19 
affected results with pre-
COVID-19 results
Sections 
2.5.4, 
5.4, 6
Removing an 
endpoint from the 
IPCW analysis to 
align with 
protocol
Removed the composite 
endpoint of HF hospitalization or 
outpatient HF from the IPCW 
analysis 
Section 
2.6.5
Update of AE 
summaries for 
clarity
Updated text for AE summaries 
Section 
2.7.1
Update of AEs of 
special interest 
risk names
Updated the risk names of AEs 
of special interest
Section 
2.7.1, 
2.7.1.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP version
Time 
point
Reason for update
Outcome for update
Section 
and title 
impacted 
(Current)
Added missing 
date handling for 
endpoint event 
with completely 
missing date
Added the data handling method 
for event with completely 
missing event date
Section 
5.1.3


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Table of contents
Table of contents .................................................................................................................8
List of abbreviations..........................................................................................................10
1
Introduction .......................................................................................................................11
1.1
Study design...........................................................................................................11
1.2
Study objectives and endpoints .............................................................................12
2
Statistical methods.............................................................................................................17
2.1
Data analysis general information .........................................................................17
2.1.1
General definitions................................................................................19
2.2
Analysis sets ..........................................................................................................20
2.2.1
Subgroups of interest.............................................................................21
2.3
Patient disposition, demographics and other baseline characteristics ...................23
2.3.1
Patient disposition.................................................................................23
2.3.2
Demographics and baseline characteristics...........................................23
2.3.3
Medical history......................................................................................24
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................25
2.4.1
Study treatment / compliance................................................................25
2.4.2
Prior, concomitant therapies..................................................................27
2.5
Analysis of the primary objective..........................................................................29
2.5.1
Primary endpoint...................................................................................29
2.5.2
Statistical hypothesis, model, and method of analysis..........................30
2.5.3
Handling of missing values/censoring/discontinuations.......................30
2.5.4
Supportive analysis and sensitivity/supplementary analysis.................31
2.5.5
Subgroup analysis .................................................................................36
2.6
Analysis of secondary efficacy objective(s)..........................................................36
2.6.1
Secondary endpoints .............................................................................37
2.6.2
Statistical hypothesis, model, and method of analysis..........................38
2.6.3
Control of familywise type I error rate .................................................38
2.6.4
Handling of missing values/censoring/discontinuations.......................39
2.6.5
Supportive analysis and sensitivity analysis .........................................39
2.6.6
Subgroup analysis .................................................................................41
2.7
Safety analyses.......................................................................................................41
2.7.1
Adverse events (AEs)............................................................................41
2.7.2
Deaths....................................................................................................43
2.7.3
Laboratory data .....................................................................................43
2.7.4
Other safety data ...................................................................................45


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2.8
Pharmacokinetic endpoints....................................................................................45
2.9
PD and PK/PD analyses.........................................................................................45
45
46
46
47
47
48
50
2.14
Interim analysis......................................................................................................51
3
Sample size calculation .....................................................................................................52
3.1
Original sample size planning ...............................................................................53
3.2
Blinded sample size re-estimation.........................................................................55
4
Change to protocol specified analyses ..............................................................................58
5
Appendix ...........................................................................................................................59
5.1
Imputation rules.....................................................................................................59
5.1.1
Missing or partially missing AE or concomitant medication 
start/end date .........................................................................................59
5.1.2
Missing visit date ..................................................................................59
5.1.3
Missing or partially missing event date ................................................59
5.1.4
Missing medication stop date................................................................59
5.2
Statistical models...................................................................................................60
5.2.1
Primary analysis....................................................................................60
5.2.2
Key secondary analysis.........................................................................60
5.3
Rule of exclusion criteria of analysis sets..............................................................60
5.4
SAS code for Bayesian sensitivity analysis...........................................................61
6
Reference...........................................................................................................................62


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
bid
bis in diem/twice a day
CRF
Case Report Form
CV
Cardiovascular
CSR
Clinical Study report
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
HF
Heart failure
IRT
Interactive Response Technology
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
o.d.
Once Daily
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
The statistical analysis plan (SAP) describes the detailed methodology and implementation of 
the planned statistical analyses outlined in the study protocol for CLCZ696G2301 (up to version 
04 – protocol amendment 4). The analyses following the SAP below will be used for clinical 
study reporting purposes while the same analysis plan will also be used for the planned interim 
efficacy analyses unless otherwise specified. 
Any future change in statistical analysis will be prospectively furnished with relevant details in 
subsequent versions as amendments and will be finalized before database lock (DBL) prior to 
the final analysis.
1.1
Study design
This is a multicenter, randomized, double-blind, active controlled, event-driven phase III 
clinical trial designed to evaluate the efficacy and safety of LCZ696 compared to ramipril when 
added to standard therapy in post-AMI patients with LV systolic dysfunction and/or pulmonary 
congestion. 
The study population consists of high risk patients who have sustained a spontaneous acute 
myocardial infarction (ST segment elevation MI (STEMI) or non-ST segment elevation MI 
(NSTEMI) within the last 12 hours to 7 days prior to randomization) with evidence of LV 
systolic dysfunction and/or pulmonary congestion associated with index MI. In addition, 
patients need to have at least one predefined risk factor and without known prior history of
chronic HF.
Figure 1-1
Study Design
As per the study design (Figure 1-1), a screening epoch of no more than 7 days after index MI 
presentation will be used to determine if patients qualify to enter the double-blind treatment 
phase of the study with respect to protocol specified inclusion/ exclusion criteria. 
Eligible patients, stratified by type of MI (STEMI/ NSTEMI) and region, will be randomized 
1:1 to receive LCZ696 titrated to a target dose of 200 mg twice daily or ramipril titrated to a 
target dose of 5 mg twice daily. Patients may be randomized on the same day that they are 


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consented and screened. To reduce the potential risk of angioedema, patients on ACEI during 
the last 36 hours prior to randomization will undergo a valsartan bridging treatment for 1 day 
in a blinded manner. 
Three dose levels of study medication will be administered in a stepwise titration (Table 1-1). 
Randomized patients are planned to start at dose level 1 while those who were on prior 
ARB/ACEI may start at dose level 2 at investigator’s discretion.  
Table 1-1
Study drug dose levels during treatment epoch
Dose Level
LCZ696 Treatment Arm*
Ramipril Treatment Arm
1
50 mg b.i.d.†
1.25 mg b.i.d.
2
100 mg b.i.d.†
2.5 mg b.i.d.
3
200 mg b.i.d.
5 mg b.i.d.
* LCZ696 dosing is based on the total amount of both components of sacubitril/valsartan; dose 
levels 1, 2 and 3 are equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, 
respectively.  
† Patients who are randomized to LCZ696 and received ACE inhibitors in the 36 hours prior to 
randomization will be given a bridging valsartan dose in a blinded manner for one day (two doses 
at either dose level V1 or V2: 40 or 80 mg b.i.d.) prior to beginning double-blind LCZ696 
treatment.
Patients can be up-titrated to the next dose level subject to satisfying pre-defined safety / 
tolerability criteria (SBP ≥ 100 mmHg, eGFR ≥ 30 mL/min/1.73m2 or serum creatinine increase 
< 0.5 mg/dl from baseline, serum potassium < 5.5 mmol/L (mEq/L)). The titration scheme aims 
to achieve the target dose within 2 weeks of randomization. 
The study is event-driven and will continue until both a total of 708 confirmed primary triple 
composite endpoint events and 592 confirmed double composite events of CV death or HF 
hospitalization (i.e., first secondary endpoint) have been achieved. Note that the actual number 
of CEC-confirmed primary events at the end of the study may differ (slightly) from the target 
number of 708 since the close-out timeline is predicted based on observed data while the study 
is still ongoing and it is subject to reporting and adjudication gaps. Approximately 5,650
randomized post-AMI patients are estimated to provide the necessary number of confirmed 
endpoints over a total study duration of 43 months with a projected patient recruitment period 
of 37 months. The overall estimated mean follow-up time will be 19 months for the study.
1.2
Study objectives and endpoints
Table 1-2
Objectives and related endpoints
Objective
Related endpoint and Definition
Analysis 
method
Primary objective


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Objective
Related endpoint and Definition
Analysis 
method
To demonstrate that LCZ696 is 
superior to ramipril in delaying the 
time-to-first occurrence of the 
composite endpoint of CV death, 
HF hospitalization or outpatient HF 
in patients with LV systolic 
dysfunction and/or pulmonary 
congestion following an AMI
The primary efficacy endpoint is defined as 
the time to the first confirmed occurrence of 
CV death, heart failure hospitalization* or 
outpatient heart failure**.
* Heart failure hospitalization also includes the 
development of new symptomatic heart failure 
during an ongoing hospitalization including the 
index AMI hospitalization.
** Outpatient heart failure is defined as:

An urgent/unscheduled visit to an ED, 
acute/urgent care facility or outpatient clinic 
or a non-urgent office/practice or study visit 
for a primary diagnosis of HF that does not 
require an overnight hospital stay.

Patients must exhibit at least one documented 
new HF symptom with objective evidence of 
clinical HF consisting of at least 2 physical 
examination findings or one physical 
examination findings and at least one 
laboratory criterion.

The event requires initiation or intensification 
of treatment specifically for HF. Such 
treatment can include administration of 
intravenous agent (e.g., diuretic, vasodilator, 
vasopressor, or inotrope) or mechanical or 
circulatory intervention for HF, OR initiation 
of oral loop diuretic treatment, or 
intensification of oral maintenance loop 
diuretics for the diagnosis of HF, over a 
sustained period (i.e., initiation or doubling of 
total daily dose through a period of ≥ 4 
weeks), which is confirmed at a subsequent
outpatient visit
Section 2.5
Secondary objective
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
delaying the time-to-first occurrence 
of CV death or HF hospitalization
Time-to-first occurrence of CV death or HF 
hospitalization (days). 
Section 2.6
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
delaying the time to new onset of 
symptomatic HF defined as time-to-
first occurrence of HF 
hospitalization or outpatient HF
Time-to-first occurrence of HF hospitalization 
or outpatient HF (days)
Section 2.6
To demonstrate the superiority of 
LCZ696 compared to ramipril, in 
delaying the time-to-first occurrence 
of CV death, non-fatal spontaneous 
MI1,3 or non-fatal stroke4
Time-to-first occurrence of CV death, non-
fatal spontaneous MI1,3 or non-fatal stroke4
(days). 
Section 2.6


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Objective
Related endpoint and Definition
Analysis 
method
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
reducing the rate of the composite 
endpoint of CV death and total (first 
and recurrent) hospitalizations due 
to HF, non-fatal spontaneous MI1,3
or non-fatal stroke4
Cumulative number of composite endpoint of 
CV death and total (first and recurrent) 
hospitalizations due to HF, non-fatal 
spontaneous MI1,3 or non-fatal stroke4 (count). 
Section 2.6
To demonstrate the superiority of 
LCZ696, compared to ramipril, in 
delaying the time to all-cause 
mortality
Time to all-cause mortality (days).
Section 2.6
To evaluate the safety and 
tolerability of LCZ696 compared to 
ramipril

Number and percentage of adverse 
events, serious adverse events, drug-
related discontinuations, etc.

Change from baseline in laboratory 
assessments and vital signs 
measurements
Section 2.7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objective
Related endpoint and Definition
Analysis 
method
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objective
Related endpoint and Definition
Analysis 
method
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.13.1


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Objective
Related endpoint and Definition
Analysis 
method
 
 
1. The protocol-defined spontaneous MI is comprised of CEC adjudicated Type 1 and Type 2 MI.
2. Refers to any hospitalization after discharge from hospitalization due to qualifying MI
3. Non-fatal spontaneous MI is CEC-confirmed Type 1 or Type 2 MI that occurred at least 14 days prior to death.
4. Non-fatal stroke is comprised of all CEC-confirmed stroke.
2
Statistical methods
The following section contains important information on detailed statistical methodology used 
for analysis and reporting purposes.
2.1
Data analysis general information
Data will be analyzed by Novartis Biostatistics and Statistical Reporting department according 
to the statistical analysis section 9.1 of the study protocol using SAS 9.4, unless otherwise 
specified. Further details on planned statistical analyses and data-driven regression diagnostics
will be presented in the following section and in CSR Appendix 16.1.9. The same analysis plan 
will also be used for planned interim efficacy analyses, as applicable.
In general, the continuous variables will be summarized descriptively by presenting n, mean, 
SD, median, quartiles, minimum and maximum while categorical variables will be summarized 
by presenting count and percentage of patients in each category. Graphical presentation of 
summary data will also be provided as applicable.
For time-to-event variables, the general censoring methods are specified in Section 2.5.3 for 
fatal or non-fatal time-to-first event endpoints, and in Section 2.6.1 for time-to-recurrent event 
endpoints. 
Some missing or partially missing dates in the analyses require imputation. The handling of 
missing or partially missing dates has been detailed in Section 5.1.
The randomization in this study will be stratified by region and type of MI (STEMI or NSTEMI).
“Other” type of MI has been grouped together with “NSTEMI” as “NSTEMI/Other” type of 
MI for stratification at randomization. In this document, “NSTEMI” refers to the grouping of 
“NSTEMI/Other” for type of MI. The stratification factors will be appropriately accounted for 
in the planned statistical analyses. At Visit 101 all eligible patients will be randomized via 
Interactive Response Technology (IRT) to one of the treatment arms. The stratification factors 
of region and type of MI entered and used by IRT at randomization sometimes can be different 
from the data collected on the Case Report Form (CRF), which is called mis-stratification. In 
this study, there have been some cases of mis-stratification by type of MI and one case of mis-
stratification by region. Analyses using region and/or type of MI will consider the following 
rules:


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-
In general, unless otherwise specified, statistical models for all efficacy endpoints will 
use region and type of MI based on information from IRT where applicable. 
-
In addition, the primary/main analysis model for each of the primary and secondary 
efficacy endpoints (Section 2.5 and 2.6) will be repeated using CRF based region and 
type of MI. 
-
Subgroup analyses corresponding to the primary/main analysis models for the primary 
and secondary efficacy endpoints (Section 2.5 and 2.6) will be repeated using both IRT 
and CRF based region and type of MI where applicable.
-
For patient disposition, demographic and background characteristics data analyses: the 
subgroup definition of type of MI (Table 2-1) will use both IRT and CRF based 
information; the subgroup definition of region (Table 2-1) will use CRF based 
information.
-
For exposure and safety data analyses, the subgroup definitions of type of MI and region 
(Table 2-1) will be based on data collected from CRF.
Two interim analyses (IAs) are planned to assess efficacy. The analysis cutoff date for the first 
IA will be determined as date when 2/3rd of target primary composite outcome i.e. 
approximately 472 primary composite outcomes will be reported and adjudication-confirmed. 
The analysis cut-off time for the second IA (IA2) is planned to be 01-Mar-2020 (estimated start 
of COVID-19 impact globally). All primary events that occurred prior to 01-Mar-2020, will be 
included in the second IA. Analyses using pre-Covid data (prior to 1-Mar-2020) will include 
patients randomized before 1-Mar-2020. It is estimated that the second IA will include 
approximately 80% of the target number of 708 Clinical Event Committee (CEC)-confirmed 
primary events. If the assumptions of the study design regarding event rate, accrual rate and 
drop-out rate remain valid, the final analysis cut-off date will be a predicted date when a total 
of 708 confirmed primary triple composite and 592 confirmed double composite events have 
been achieved, or study termination has been decided based on other study termination criteria.
The final analysis cut-off date for this study is 31-Dec-2020.
Additional efficacy analyses (for primary, secondary,
 efficacy endpoints) will be
considered to assess the potential impact of COVID-19 on study outcomes. See the following 
table for an overview of these analyses under different trial conduct scenarios:
Scenario
Primary/main analysis
Sensitivity/supplementary analysis
Early termination 
(without IA2)
Pre-specified primary/main
analysis model, using pre-Covid 
data (prior to 1-Mar-2020)
Pre-specified primary/main analysis 
model, using all data accrued up to 
the end-of-study analysis cut-off
With IA2, early stop
Pre-specified primary/main
analysis model, using pre-Covid 
data (prior to 1-Mar-2020)
Pre-specified primary/main analysis 
model, using all data accrued up to 
the end-of-study analysis cut-off
With IA2, no early 
stop
Pre-specified primary/main
analysis model, using all data 
accrued up to the end-of-study 
analysis cut-off (31-Dec-2020 )
Pre-specified primary/main analysis 
model, using pre-Covid data (prior 
to 1-Mar-2020);


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For primary endpoint, additional 
sensitivity and  supplementary 
analyses will be performed as 
specified in Section 2.5.4
Note: Analyses using pre-Covid data (prior to 1-Mar-2020) will include patients randomized 
before 1-Mar-2020.
 
 
 
2.1.1
General definitions 
Study treatment or drug
In future sections through this document, ‘study treatment’ or ‘study drug’ will be used to refer 
to investigational therapy assigned to a patient. Specifically, for the double-blind treatment 
phase, study treatment refers to LCZ696 or ramipril as assigned to a patient at randomization.
Screening epoch or screening period
Screening epoch or screening period is defined as the period starting from date of signed of 
informed consent until date of randomization or decision on randomization.
Randomized treatment phase 
The randomized treatment phase begins at the time of randomization and ends with the last 
study drug intake or the death of the patient, whichever comes earlier. During the randomized 
treatment phase, patients will return for scheduled clinic visits. For all related safety analyses 
randomized treatment starts with the first intake of randomized, double-blind study drug. 
Temporary interruption of the study drug will not be counted as randomized treatment phase 
discontinuation.
Post-treatment follow-up phase
The post-treatment follow-up phase (usually after premature permanent study drug 
discontinuation) begins after last study drug intake + 1 day and ends on the date last seen (or 
vital status confirmed by indirect contact).
Double-blind period or double-blind treatment epoch
The double-blind period, also called the double-blind treatment epoch, is the combination of 
the randomized treatment phase and the post-treatment follow-up phase.


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Baseline and study day
For analysis purpose, baseline value for all variables is defined to be the last results obtained at 
or prior to randomization date (or prior to 1st study drug intake for safety assessments). Most of 
variables will have their baseline at visit 101, unless otherwise specified. 
 
 
Study day of any assessment refers to the number of days to the assessment relative to 
randomization (day 1), or relative to the 1st study drug intake for safety assessments. 
Unscheduled visit
Only for the analysis of safety laboratory evaluation will unscheduled measurements be taken
into account. For efficacy evaluations, measurements from unscheduled visits will generally
not be used, unless specifically specified.
On-treatment data for an efficacy endpoint
The on-treatment data refers to any observation occurring while the patient is on-study 
medication or within 28 days inclusive of permanent treatment discontinuation excluding any 
observation occurring thereafter.
2.2
Analysis sets
The following analysis populations will be defined for statistical analysis:

Screened (SCR) set – All patients who have signed informed consent. The screened set 
includes only unique screened patients, i.e., in the case of re-screened patients only the 
chronologically last screening data is counted.

Randomized (RAN) set – All patients who received a randomization number, regardless 
of receiving trial medication.

Safety set (SAF) - All randomized patients who received at least one dose of study drug. 
Patients in the SAF will be analyzed according to treatment received. 

Full analysis set (FAS) – All patients in the RAN population who were not mis-
randomized patients*. Following the intent-to-treat (ITT) principle, patients in the FAS 
are analyzed according to the treatment they have been assigned to at the randomization. 

Per-protocol set (PPS) will be a subset of the FAS which will consist of the patients who 
do not have major deviations. Major protocol deviations will be pre-specified prior to 
unblinding.
* Mis-randomized patients are those who were not qualified for randomization and who did 
not take study drug, but have been inadvertently randomized into the study.
Subjects without valid written informed consent will be excluded from all analysis sets.
A sample of rules leading to exclusion from specific analysis sets of patients violating protocol 
specified inclusion/ exclusion criteria and any other protocol deviations developed during the 
study has been provided in Appendix 5. The final list may be different from this which will be 
finalized and signed off before DBL.


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2.2.1
Subgroups of interest
Subgroups will be formed to explore the consistency of treatment effects and safety profiling 
on selected parameters between the subgroups and the overall population. In general, subgroups 
will be defined based on baseline information as defined in section 2.1. 
In Table 2-1, we have listed all subgroups defined for this study and the ways to derive them. 
Subsets of these subgroups will be used depending on the parameter under consideration. Also 
note that only important parameters or variables in these analyses will have subgroup analyses. 
The details about the parameters having subgroup analyses will be presented in the 
corresponding sections as appropriate. Also, additional subgroups may be formed later for 
regional or country-wise analyses as applicable.
Table 2-1
Specification of subgroups
Subgroup
Method of derivation
Disposition/ 
Background & 
Demographics / 
Exposure
Efficacy
Safety
Number of 
cardiovascular (CV) 
risk factors (1 CV risk 
factor vs. > 1 CV risk 
factor)1
Screening
X
Age groups:
(<65 vs. ≥65 years, 
<75 vs. ≥75 years)
Screening (derived)
X
X
X
Gender (male/ 
female)
Screening
X
X
X  
Race
Screening
X
X
X
Region*
Derived (pooled
countries or country), 
using
Screening 
X
X
X
Baseline LVEF (by 
quartiles)
Screening
X
Baseline LVEF ≤40% 
vs. > 40%
Screening
X
Worst Killip class (I 
vs. ≥ II)
Randomization
X
Type of MI (STEMI 
vs. NSTEMI)
Randomization 
X
X
X  
Infarct location 
(anterior, inferior, and 
other)
X
PCI use at baseline 
(PCI use versus 
medical management 
after index MI)
X
X
  


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Subgroup
Method of derivation
Disposition/ 
Background & 
Demographics / 
Exposure
Efficacy
Safety
Time from the index 
MI presentation to 
randomization (< 
median, ≥median)
X
Baseline SBP (three 
groups: ≤110 
mmHg; >110 mmHg 
and ≤140 
mmHg; >140 mmHg)
Randomization
X
Screening eGFR (<60 
vs ≥ 60 mL/min/1.73 
m2)
Screening
X
History of diabetes 
(yes/no)
X
Atrial Fibrillation 
associated with index 
MI at baseline 
(yes/no)
X
Prior history of MI
X
History of 
hypertension (yes/no)
Screening 
X
Prior ACEi or 
ARB use (yes/no) 
Randomization 
X
Use of β-blocker at 
baseline (yes/no)
X
Use of 
mineralocorticoid 
antagonists at 
baseline (yes/no) 
X
Use of loop diuretics 
at baseline (yes/no)
X
* North America: Canada, USA
1 Patients with no CV risk factor are categorized in the “1 CV risk factor” group.
Latin America (including Central America): Argentina, Peru, Brazil, Colombia, Mexico
Western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Portugal, 
Spain, Sweden, Switzerland, United Kingdom
Central Europe: Bulgaria, Croatia, Czech Republic, Greece, Hungary, Poland, Romania, Russia, Slovakia, 
Turkey
Asia Pacific & Others: Australia, South Africa, Israel, China, India, Korea, Philippines, Singapore, Taiwan, 
Thailand


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Based on all patients in the screened set, number and percentage of patients screened 
successfully will be provided. In addition, screen failure patients will be summarized by primary 
reason for screen failure.  
The number and percentage of randomized patients included in different analysis sets (Section 
2.2) will be summarized based on the randomized patients. Patients with premature study 
discontinuation during the double-blind treatment epoch will be summarized by the primary 
reason of discontinuation for each randomized treatment group and overall based on all patients 
in randomized set (RAN).
In addition, the number and percentage of patients with protocol deviations as well as the criteria 
leading to exclusion from analysis sets will be provided for the patients in randomized set 
(RAN).  All the disposition data will also be listed at a patient level for double-blind period
disposition.
The number and percentage of patients with any and each of the following COVID-19 impacted
criteria will be provided for all randomized patients, patients randomized prior to 1-Mar-2020, 
and patients randomized on or after 1-Mar-2020: (1) cancelled/rescheduled doctor’s 
appointment due to COVID-19; (2) cancelled/rescheduled procedure due to COVID-19; (3) 
missed study visit due to COVID-19; (4) study visit performed outside the study site due to 
COVID-19; (5) study assessment or visit procedures changed due to COVID-19; (6) method of 
dispensing the study drug to the subject changed due to COVID-19; (7) study drug interruption 
due to COVID-19; (8) study drug discontinuation due to COVID-19; (9) endpoint(s) impacted 
by COVID-19; (10) had symptom(s) for which the patient felt the need to go to an outpatient 
clinic, urgent care, emergency department, or hospital but chose not to due to COVID-19.
2.3.2
Demographics and baseline characteristics
Following demographic and baseline characteristics will be summarized by randomized 
treatment group for all patients in full analysis set (FAS): 

Continuous variables
Age (in years), height (in centimeters), weight (in Kg.), body mass index (BMI) in Kg/m2, 
SBP (in mmHg), DBP (in mmHg), heart rate (in bpm), eGFR (in ml/min/1.73m2), 
Categorical variables

Age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years)

Sex

Race

Ethnicity

Region


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2.3.2.1
Characteristics and therapies associated with qualifying MI
Qualifying MI related characteristics, cardiovascular (CV) risk factors associated with 
qualifying MI and therapies used to manage qualifying MI will be summarized separately for 
all patients in the Full Analysis set (FAS) which includes: 

Disease characteristics
      Time from index MI presentation to randomization,
Location of infraction (anterior / inferior), type of MI (STEMI/ NSTEMI), number of 
diseased vessels, ejection fraction (EF) (in %), Killip class

CV risk factors/co-morbidity/past history at baseline
Age (<70, ≥70 years), screening eGFR (<60, ≥60 ml/min/1.73m2), diabetes (yes/no), 
history of prior MI (yes/ no), atrial fibrillation associated with qualifying MI (yes/ no), 
categories of EF (<30%, >=30%), worst Killip class (<III, ≥III), STEMI without 
reperfusion therapy within the first 24 hours after presentation (yes/no).
Number of CV risk factors will be summarized descriptively.

Therapies used to manage qualifying MI –
Use of reperfusion therapies (yes / no) –

use of PCI (yes/ no) (including procedures performed for qualifying MI both prior to 
and after randomization but before discharge)

type of stenting if PCI performed (bare metal/drug eluting stent)

use of antithrombotic therapy (yes/no) which includes aspirin, P2Y12 inhibitor,
antithrombin agents, glycoprotein (GP) IIb/IIIa inhibitors

use of oral CV medications  including (but not limited to) ARB/ACE inhibitors, beta 
blockers, mineralocorticoid receptor antagonists (MRA), statins, oral anticoagulants, 
non-loop diuretics, loop diuretics, digitalis glycosides, oral nitrates and calcium 
channel blockers..

use of IV diuretics (yes/no), IV vasodilator (yes/no), IV vasopressors (yes/no), IV 
inotropes (yes/no)
In general, all continuous variables will be summarized by presenting descriptive statistics (n, 
mean, SD, Q1, Q3, median, minimum, maximum) and all categorical variables will be 
summarized by number and percentage of patients in each category. The summaries will be 
provided by randomized treatment group for all patients in Full Analysis set (FAS).
2.3.3
Medical history
Any condition entered on the relevant medical history / current medical conditions CRF will be 
coded using the most updated version of MedDRA dictionary. Medical history includes 
cardiovascular disease history and other medical history in this study, which are collected at 
Visit 1 (Screening visit). The number and percentage of subjects with each medical condition 
will be provided by treatment group and system of organ class and preferred term for the Full 
Analysis Set (FAS).
Patient disposition, demographic/ baseline and other disease characteristics will also be 
summarized similarly for the following subgroups:

Age group (<65 vs. ≥65 years), age group (<75 vs. ≥75 years)


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
Gender (male/female)

Region

Race

Type of MI (STEMI vs. NSTEMI)

PCI use at baseline (Yes vs. No)
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Overall treatment exposure
The duration of overall treatment exposure (in days) will be calculated as –
Last known date when the patient took study medication – Date of 1st intake of 
randomized study medication during double-blind treatment epoch + 1
This includes days patient is off-treatment due to temporary treatment interruption.
The overall treatment exposure duration (in days) will be summarized by randomized treatment 
group using mean, standard deviation, median, minimum and maximum. Additionally, the 
treatment exposure duration will also be summarized categorically by presenting number and 
percentage of patients with exposure 

<2 weeks 

2 to < 4weeks 

4weeks to < 6months 

6months to < 1 year

1 year to < 2 years

>= 2 years 
Mean daily dose and mean dose level for each patient will be summarized by treatment group. 
Mean daily dose and mean daily dose level for each patient will be calculated as –
∑
(Number of days spent on Dose)X(Dose)


∑
(Number of days spent on Dose)


For mean daily dose calculation ‘Dose’ represents actual dose (in mg) administered at dose 
level ‘i’ according to Table 1-1, whereas for mean daily dose calculation ‘Dose’ represents the 
categorical dose level (0, 1, 2 or 3) administered at dose level ‘i’. Further, dose level ‘0’ refers 
to zero dose signifying treatment interruption. Mean daily dose and mean daily dose level
calculated as above will be summarized by treatment groups for overall study duration. Mean 
doses and mean dose levels of study drug at each visit will also be summarized by treatment 
group and visit. Last dose and last dose level when patients are alive will also be summarized 
by treatment group.
Descriptive summary of number of days spent at each dose level as mentioned in Table 1-1 will 
be provided by treatment group. Also, number and percentage of randomized patients at each 


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dose level will be summarized by visit and treatment group.  Time to first reach the dose at each 
dose level and time to first reach the target dose will be summarized for each treatment group 
during the double-blind treatment epoch. In addition, reasons for down-titrating treatment will 
be summarized by each treatment group for each dose level. 
Time to permanent discontinuation of study medication not due to death will be summarized 
according to the Kaplan-Meier analysis. A summary table by treatment group will be provided 
to display the number and percentage of patients who discontinued study medication by the 
primary reason for discontinuing and the number and percentage of patients who subsequently 
received the following medications during the study: ACE inhibitors, ARB, and Entresto™ 
(sacubitril/valsartan). Exposure durations will be summarized by treatment group for these 
medications. The last doses and dose levels of study drugs for these switchers will also be 
summarized by treatment group.
Overall study drug exposure
Duration of overall study drug exposure is defined as the duration of treatment exposure (in 
days) excluding days of treatment interruption and is calculated as –
(Last known date when the patient took study medication – Date of 1st intake of 
randomized study medication during double-blind treatment epoch + 1) – number of days 
of treatment interruption
The duration of study drug exposure (in days) will be summarized by randomized treatment  
group using mean, standard deviation, median, minimum and maximum. Additionally, the 
treatment exposure duration will also be summarized categorically by presenting number and 
percentage of patients with exposure 

<2 weeks 

2weeks to < 4weeks 

4weeks to < 6months 

6months to < 1 year

1 year to < 2 year

>=2 years 
Treatment and study drug exposure in subgroups
Both overall treatment exposure and overall study drug exposure will be summarized by the 
following subgroups -  

Age group (< 65 vs ≥ 65 years; < 75 vs ≥ 75 years)

Gender

Race

Region

Type of MI (STEMI vs. NSTEMI)


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Overall study exposure (Follow-up duration)
Following the definition of double blind phase in section 2.1.1, for each patient duration of 
study exposure (in days) during double blind phase is calculated as total duration of on-
treatment randomized phase and post-randomized treatment phase where –
Duration of on-randomized treatment phase (in days) is calculated as –
Date of last study drug intake – randomization date + 1.
Duration of post-randomized treatment phase or off-treatment phase (in days) is calculated 
as –
min(Last date patient is known to be alive, Last visit date before analysis cutoff date) –
Last known date patient took randomized study medication + 1
Hence, overall study exposure duration (follow-up duration) = Duration of on-randomized 
treatment  phase + Duration of post-randomized treatment phase – 1.
Of note, for randomized patients not receiving double-blind randomized study medication, 
overall study exposure duration is calculated as –
min(Last date patient is known to be alive, Last visit date before analysis cutoff date) –
randomization date + 1
The duration of overall study exposure and on-treatment randomized phase are summarized by 
randomized treatment group for all patients in FAS by providing descriptive statistics (n, mean, 
SD, Q1, Q3, median, minimum, maximum).
2.4.2
Prior, concomitant therapies
‘Prior medications’ are defined as drugs taken prior to first dose of double-blind study 
medication. Any medication which has been started during the double-blind treatment epoch 
including medications started prior to randomization but continued in the double-blind 
treatment epoch are identified as ‘Concomitant medications’.
Prior and Concomitant medications will be summarized separately by therapeutic class (by 
ATC code), preferred term, and treatment group for the safety set. Prior and Concomitant non-
drug therapies will be summarized separately by SOC, preferred term, and treatment group for 
the safety set. The number and percentage of patients on following CV background medications 
during double-blind treatment epoch will be tabulated by randomized treatment group –

Aspirin

Antiplatelet agents (excl. Aspirin)

P2Y12 inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors

Other

ARBs

ACE inhibitors

Beta Blockers


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
Mineralocorticoid Receptor Antagonists 

Statins

Diuretics (Loop/non-loop diuretics, summarized by IV/ oral diuretics)

Cardiac glycosides (Digoxin/digitalis glycoside)

Calcium channel blockers

Anticoagulants

Antiarrhythmic agents

Nitrates

Other lipid lowering agents

Anti-diabetic drugs

Insulins

Oral anti-diabetic drugs

Other
Apart from the CV medications listed above, reperfusion therapies used during post-
randomized treatment phase for managing index MI and any other post-randomization  MI will 
be summarized separately in a similar way as in section 2.3.2.1. The summaries of background 
medications and non-drug therapies will be provided for Safety set (SAF) unless otherwise 
specified.
Analysis of dose intensity of RAS blockade during double-blind period
Dose intensity of RAS blockades during double-blind period will be captured in terms of mean 
total daily dose levels of open label ARB/ACEIs/Entresto used after study drug discontinuation.
Mean total daily dose for each study medication is defined by average of different doses for the 
medications (including no or zero dose) weighted by number of days patient is on that dose 
during the specified analysis period. The total daily dose of RAS blockades (high/low) are 
categorized based on the table 2-2 below.
Table 2-2
Definition of high and low RAAS blockade group based on total daily 
dose of commonly used ARB/ACEIs
ARBs
Low RAAS 
blockade 
group
High RAAS 
blockade 
group
ACEIs
Low RAAS 
blockade 
group
High RAAS 
blockade 
group
Azilsartan
<80 mg
≥80 mg
Enalapril
<10 mg
≥10 mg
Candesartan
<16 mg
≥16 mg
Benazepril
<20 mg
≥20 mg
Eprosartan
<400 mg
≥400 mg
Captopril
<100 mg
≥100 mg
Irbesartan
<150 mg
≥150 mg
Cilazapril
<2.5 mg
≥2.5 mg
Losartan
<50 mg
≥50 mg
Delapril
<30 mg
≥30 mg
Olmesartan
<10 mg
≥10 mg
Fosinopril
<20 mg
≥20 mg
Telmisartan
<40 mg
≥40 mg
Imidapril
<10 mg
≥10 mg
Valsartan
<160 mg
≥160 mg
Lisinopril
<10 mg
≥10 mg
Moexipril
<7.5 mg
≥7.5 mg
Perindopril
<4 mg
≥4 mg
Quinapril
<20 mg
≥20 mg


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ARBs
Low RAAS 
blockade 
group
High RAAS 
blockade 
group
ACEIs
Low RAAS 
blockade 
group
High RAAS 
blockade 
group
Ramipril
<5 mg
≥5 mg
Spirapril
<6 mg
≥6 mg
Temocapril
<2 mg
≥2 mg
Trandolapril
<2 mg
≥2 mg
Zofenopril
<30 mg
≥30 mg
For patients taking open-label Entresto, total mean daily dose is categorized into high/low dose 
level according to LCZ696 dose levels 50mg bid (low), 100 mg bid (high), 200 mg bid (high).
The open label ARB/ACEI and open-label Entresto/LCZ696 dose level will be considered to 
determine whether a patient is on high or low dose level of RAS blockade.
Overall mean total daily dose levels of open label ARB/ACEIs/Entresto will be summarized 
for the double-blind period for each treatment group by providing number and percentage of 
patients on high and low dose level during the first 12 months from randomization for the 
following patient populations -

FAS

FAS patients who discontinue study treatment during the first 12 months after 
randomization. 
2.5
Analysis of the primary objective
All patients in the Full Analysis Set (FAS) will be included in the primary analysis.
In the event that the study is stopped early for efficacy at the second interim analysis, or the 
study is terminated early by the sponsor due to prolonged COVID-19 impact, the main, 
supportive and subgroup analyses for the primary endpoint described in this section will be 
performed using the same analysis cut-off date as the second interim analysis to include data 
prior to 01-Mar-2020. 
If the study is not stopped at the second interim analysis and continues to the end, the main, 
supportive and subgroup analyses for the primary endpoint described in this section will be 
performed as planned using all data accrued up to the end-of-study analysis cut-off (31-Dec-
2020).
See Section 2.5.4 for sensitivity and supplementary analyses for the primary endpoint, including 
those added for the COVID-19 impact.
2.5.1
Primary endpoint
The primary efficacy variable is time to first occurrence of a confirmed composite endpoint of 
cardiovascular death, HF hospitalization or outpatient HF. The confirmation of the primary 
composite events will be based on an adjudication process by an independent CEC. 
Note that deaths which cannot be classified by the adjudication committee as CV or non-CV 
death (for example due to lack of information), will be counted as a CV death for the purpose 


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of the primary endpoint. Unless otherwise specified, this is applicable to all efficacy endpoints 
with a CV death component.
Time-to-event is computed as the number of days from randomization to the date of the primary 
endpoint event (first occurrence). A patient without an event will be censored at the last date 
the endpoint status was completely known* or at the time of death from non-CV causes (i.e. 
any death which is confirmed to be a non-CV death by the CEC). 
* This date could include the date of withdrawal of informed consent, date of the patient’s last 
visit prior to the cut-off date of the analysis (whichever occurred first).
2.5.2
Statistical hypothesis, model, and method of analysis
The following null hypothesis versus the alternative will be tested at the 1-sided 2.5% type I 
error rate. 
H0 : λ2/λ1 ≥ 1 (i.e., the hazard rate of the first confirmed primary event in the LCZ696 group 
(λ2) is greater than or equal to the hazard rate in the ramipril group (λ1)) versus
H1 : λ2/λ1 < 1 (i.e. the hazard rate of the first confirmed primary event in the LCZ696 group (λ2)
is less than the hazard rate in the ramipril group (λ1))
λ2/λ1 is called the hazard ratio of LCZ696 relative to ramipril.  
The time-to-first confirmed primary endpoint will be analyzed using a Cox proportional hazards 
model stratified by STEMI/NSTEMI, with treatment, PCI use at baseline and region included 
as factors in the model. This model allows the hazard rates to vary with time while the hazard 
ratio is assumed to be constant, i.e., independent of time, within each stratum. The hazard ratio 
for LCZ696 vs. ramipril, the associated 2-sided 95% confidence interval and the 1-sided and 2-
sided p-values will be presented from the analysis. 
The Kaplan-Meier estimates of the cumulative event rate (1-survival function) for each 
treatment (and strata) will be tabulated and will also be presented graphically.
2.5.3
Handling of missing values/censoring/discontinuations
In general, for a time-to-first event endpoint, the censoring date for a non-fatal endpoint or an 
endpoint with non-fatal event as a component (even if fatal event is also another component) is 
defined as one of the following (whichever occurred first):

Date when the patient withdrew informed consent

Date of the patient’s last visit (including telephone visit)

Date of death 

Analysis cut-off date1
The censoring date for a fatal endpoint (time-to-first event) is defined as one of the following 
(whichever occurred first):

Date when the patient withdrew informed consent

Patient’s last known alive date

Date of death

Analysis cut-off date1


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1 Analysis cut-off date will be 31-Dec-2020 for the primary/main analyses, and 29-Feb-2020 
for analyses using pre-COVID impact data prior to 1-Mar-2020.
Note that every effort will be made to follow all patients until the end of the study, regardless 
of adherence to study treatment. The analysis methods specified are valid under the assumption 
that the censoring mechanism is independent of the event generating process (non-informative 
censoring).
Missing or partially missing event dates will be imputed according to the rules specified in 
Section 5.1.3.
The censoring date for the primary endpoint will be derived using the non-fatal endpoint 
censoring method as described above in this section, with the censoring component date of 
death being that of non-CV death.
The censoring date for the components of the primary endpoint will be derived using the same 
principle for fatal/non-fatal endpoint as described above in this section:

Time-to-first event of HF hospitalization (using censoring method for non-fatal 
endpoint)

Time-to-first event of outpatient HF (using censoring method for non-fatal endpoint)

Time to CV death (using censoring method for fatal endpoint)
2.5.4
Supportive analysis and sensitivity/supplementary analysis
Supportive analysis
The composition of the first confirmed composite primary efficacy endpoint will be 
summarized by treatment group descriptively. The time to reach the first of each individual 
component will be analyzed using the same methodology as the described for the primary 
endpoint. Note that for the components CV death and HF hospitalization, all events observed 
will be included in the individual component analyses and not just those which were counted 
as a ‘first event’ in the primary composite endpoint. In addition to the standard censoring 
mechanism described in Section 2.5.3, for the analysis of time to outpatient HF, patients will 
be censored at the time of HF hospitalization or CV death. For the analysis of time to first HF 
hospitalization, patients will be censored at the time of CV death.
As supportive analyses, the following alternative definitions of the primary endpoint will be 
used with the primary analysis model described in Section 2.5.2: 
(a) Time to first occurrence of an investigator-reported composite endpoint of CV death, HF 
hospitalization or outpatient HF (with and without the analysis cut-off date of 31-Dec-2020); 
(b) Time to first occurrence of a confirmed composite endpoint of all-cause death, HF 
hospitalization or outpatient HF;
(c) Time to first occurrence of a confirmed composite endpoint of CV death (including only 
deaths from CV causes, unknown or missing cause of deaths are not included as events), HF 
hospitalization or outpatient HF. 
Above (a) is the investigator-reported version of the primary endpoint. (b) is the alternative 
definition of the primary endpoint by replacing the CV death component with all-cause death. 


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(c) differs from the primary endpoint in that the CV death is defined as death from CV causes
only, while the primary endpoint includes CV death from unknown causes. For (c), the 
component analysis of CV death will also include deaths from CV causes only, and unknown 
or missing cause of deaths will not be considered as events.
An ‘on-treatment’ analysis (Section 2.1.1) will also be performed for the primary endpoint 
whereby events that occurred more than 28 days after permanent study treatment 
discontinuation will be excluded from the analysis. For patients without events before or at 28 
days after treatment withdrawal, the censoring date will be the minimum of the date of 
permanent study treatment discontinuation + 28 days and the date of standard censoring for the 
endpoint.
The primary analysis will also be repeated for per-protocol set (PPS) for assessing robustness 
of results to significant protocol deviations leading to exclusion from FAS.
Sensitivity and supplementary analyses
1. If the study is stopped early for efficacy at the second interim analysis, or the study is 
terminated early by the sponsor due to prolonged COVID-19 impact, the following 
sensitivity and supplementary analyses will be performed:
(1) As a sensitivity analysis to the above proportional hazards analysis, treatment groups 
will be compared for the primary efficacy variable using a stratified log-rank test 
with STEMI/NSTEMI as a stratification factor, including CEC-confirmed primary 
endpoint events that occurred prior to 01-Mar-2020 (estimated start of COVID-19 
impact globally).
(2) Analysis with adjustment of country instead of region in the primary analysis model 
as specified in Section 2.5.2, using CEC-confirmed primary endpoint events that 
occurred prior to 01-Mar-2020. 
(3) A supplementary analysis using the primary analysis model as specified in Section 
2.5.2, including all CEC-confirmed primary endpoint data accrued up to the end-of-
study analysis cut-off. 
2. If the study is not stopped at the second interim analysis and continues to the end, the 
following sensitivity and supplementary analyses will be performed:
(1) As a sensitivity analysis to the above proportional hazards analysis, treatment groups 
will be compared for the primary efficacy variable using a stratified log-rank test 
with STEMI/NSTEMI as a stratification factor, including all CEC-confirmed 
primary endpoint data accrued up to the end-of-study analysis cut-off. 
(2) Hypothetical estimand approach (see Table 2-4 for the definition of the hypothetical 
estimand in a world without the COVID-19):
The estimand targeted in the original study protocol is defined in Table 2-3. In 
comparison, in a hypothetical world without COVID-19, the new intercurrent event 
due to COVID-19 is the onset of COVID-19 pandemic impact on study (see Table 
2-4), which can be derived by a fixed global COVID-19 impact start date (01-Mar-


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2020) or subject-specific impact start date based on information from the COVID 
CRF pages. A hypothetical strategy (see below methods i and ii) will be used for 
this new intercurrent event. 
The analyses targeting this estimand will be performed with the following censoring 
methods:
i.
Endpoint data will be censored on 29-Feb-2020 if the patient has not 
experienced the endpoint by this time
This analysis will be performed using the primary analysis model as 
specified in Section 2.5.2.
ii.
Endpoint data will be censored at the time of subject-specific COVID-19 
impact start date, derived as the earliest date of the following for each patient 
based on the COVID-19 eCRF: (a1) study treatment discontinuation due to 
COVID-19; (a2) start of treatment interruption for > 3 months due to
COVID-19; (b) first missed visit due to COVID-19; (c) first endpoint event 
impacted by COVID-19; (d) symptom onset of the first occurrence of a 
condition for which the patient felt the need to go to an outpatient clinic, 
urgent care, emergency department, or hospital but chose not to due to 
COVID-19. 
This analysis will be performed using inverse probability of censoring 
weighted (IPCW) Cox proportional hazards model (Robins and Finkelstein 
2000) as described in Section 2.6.5. IPCW is used to account for potential 
informative censoring using the subject-specific censoring method. 
Table 2-3 Estimand in the original protocol :
Intercurrent event
Strategy
Permanent treatment discontinuation
Treatment policy strategy
Non-CV death
Hypothetical strategy
Primary scientific question of interest / Estimand: 
What would be the relative risk reduction (HR) for Entresto vs Ramipril (regardless 
of treatment discontinuation) in patients with LV systolic dysfunction and/or 
pulmonary congestion following an AMI, in the composite primary endpoint, as 
measured by the time to first composite of CV death, HFH and outpatient HF, in the 
absence of death from non-CV related causes?
Table 2-4 Estimand in a world without the COVID-19 pandemic:
Intercurrent event
Strategy
Permanent treatment discontinuation
Treatment policy strategy


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Non-CV death
Hypothetical strategy
Onset of COVID-19 pandemic impact on study
Hypothetical strategy
Primary scientific question of interest / Estimand:
What would be the relative risk reduction (HR) for Entresto vs Ramipril (regardless 
of treatment discontinuation) in patients with LV systolic dysfunction and/or 
pulmonary congestion following an AMI, in the composite primary endpoint, as 
measured by the time to first composite of CV death, HFH and outpatient HF, in the 
absence of COVID-19 pandemic and death from non-CV related causes?
Since the study was designed without a COVID-19 pandemic in mind, both the analysis 
targeting the estimand “in a world without COVID-19 pandemic” and the primary 
analysis based on all data up to the end-of-study analysis cut-off may be interpreted as 
addressing the estimand in the original study protocol, acknowledging that the treatment 
effect estimate based on the latter might be affected by the pandemic.   
(3) Bayesian analysis with robust prior
Let us denote by  = log(#$
% ) the observed log(hazard ratio) based on data 
obtained before the global outbreak of COVID-19, and by &'( = log(#$
% &'() the 
observed log(hazard ratio) based on data obtained after the outbreak. The true 
underlying log(hazard ratio) is denoted by ). We use the normal approximation for the 
log(hazard ratio), and thus, when denoting the number of events by *, *&'(, we 
obtain for the likelihood
| ) ∼- .),
4
*
1
&'(|) ∼.),
4
*&'(
1
Our goal is to leverage the information obtained after the outbreak to inform the 
hazard ratio from the data obtained before the outbreak. However, since the impact of 
COVID-19 on the endpoint is unclear, we aim doing so in a robust way. Therefore, we 
build a prior for ) that fulfills the following two requirements:

In case of similarity of  and &'(, the information obtained after the 
outbreak is, to a substantial extent, taken into account

In case of a conflict between  and &'(, the information obtained after the 
outbreak is down-weighted in a dynamic way
These requirements can be addressed using a robust mixture prior (see e.g. Schmidli et 
al, 2014) consisting of two components:
Component 1: Informative prior distribution 2345()) = -(&'(,
6
4789:), which is the 
posterior distribution of ) given &'(, when starting with an improper prior for )


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Component 2: Vague prior distribution 2;<=>()) = -(&'(, 2@), which is a vague 
(unit-information) prior distribution for )
The robust mixture prior is obtained by mixing these distributions with weights A and 
1 −A, respectively: 
2()) = A ∗2345()) + (1 −A) ∗2;<=>())
Finally, we obtain the posterior distribution 2F)GH through standard Bayesian 
updating. As a fact of mixture calculus, the posterior is a mixture of the component-
wise posteriors, but with updated weights:
2F)|H = AI × 2345F)GH + (1 −AI) × 2;<=>F)GH
where 2KF)|H is the posterior distribution of ) given data  and prior L ∈
{O*P, QRSTU}.
The weights are updated according to the following rule:
AI =
A ∗W
A ∗W + (1 −A) ∗W′
W = ∫2FG)H2345())Z)
W[ = ∫2FG)H2;<=>())Z)
Finally, the weights chosen for the analysis are A = 1 −A = 0.5, i.e. we a priori 
assume there is an equal chance of similarity and conflict between  and &'(. This 
choice is common practice in applications (Dominguez et al, 2017). The point estimate 
and 95% probability interval will be obtained from this posterior distribution as the 
median and 2.5th and 97.5th percentile, respectively. Furthermore, the posterior 
probability that the hazard ratio is favoring LCZ696 (i.e., HR < 1), will be provided.
SAS code for this analysis can be found in Appendix 5.4.
(4) Analysis of all CEC-confirmed primary endpoint data accrued up to the end-of-study 
analysis cut-off, using a Cox model with a “during-COVID” indicator and its 
interaction with treatment as time-varying covariates. 
Consider the following model:
ℎ(`) = ℎ(`)exp(bc × `d` + b@ × e{f(`)} + b × e{f(`)} × `d`),
where e{f(`)} is an indicator of “during-COVID” at patient-time `. e{f(`)} is 
equal to 1 if the patient-time t falls in the COVID-19 impacted period ( on or after 
1-Mar-2020), and is equal to 0 otherwise.
This analysis model will allow the assessment of the treatment effect in non-COVID
impacted periods (before and after the COVID-impacted period, estimated by β1). It 
will also allow to quantify the change in event rate during the COVID-impacted 
period (β2) and the change of the treatment effect during the COVID-impacted 
period (β3), however the number of events and hence precision may be low. In 
addition to including treatment, “during-COVID” indicator, treatment by “during-
COVID” indicator interaction as covariates, this model will also adjust for region 
and PCI use at baseline, and be stratified by type of MI (STEMI/NSTEMI). 


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(5) Weibull regression model stratified by type of MI (STEMI/NSTEMI), with 
treatment, PCI use at baseline and region included as factors in the model, including 
all CEC-confirmed primary endpoint events that occurred prior to 01-Mar-2020. 
Parametric model may be more powerful than the semiparametric primary model.
(6) Analysis with adjustment of country instead of region in the primary analysis model 
as specified in Section 2.5.2, both using all CEC-confirmed primary endpoint data 
accrued up to the end-of-study analysis cut-off and event data with onset date prior 
to 01-Mar-2020. This may recover some of the lost power by accounting for the 
heterogeneity of the COVID-19 impact and also the standard of care among 
countries within regions)
2.5.5
Subgroup analysis
For primary endpoint and its components, subgroup analyses will be performed based on the 
pre-defined subgroups in section 2.2.1 for patients in FAS only. 
Displays of treatment effects by subgroup categories (defined as marginal groupings) will be
provided for descriptive purposes. 
The estimated hazard ratio, and 2-sided 95% confidence interval, will be provided for each 
individual subgroup using a Cox’s proportional hazards model stratified by STEMI/NSTEMI 
with treatment, region and PCI use at baseline as fixed effects factor in the model, with the 
exception for type of MI (STEMI/ NSTEMI) subgroup for which the analysis will not be 
stratified by STEMI/ NSTEMI.
For subgroups other than type of MI (STEMI vs. NSTEMI), the p-value associated with the test 
of treatment-by-subgroup interaction effect will be calculated from a Cox’s proportional 
hazards model, stratified by STEMI/NSTEMI, including treatment, PCI use at baseline, region, 
subgroup, and treatment-by-subgroup as fixed-effect factors. For STEMI vs. NSTEMI, p-value 
for interaction term will be provided from a similar model but STEMI/NSTEMI only included 
as a fixed effect factor and not a stratifying factor.
Since no adjustment for multiple comparisons will be made, findings should be interpreted with 
caution.  Additionally, the frequency and percentage of patients reaching primary composite 
endpoint will be presented by treatment group for each of the subgroups listed in Section 2.2.1.
2.6
Analysis of secondary efficacy objective(s)
The Full Analysis Set (FAS) will be used for all secondary analyses.
The general strategies for the main, sensitivity, and subgroup analyses of the secondary efficacy 
endpoints will be similar to those of the primary efficacy endpoint (see Section 2.5). 
In the event that the study is stopped early for efficacy at the second interim analysis, or the 
study is terminated early by the sponsor due to prolonged COVID-19 impact, the main and 
subgroup analyses for the secondary endpoints described below (Section 2.6.2 and 2.6.6) will 
be performed using the same analysis cut-off date as the second interim analysis to include data 
prior to 01-Mar-2020. 


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If the study is not stopped at the second interim analysis and continues to the end, the main and 
subgroup analyses for the secondary endpoints described in this section will be performed as 
planned using all data accrued up to the end-of-study analysis cut-off (31-Dec-2020).
See Section 2.6.5 for sensitivity analyses added for the COVID-19 impact. 
2.6.1
Secondary endpoints
The secondary variables are as follows-
(1) Time from randomization to first occurrence of a confirmed composite of CV death or HF 
hospitalization
(2) Time from randomization to first occurrence of a confirmed composite of HF 
hospitalization or outpatient HF
(3) Time from randomization to first occurrence of a confirmed composite of CV death, non-
fatal spontaneous MI or non-fatal stroke

Non-fatal spontaneous MI is defined as either Type 1 or Type 2 MI confirmed by 
the independent Clinical Event Committee
(4) The cumulative number of composite events, including hospitalizations due to HF, 
hospitalizations due to non-fatal spontaneous MI, hospitalizations due to non-fatal stroke and 
CV death. 
(5) Time from randomization to all-cause mortality
Censoring of secondary endpoints
For time-to-first event endpoints, the general rules of the censoring methods in Section 2.5.3 
will be followed.
For a time-to-recurrent event endpoint, the censoring date is defined as one of the following 
(whichever occurred first):

Date when the patient withdrew informed consent

Date of the patient’s last visit (including telephone visit)

Date of death

Analysis cut-off date1
1 Analysis cut-off date will be 29-Feb-2020 for analyses using pre-COVID impact data prior to 
1-Mar-2020.
The event generating process for the secondary endpoints will be censored following the 
mechanism below-

Endpoints (1), (2) and (3) will be censored following a similar censoring mechanism 
followed for a non-fatal endpoint (Section 2.5.3). 

Event generating process for endpoint (4) will be censored following the censoring 
mechanism for a recurrent time-to-event endpoint as summarized above in this section.

Endpoint (5) will be censored following the fatal endpoint censoring method (Section 
2.5.3). For all-cause death, this means censoring at the earlier of 

date when the patient withdrew informed consent

Patient’s last known alive date


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
Analysis cut-off date1
2.6.2
Statistical hypothesis, model, and method of analysis
The secondary endpoints will be analyzed in order to compare LCZ696 vs ramipril using the 
ITT approach (i.e. estimation of the treatment effect under the ‘treatment policy’).
Analysis of time to event variables
The time to event endpoints (1), (2), (3), (5) will be analyzed using the same statistical analysis 
methods as specified for the primary analysis. Treatment groups will be descriptively compared 
by presenting number and percentage of patients with events while inferential comparisons 
between treatment groups will be provided based on estimated hazard ratio and 95% CI. Both 
1-sided and 2-sided p-values will be reported for treatment group comparison (LCZ696 vs. 
ramipril). Kaplan-Meier estimates of event rates will be tabulated for specific time points and 
will also be presented graphically.
Analysis of count variable
Secondary endpoint (4) will be analyzed using a negative binomial regression model with a 
Weibull baseline intensity function to allow flexibility if the baseline intensity is non-constant 
(Lawless, 1987). The regression model will consider the number of composite events as 
dependent variable with randomized treatment, STEMI/NSTEMI, PCI use at baseline and 
region as factors having fixed effects. Every event jump time, including the terminal event time, 
will be used to estimate the parameters specified in this model. For treatment group comparison 
LCZ696 vs ramipril, the relative rate ratio will be presented together with 2-sided 95% 
confidence interval and 1-sided and 2-sided p-values from the fitted model.
For descriptive summary, unadjusted annualized incidence rate will be provided along with the 
model-based estimates and their 95% confidence intervals will be presented by treatment 
groups. Also, adjusted event rate functions over time will be graphically presented from the 
estimated Weibull intensity.
2.6.3
Control of familywise type I error rate
The primary endpoint and the first four secondary efficacy endpoints will be included in a 
statistical testing strategy to control the familywise type I error rate at the 1-sided 2.5% level 
(in the strong sense). A hierarchical testing procedure will be employed whereby the primary 
hypothesis will be tested first, if rejected then the hypothesis associated with the first secondary 
endpoint will be tested and so on.  The order of testing of the composite endpoints will be as 
follows:
1. Primary endpoint
2. Time to first CV death or HF hospitalization
3. Time to first HF hospitalization or outpatient HF
4. Time to first CV death,  non-fatal spontaneous MI or non-fatal stroke
5. The total number of composite events (hospitalizations (including CV death) due to HF, 
non-fatal spontaneous MI or non-fatal stroke and CV death).


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Note: Time to CV death, time to first HF hospitalization, and time to first outpatient HF (as 
components of the primary composite endpoint) will not be part of the above-mentioned 
hierarchical testing procedure. 
2.6.4
Handling of missing values/censoring/discontinuations
For each patient, the information on secondary endpoints censoring will be censored as defined 
earlier. The primary analysis methods are valid under the assumption that the censoring 
mechanism is independent of the event generating process (non-informative censoring). 
Sensitivity analyses have been proposed to assess robustness of the results to the potential 
violation of this assumption, wherever applicable.
2.6.5
Supportive analysis and sensitivity analysis
Supportive analysis
It is recognized that at the time of the first onset of symptomatic HF event some patients may 
discontinue randomized treatment and may be prescribed an alternative treatment for HF which 
could be locally available EntrestoTM (sacubitril/valsartan, LCZ696). For the pre-specified
secondary endpoints (1), (3) and (5) (numbering refers to Section 2.6.1), the analysis described 
in Section 2.6.2 will estimate the treatment effect of LCZ696 vs ramipril including any effect 
of prescribed Entresto™ for ramipril patients who discontinued study drug and took Entresto™ 
as an alternative treatment. Hence, the following supportive analyses aim to estimate the pure 
treatment effect as though in a situation whereby Entresto™ was not an available treatment 
option for HFrEF. In this regard, as a sensitivity analysis, inverse probability of censoring 
weighted (IPCW) Cox proportional hazards model (Robins and Finkelstein 2000) will be 
performed on the secondary endpoints (1), (3) and (5).
Inverse probability of censoring weighted (IPCW) Cox proportional hazards 
model
In the IPCW analysis, the following censoring mechanism will be used for the event generating 
process for secondary endpoints:

For patients randomized to LCZ696 and patients randomized to ramipril but did not take 
open label Entresto upon diagnosis of HFrEF event will be censored according to the 
mechanism described for the secondary endpoints.

For patients randomized to ramipril who subsequently start taking open label Entresto, 
(defined as treatment switch), censoring will occur at the minimum of the last date the 
endpoint status was known, the time of death from non-CV causes, 28 days after study 
treatment discontinuation or start of open-label Entresto.
To adjust for the potential informative censoring, patients in the ramipril arm with event times 
censored due to treatment switch will be dynamically replaced in the patient risk-set by 
remaining uncensored patients in the ramipril arm with a matching prognostic profile by up-
weighting such patients in the analysis set. At a specific time, patients in the ramipril arm who 
have not switched to taking open label Entresto will be assigned a weight inversely proportional 
to the probability of not switching till that time (i.e., patients who do not switch, but have 
covariates implying a high probability of switching, get a larger weight in the analysis). 


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Estimating IPC weights
In order to predict these patient specific time-varying probabilities, the time scale is split into 
small intervals based on the visit schedules. In each interval the conditional probability of being 
switched given patient has not switched at any earlier interval is modelled using a logistic 
regression model with the following covariates–

Time independent (baseline) covariates:
Age (in years), baseline LVEF, baseline eGFR (ml/min/1.73m2), history of prior MI (yes/ 
no), history of diabetes (yes/ no), Atrial Fibrillation associated with qualifying MI (yes/ 
no), baseline Killip class, use of PCI for qualifying MI (yes/ no), use of ACEI/ARB in last 
24 hours prior to randomization (yes/ no), use of IV treatment for qualifying MI (yes/ no)

Time dependent covariates:
Systolic BP (mmHg), Heart rate (bpm), eGFR (ml/min/1.73m2), *use of PCI or CABG 
(yes/ no), *use of ICD/CRT (yes / no)
(*procedures related to any post-randomization MI event)
Predicted probability of switching at a specific time for a patient will be obtained by multiplying 
individual conditional probabilities of switching in intervals prior to that time point. To 
minimize impact of extreme weights (e.g. patients not switched though having very high 
estimated probability to switch), the stabilized version of weights will be used which is defined 
as the ratio of predicted probabilities of not being switched by time t –

from the logistic regression with only baseline covariates

from the logistic regression with both baseline and post-baseline covariates
It is conceivable that the above logistic regression procedure of estimating weights may not 
converge due to reasons including (but not limited to) sparseness of switchers in the 
subpopulations implied by the selected covariates resulting into an infinite likelihood due to 
complete or quasi-complete separation or numerical difficulties in evaluating an overly complex 
likelihood function. Should such problems arise, the logistic regression model used to determine 
the IPC weights will be simplified by pooling pre-specified time intervals (thereby extending 
the time windows in which time-dependent covariates are assessed). If that still does not solve 
convergence problems, the model will be simplified by removing covariates.
All patients randomized to LCZ696 will be assigned a weight of 1 for all time intervals.
Estimation of treatment effect
Following the estimation of weights, a weighted Cox proportional hazard model will be fitted 
to the time to event endpoints (1), (3) and (5). The model will be stratified by STEMI/NSTEMI 
while treatment, region, PCI use at baseline will be included as fixed effects factors. The hazard 
ratio for LCZ696 vs. ramipril, the associated 2-sided 95% confidence interval and the 1-sided 
and 2-sided p-values will be presented from the analysis.
On-treatment analysis
Endpoint (4), the total number of confirmed hospitalizations for HF, MI and stroke (including 
CV death) will be redefined for the patients who are prescribed open label Entresto™ as the 


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total number of composite endpoints from randomization up to 28 days after the time of study 
treatment discontinuation. The analysis methods will remain the same as specified above.
Sensitivity analysis
If the study is stopped early for efficacy at the second interim analysis, or the study is terminated 
early by the sponsor due to prolonged COVID-19 impact, a sensitivity analysis using the 
primary/main analysis model as specified in Section 2.6.2 will be performed for each secondary 
endpoint, including all data accrued up to the end-of-study analysis cut-off. 
If the study is not stopped at the second interim analysis and continues to the end, a sensitivity 
analysis using the primary/main analysis model as specified in Section 2.6.2 will be performed 
for each secondary endpoint, including data accrued prior to 01-Mar-2020.
2.6.6
Subgroup analysis
Subgroup analysis for the secondary endpoints (1), (2), (3) and (5) will also be performed 
similarly as described in Section 2.5.5 for the primary endpoint based on pre-defined subgroups 
(Section 2.2.1).
For secondary endpoint (4), subgroup analysis will be performed following a similar modeling 
as used for primary analysis of this endpoint (Section 2.6.2). Specifically, a negative binomial 
regression with Weibull baseline intensity function will be fitted within each subgroup with 
randomized treatment, STEMI/NSTEMI, PCI use at baseline and region as factors having fixed 
effects. P-value for treatment-subgroup interaction will be reported based on the same model 
but including factors for subgroup and treatment-subgroup interaction fitted to the overall 
population. Additionally, for descriptive purposes, exposure adjusted incidence rate and 95% 
CI for the secondary events will be reported by treatment group for each subgroup.
All the subgroup analyses for secondary endpoints will be performed for patients in FAS only.
2.7
Safety analyses
All safety analyses will be carried out for the Safety set (SAF).  
2.7.1
Adverse events (AEs)
The following safety data will be collected and reported in this study for the double-blind period:

all adverse events,

all serious adverse events,

adverse events of special interest (angioedema, hyperkalemia, hypotension, renal 
impairment, cognitive impairment, hepatotoxicity, statin drug-drug interaction , 
hypersensitivity, anaphylaxis, malignancy, embryo-fetal toxicity/lethality and 
neonatal/infantile toxicity through exposure from breast milk)

adverse events leading to a change in dose (down titration), interruption or 
discontinuation of study drugs

AEs occurred in the specific treatment phases are described in Table 2-5. AEs/ SAEs 
occurred during screening and double blind period will be summarized.


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Table 2-5
Allocation of AEs
Screening 
epoch 
(V1-V101)
Double-blind treatment 
epoch
Phase AE to be reported in
Randomization 
- EOT (V101-
EOT)
EOT – EOS 
(EOT-
V199)
X
Reported by site from informed consent
X
Report AE in double-blind period
X
X2
Report as two separate AEs:
One with onset date X (X) during screening 
epoch and one with onset date X2 for DB
X, X2
Report as one AE: 
One with onset date X during DB
X
Report AE in post-EOT phase
X, X2
Report as one AE: 
One with onset date X after EOT
X
X2
Report as one AE in summaries for double-blind
treatment epoch. 
For other summaries, report as two separate 
AEs; One with onset date X before EOT and 
one with onset date X2 during post-EOT
X indicates onset date of an AE.
X2 stands for the same AE but with increased severity
The number (and proportion) of patients with treatment emergent adverse events (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 in the following ways:

by treatment, primary System Organ Class (SOC) and Preferred Term (PT).

by treatment, primary System Organ Class (SOC), Preferred Term (PT) and maximum 
severity.

by treatment, Standardized MedDRA Query (SMQ) and Preferred Term (PT)
AEs will be summarized according to the Medical Dictionary for Regulatory Activities 
(MedDRA). The MedDRA version used for reporting will be described in the footnote.
Within each reporting phase (Table 2-5), the following rules are applicable. 

If a subject reported more than one adverse event with the same preferred term, the 
adverse event with the maximum severity will be presented. 

If a subject reported more than one adverse event within the same primary system organ 
class, the subject will be counted only once with the maximum severity at the system 
organ class level, where applicable. 


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
Statistical analyses performed for the double-blind period will include all post-
randomization AEs up to the end of double-blind period irrespective of whether patient 
was on or off study drug.
The most common adverse events reported (≥ 2 % in any group for each preferred term in the 
SOC-PT table) will be presented in descending frequency according to its incidence in the 
LCZ696 group starting from the most common event. Summaries for the double-blind period
will be provided for study medication related adverse events, death, serious adverse event, other 
significant adverse events leading to study discontinuation and adverse events leading to dose 
adjustment / interruption.
COVID-19 infections will be collected as AEs. 
For each reporting period, incidence of AEs will also be listed at a patient level by randomized 
treatment group including outcome, severity and action taken with the AE. 
2.7.1.1
Adverse events of special interest / grouping of AEs
Specific AEs of interest will be summarized separately in addition to the above analysis. These 
specific AEs of interest are: angioedema (AAC adjudicated), hyperkalemia, hypotension, renal 
impairment, cognitive impairment, hepatotoxicity, statin drug-drug interaction, anaphylaxis, 
hypersensitivity, malignancy, embryo-fetal toxicity/lethality and neonatal/infantile toxicity 
through exposure from breast milk. Besides providing the crude percentages, annualized 
exposure adjusted incidence rates will also be provided by treatment group.
The search paths for the related preferred terms (PTs), high level group term (HLGT), high 
level term (HLT), in Standard Medical Queries (SMQs), or NMQ in MedDRA for these risks 
are stored (or alternatively "summarized") in the latest version of LCZ696 Case Retrieval 
Strategy.
In addition to above standard analyses, for double blind phase, analysis for time-to-first selected 
AEs by treatment group will be performed using Kaplan-Meier estimate. The annualized 
exposure duration adjusted event rates will also be provided. 
2.7.2
Deaths
Patients experiencing deaths during the study period will be reported separately for screening 
epoch and double-blind treatment epoch. Deaths occurring during double-blind treatment epoch 
will be summarized by actually received treatment group to present number and percentage of 
patients died by overall and adjudicated reason categories (CV/ non-CV). Separate listings will 
be provided for patients died during the study period with primary reason of death as confirmed 
by adjudication committee.
2.7.3
Laboratory data
Each laboratory parameter, evaluations will be summarized by visit and actually received 
treatment group by presenting summaries (n, mean, standard deviation, median, minimum and 
maximum) for actual and change from baseline values. The summary will be provided 
separately for biochemistry and hematology laboratory parameters. Central laboratory data will 
be used for the summaries.


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Shift tables based on the standard ranges for each laboratory parameters will be provided by 
treatment group at each visit to present incidence of transitions from a baseline high, normal or 
low laboratory value to a post-baseline high, normal or low value. 
The number and percentage of patients with clinically notable laboratory results after baseline 
will be presented in accordance with Table 2-6. 
Table 2-6
Clinically notable laboratory values and vital signs
Hematology
Hematocrit
>50% increase, >20% decrease
Hemoglobin
>50% increase, >20% decrease
Platelet count
>75% increase, >50% decrease
RBC Count
>50% increase, >20% decrease
WBC count
>50% increase, >50% decrease
Blood chemistry
Alkaline phosphatase
>100% increase 
ALT (SGPT)
>150% increase
AST (SGOT)
>150% increase 
BUN
>50% increase 
Calcium
>10% increase, >10% decrease 
Chloride
>10% increase, >10% decrease 
Creatinine
>50% increase 
Potassium
>20% increase, >20% decrease 
Total bilirubin
>100% increase 
Uric acid
>50% increase
Patients with liver enzymes (ALT/AST and CPK) falling within predefined categories of 
elevations and persistent elevations will be summarized by treatment group in accordance with 
the Table 2-7 for the double-blind period.
Descriptive summaries will be provided by presenting count and percentage of patients with 
each type of Liver event in addition to graphical summaries, as applicable.
Table 2-7
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 


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
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
2.7.4
Other safety data
2.7.4.1
Vital signs
Sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP) and Sitting pulse 
pressure (PP) will be descriptively summarized by presenting summaries (n, mean, standard 
deviation, median, minimum, maximum) of actual value and change from baseline values for 
each scheduled assessment visit and treatment group. 
The number and percentage of patients with clinically notable vital signs changes from baseline 
will be presented. Clinically notable vital sign results are provided in Table 2-8 below.
Table 2-8
Clinically notable changes in vital signs
Vital Sign (unit)
Clinically notable criteria
Weight (kg)
decrease > 7% from Baseline
increase > 7% from Baseline
Sitting systolic blood pressure (mmHg)
<=90 and decrease from baseline >=20
>=180 and increase from baseline >=20
Sitting diastolic blood pressure (mmHg)
<=50 and decrease from baseline >=15
>=105 and increase from baseline >=15
Pulse (bpm)
<=50 and decrease from baseline >=15
>=120 and increase from baseline >=15
2.8
Pharmacokinetic endpoints  
Not applicable
2.9
PD and PK/PD analyses
Not applicable
 
 
 


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2.14
Interim analysis
One interim analysis for efficacy was initially planned. The cut-off time for the first interim 
analysis was planned to be when about two-thirds of the target number of 708 primary events 
were reported and adjudication-confirmed. Approximately 472 of adjudication-confirmed 
primary events (i.e., first CV deaths, HF hospitalizations, or outpatient HF events) were planned; 
464 adjudication-confirmed primary events were included. In the first interim analysis, the 
analysis dataset was comprised of all patients who were randomized before the cutoff date. 
A second interim analysis for efficacy will be added in response to the potential impact from 
the COVID-19 pandemic, allowing the study to stop for overwhelming efficacy for the primary 
endpoint at one-sided alpha of 0.005. The second efficacy interim analysis will include all 
patients randomized prior to 01-Mar-2020 and all primary endpoint events that occurred prior 
to 01-Mar-2020, approximately 80% of the target 708 total primary endpoint events in the 
PARADISE-MI study. The data collected prior to 01-Mar-2020 are generally considered not 
impacted by the COVID-19 pandemic at the global level.  Accordingly, patients who do not 
have a primary endpoint event prior to 01-Mar-2020 will be included in the second IA as 
censored.
Generalized Haybittle-Peto boundaries will be adopted for the interim statistical comparisons 
between treatments. An alpha of 0.001 (1-sided) was spent at the first interim analysis, and an 
alpha corresponding to the nominal level of 0.005 (1-sided) will be spent at the second interim 
analysis for the comparison of the primary endpoint. The rest of alpha (resulting in a nominal 
1-sided 0.0244, with the currently specified target number of primary events of 708 and the 
planned addition of a second interim analysis to include 80% of the target 708 primary events, 
based on East version 6.4) will be utilized at the final analysis. The alpha to be spent for the 
final analysis will be updated according to the actual number of primary events included in the 
second IA and final analysis in case of deviation from the current specification. In the first 
interim analysis, as designed, the study could be stopped for superior efficacy only when both 
the primary endpoint and CV death were significant at an alpha level of 0.001 (1-sided).  In the 
second interim analysis, the study may be stopped for superior efficacy when the primary 
endpoint is significant at the alpha level of 0.005 (1-sided).


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If the study is stopped early for superior efficacy at the interim analysis, the secondary endpoints 
will be tested using the same hierarchical testing procedure as described in Section 2.6.3 for the 
same level of alpha (i.e. 1-sided alpha of 0.001 if stopped at the first interim analysis, or of 
0.005 if stopped at the second interim analysis).  If the study continues, then secondary 
endpoints will be tested at the final analysis using the same 1-sided alpha as the primary 
endpoint (i.e., 1-sided alpha of 0.0244, which may be updated according to the actual number 
of primary events included in the second IA and final analysis in case of deviation from the 
current specification).
In the event that the COVID-19 pandemic continues over a prolonged period of time, the 
sponsor may consider terminating the study early without performing the second interim 
analysis. In this case, the final analysis will include all primary endpoint events with onset date 
prior to 01-Mar-2020. The remaining alpha to be spent at the final analysis will be calculated 
based on the number of primary events included in the final analysis using the generalized 
Haybittle-Peto boundaries, and will be specified in the SAP prior to database lock. 
Interim analyses are also planned for the monitoring of safety data, and will be performed 
approximately every 6 months during the course of the study. Such safety analyses do not inflate 
the type I error for the primary efficacy hypothesis testing and thus no adjustment for 
multiplicity is required.  
Interim analyses will be performed by an independent statistician (at a CRO or academic 
institution) who will not be involved in the trial conduct. The results will be reviewed by an 
independent DMC. The trial investigators, Novartis employees and other personnel who are 
involved in the conduct of the trial and in the analysis of the final trial results, or who have 
contact with study centers, will remain blinded to the treatment codes and interim analysis 
results until all monitoring decisions have been made and the database has been locked for final 
analysis. Full details of the interim analysis plan will be described in the DMC charter.
3
Sample size calculation
The sample size and power calculations described in the entire Section 3 are based on the study 
design prior to the protocol amendment 4 when only one efficacy interim analysis had been 
planned. With the planned addition of a second efficacy interim analysis to include 80% of the 
target 708 primary events (see Section 2.14), there will be a small impact on power for the 
primary endpoint (approximately 0.1% power loss for the primary endpoint with a second 
interim analysis, compared to 80% power with only one planned interim analysis). 
The study was initially planned to randomize 4,650 patients to LCZ696:ramipril with a 1:1 
allocation ratio, with the aim to obtain at least 800 primary endpoint events and at least 633 first 
CV death or HF hospitalization events. See details in Section 3.1. 
Following the planned sample size re-estimation using blinded data, the study has been re-
designed to randomize 5,650 patient to LCZ696:ramipril with a 1:1 allocation ratio. This aims 
to obtain at least 708 confirmed first primary endpoint events and at least 592 first confirmed 
CV death or HF hospitalization events in this event-driven study. Seven hundred eight primary
endpoint events will provide 80% power assuming a true Relative Risk Reduction (RRR) of 19% 
(i.e. a hazard ratio of 0.81) for LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-
sided type I error rate (with strong control of the Family Wise error rate (FWER)). Five hundred 


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ninety two first CV death or HF hospitalization events will provide 77.5% nominal power 
assuming a true RRR of 20% (for the ITT analysis) for this double composite endpoint for the 
same type I error rate. See details in Section 3.2.
3.1
Original sample size planning
A sample size of 4,650 patients, randomized to LCZ696:ramipril using a 1:1 allocation ratio, 
has been chosen with the aim to obtain at least 800 first primary events and at least 633 CV 
death or HF hospitalization events in this event-driven study.  Eight hundred primary events 
provide at least 80% power assuming a true Relative Risk Reduction (RRR) of 18% (i.e. a 
hazard ratio of 0.82) for LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-sided 
type I error rate (with strong control of the FWER).  Six hundred and thirty three CV death or 
first HF hospitalization events will provide at least 80% nominal power assuming a true RRR 
of 20% (for the intent-to-treat analysis) for the secondary endpoint for the same type I error rate.
Additional assumptions are described below.

0.5% per year lost to follow-up rate

Recruitment duration of 24 months, with approximately 8 months follow-up anticipated 
for last randomized patient (i.e. 32 months total study duration) and constant recruitment 
rate

One interim analysis is planned to allow for stopping for efficacy, using a Haybittle-Peto 
boundary, thus 2.49% 1-sided alpha will be available for the final analysis (Section 2.14).

Cumulative event rates of CV death or HF hospitalization were estimated from selected 
patients from the VALIANT database (Pfeffer et al, 2003) who were considered to be 
representative of the target patient population of this study.  In the calculation, adjustments 
were made for expected differences between the sample of patients from VALIANT and 
the patients likely to be recruited in PARADISE-MI. In particular PCI use is expected to 
increase (2/3 PCI use vs. 1/3 in VALIANT), and a larger number of NSTEMI patients are 
expected (60% NSTEMI patients vs. approximately 30% in VALIANT). Following these 
adjustments, a further 10% reduction in hazard rate for other changes in standard of care 
was also included. The cumulative event rates for the primary endpoint were based on a 
further 15% increase in hazard rate in order to account for the third component of 
outpatient HF (refer to Table 3-1 for the cumulative event rates assumed for the sample 
size calculation.
Table 3-1
Cumulative event rates assumed for the sample size calculation
Time period following 
randomization
CV death or HF 
hospitalization
CV death, HF hospitalization or outpatient HF
(assuming 15% increase in hazard rate compared 
to CV death or HF hospitalization)
0-3 months
9.9%
11.3%
3-6 months
12.3%
14.0%
6-12 months
14.8%
16.8%
12-32 months
19.4%
21.9%
The sample size calculations were carried out using PASS 2008, citation software and applying 
the Lakatos method (Lakatos, 1988) and confirmed using East version 6.3.


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Sample size sensitivity
This is an event driven study and the assumption about the event rates for the primary endpoint 
is a key driver for the sample size calculation. In this regard there are two main areas of 
uncertainty:

The hazard rates calculated from the post-hoc analysis of VALIANT data as described 
above are thought to reflect the contemporary setting, however, there may have been other 
changes over time which are difficult to quantify and may decrease the event rates, hence 
for the final sample size calculation an additional 10% discount of the hazard rate was 
assumed.   

The hazard rates for the primary endpoint were calculated as 1.15 x the hazard rate for the 
secondary endpoint of CV death or HF hospitalization (i.e. assuming a 15% increase in 
hazard will be observed when adjudicated outpatient HF is included in the composite 
endpoint together with CV death and HF hospitalization). However, there is no adequate 
information available about the expected event rates of the primary triple composite 
endpoint.
In order to understand the impact of the uncertainties described above, Table 3-2 provides the 
sample sizes estimated to achieve at least 800 primary events with different underlying 
assumptions.
Table 3-2
Total sample size required to achieve 800 primary events for different 
event rate assumptions
Increase in hazard 
rate when outpatient 
HF is included in 
primary composite 
endpoint
Discount of event rates for change in SoC
0%↓
10%↓*
20%↓
20%↑
4066
4468
4968
15%↑*
4224
4643
5167
10%↑
4395
4834
5382
* Assumptions used for protocol specified study design
Number of randomized patients required calculated using East version 6.3
Power for secondary endpoints
Table 3-3 summarizes the nominal power for secondary endpoints which will be included in 
the statistical testing strategy. A 1-sided alpha of 2.5% has been used for the calculations.  All 
assumptions are based on exploratory analyses performed using VALIANT data (data on file).
Table 3-3
Summary of power to reject secondary hypotheses 
Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(1) Time to first CV death or 
HF hospitalization
20% RRR
Expect 698 
events1
84%


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Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(2) Time to first HF 
hospitalization or outpatient 
HF
17% RRR
Expect 536 
events2
58%
(3) Time to first composite of 
CV death, non-fatal MI or 
non-fatal stroke
15% RRR
Expect 680 
events3
56%
(4) Total number of 
hospitalizations for HF, MI 
and stroke related reasons 
including CV death
17% reduction in rate 
ratio
Over-dispersion=9;
Rate of events on 
ramipril per year = 
0.2364
46%
1Event rates as per Table 3-1
2 Cumulative event rates for HF hospitalization of 6.5%, 8.2%, 9.9% and 12.8% were assumed for 0-3m, 3-6m, 
6-12m and 12-32m periods respectively. Then event rates were increased by a further 15% to account for 
outpatient HF.
3 Cumulative event rates of 8.5%, 10.9%, 14.0% and 18.6% were assumed
4 For the power calculation the rate was assumed to be constant over time 
The number of events were calculated for a sample size of 4,650 patients; 24 months recruitment and 8 
months minimum follow-up. 
HF = Heart Failure; RRR = Relative Risk Reduction
The power calculations were carried out using East Version 6.3.
Blinded sample size re-estimation
When approximately 1/2 of patients have been randomized and have reached the 3 month time 
point, the piecewise hazard rates for the primary endpoint and the double composite endpoint 
(CV death or HF hospitalization) will be estimated based on blinded data.  
The piecewise hazard rates estimated from the observed data will be compared to the original 
assumptions. If there is reason to believe that the original assumptions about event rates may 
not hold, the sample size will be re-estimated taking into consideration the new information. 
The duration of the trial and minimum follow-up will also be reconsidered as part of the 
calculation. This approach will allow flexibility to achieve the required number of events in an 
acceptable time frame.
3.2
Blinded sample size re-estimation
Sample size re-estimation was planned and performed when approximately 1/2 of patients had 
been randomized and had reached the 3 month time point. The cumulative event rates and the 
corresponding piecewise hazard rates for the primary endpoint (first CV death, HF 
hospitalization or outpatient HF event) and the double composite endpoint (first CV death or 
HF hospitalization event) were estimated based on blinded data according to the plan. The 
estimated cumulative event rates based on the available blinded data were sizably lower than 
the originally assumed event rates for both the primary endpoint and the double composite 
endpoint (see Table 3-4 and Table 3-5 for the comparisons), which indicates that the original 
assumptions about the event rates may not hold. Therefore, in order to limit the impact in terms 


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of a considerable increase in overall trial duration, sample size re-estimation was performed, 
taking into consideration the new information. The minimum follow-up was also reconsidered 
in the calculation.  
There are two points to be considered in the sample size re-estimation: the estimated lower 
event rates and a potentially higher hazard reduction in the primary endpoint. As shown in Table 
3-4 and Table 3-5, the estimated event rates using blinded data are lower than the originally 
assumed event rates, for both the primary endpoint (see Table 3-4) and the double composite 
endpoint (see Table 3-5). An RRR of 19% is assumed for the primary endpoint in place of the 
original RRR of 18%. This change is based on the newly available efficacy data from the 
PIONEER-HF (CLCZ696BUS01) study in hospitalized patients with stabilized acute 
decompensated heart failure, which showed a 46% relative risk reduction (HR 0.54, 95% CI 
0.37, 0.79) in patients treated with sacubitril/valsartan for 8 weeks compared to enalapril for an 
exploratory composite of serious clinical endpoint of death, rehospitalization for heart failure, 
implantation of a left ventricular assist device, and inclusion on the list of patients eligible for 
heart transplantation (Velazquez, et al. 2019). The observed risk reduction on the composite 
endpoint from the PIONEER-HF study was primarily driven by rehospitalization. Given a 
similar underlined pathophysiological mechanism between HFrEF and post-AMI with left 
ventricular dysfunction, and also acute setting for both PIONEER-HF and PARADISE-MI 
studies, this new data indicated that the effect size may have previously been underestimated. 
Following the blinded sample size re-estimation, a sample size of 5,650 patients, randomized 
to LCZ696:ramipril using a 1:1 allocation ratio, has been chosen with the aim to obtain at least 
708 first primary endpoint events and at least 592 first CV death or HF hospitalization events 
in this event-driven study. Seven hundred eight primary endpoint events will provide 80% 
power assuming a true Relative Risk Reduction (RRR) of 19% (i.e. a hazard ratio of 0.81) for 
LCZ696 vs ramipril with statistical testing at the overall 2.5% 1-sided type I error rate (with 
strong control of the FWER).  Five hundred ninety two first CV death or HF hospitalization 
events will provide 77.5% nominal power assuming a true RRR of 20% (for the ITT analysis) 
for this double composite endpoint for the same type I error rate.
Additional assumptions are described below.

0.5% per year lost to follow-up rate (same as the original protocol assumption)

Recruitment duration of 37 months, and approximately 4 months follow-up for the last 
randomized patient are assumed (i.e., approximately 41 months for endpoint accrual). 
Constant recruitment rates are assumed in each of the following time period based on the 
observed PARADISE-MI study data and projection: (1) 0 to 10 months, with a total of 
463 patients randomized by month 10; (2) 10 to 24 months, with approximately a total of 
2400 patients randomized by month 24; (3) 24 to 37 months, with 250 patients 
randomized each month. 

One interim analysis is planned to allow for stopping for efficacy, using a Haybittle-Peto 
boundary, thus 2.49% 1-sided alpha will be available for the final analysis, see 
Section 2.14.

Cumulative event rates for the primary composite endpoint at 3, 6, 12, and 18 months 
were derived based on Kaplan-Meier estimates using blinded data from all randomized 
patients in the PARADISE-MI study at the time of sample size re-estimation. Constant 


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piecewise hazard rates were then derived accordingly for the following time periods: 0 to 
3 months, 3 to 6 months, 6 to 12 months, and 12 to 41 months. The hazard rate for the 
time period of 12 to 41 months was derived through extrapolation of the 18 months 
cumulative event rate assuming a constant hazard rate during this time period. See Table 
3-4 for the cumulative event rates (pooled) based on the originally assumed event rates 
from Table 3-1, as well as the estimated event rates from the blinded sample size re-
estimation. 
Table 3-4
Cumulative event rates (pooled) for the primary endpoint (first CV 
death, HF hospitalization or outpatient HF event)
Time from 
randomization
Cumulative event rate 
(original assumption)2
Cumulative event rate 
(estimated using blinded data) 
3 months
10.3%
7.2%
6 months
12.8%
8.6%
12 months
15.4%
11.0%
32 months1
20.1%
17.5%
1 32 months event rates were derived through extrapolation of the 18 months cumulative event rates, 
assuming constant monthly hazard rates from 12 to 32 months. The 18 months cumulative event rate 
was estimated to be 13.0% for the primary endpoint (first CV death, HF hospitalization or outpatient 
HF event).
2 Cumulative event rates (pooled) were derived according to the original assumption of the control 
group rates in Table 3-1.
Table 3-5
Cumulative event rates (pooled) for the double composite endpoint 
(first CV death or HF hospitalization event)
Time from 
randomization
Cumulative event rate 
(original assumption)2
Cumulative event rate 
(estimated using blinded data)
3 months
9.0%
6.0%
6 months
11.1%
7.5%
12 months
13.4%
9.6%
32 months1
17.6%
13.9%
1 32 months event rates were derived through extrapolation of the 18 months cumulative event rates, 
assuming constant monthly hazard rates from 12 to 32 months. The 18 months cumulative event rate 
was estimated to be 10.9% for the double composite endpoint (first CV death or HF hospitalization 
event).
2 Cumulative event rates (pooled) were derived according to the original assumption of the control 
group rates from Table 3-1.
The sample size calculations were carried out using East version 6.4.
Power for secondary endpoints
Table 3-6 summarizes the nominal power for secondary endpoints which will be included in 
the statistical testing strategy. A 1-sided alpha of 2.5% has been used for the calculations.  All 
assumptions are based on the sample size re-estimation using blinded data.


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Table 3-6
Summary of power to reject secondary endpoints’ null hypotheses
Endpoint
Assumption about true 
treatment effect for 
LCZ696 vs ramipril for 
ITT analysis
Assumptions
Nominal power
(1) Time to first CV death or 
HF hospitalization
20% RRR
Expect 592 
events1
77.5%
(2) Time to first HF 
hospitalization or outpatient 
HF
17% RRR
Expect 566 
events2
60.1%
(3) Time to first composite of 
CV death, non-fatal MI or 
non-fatal stroke
15% RRR
Expect 594 
events3
50.8%
(4) Total number of 
hospitalizations for HF, MI 
and stroke related reasons 
including CV death
17% reduction in rate 
ratio
Over-dispersion=6;
Rate of events per 
year (pooled) = 
0.1924
55.1%
1 Event rates as per Table 3-5, estimated using blinded data
2 Cumulative event rates (pooled) for the composite endpoint (first HF hospitalization or outpatient 
HF event) at 3, 6, 12, and 18 months were estimated to be 5.4%, 6.6%, 8.3% and 10.3%, 
respectively. Constant piecewise hazard rates were derived accordingly for the following time 
periods: 0 to 3 months, 3 to 6 months, 6 to 12 months, and 12 to 41 months. The hazard rate for the 
time period of 12 to 41 months was derived through extrapolation of the 18 months cumulative event 
rate.
3 Cumulative event rates (pooled) for the composite endpoint (first CV death, non-fatal MI or non-
fatal stroke event) at 3, 6, 12, and 18 months were estimated to be 4.6%, 6.0%, 8.7% and 11.0%, 
respectively. Constant piecewise hazard rates were derived accordingly for the following time 
periods: 0 to 3 months, 3 to 6 months, 6 to 12 months, and 12 to 41 months. The hazard rate for the 
time period of 12 to 41 months was derived through extrapolation of the 18 months cumulative event 
rate.
4 For the power calculation the rate was assumed to be constant over time 
The number of events were calculated for a sample size of 5,650 patients; 37 months recruitment 
and approximately 4 months minimum follow-up. 
HF = Heart Failure; RRR = Relative Risk Reduction
The power calculations were carried out using East Version 6.4.
4
Change to protocol specified analyses
Not applicable


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5
Appendix
5.1
Imputation rules
5.1.1
Missing or partially missing AE or concomitant medication start/end 
date
The partially missing AE start/end date and concomitant medication start/end date will be 
imputed using the Novartis ADaM Governance Board (AGB) global standard approach. Details 
will be provided in the study Programming Datasets Specifications.
5.1.2
Missing visit date
In any analysis or evaluation, if the visit date(s) is used but is missing, then the date(s) calculated
based on the planned date(s) in the schedule specified in the protocol should be used to impute
the missing date(s).
5.1.3
Missing or partially missing event date
If the date of an event is not known or is incomplete, the imputation rules are:
1) If the day of the event is unknown, then the 15th day of this month will be imputed for a
missing day;
2) If only the month is unknown, then July will be used for imputation of the missing;
3) If only the year of the event is known, then the 1st of July will be imputed for a missing day 
and month;
4) If the event date is completely missing, the last visit date (for non-fatal endpoint, an endpoint 
with non-fatal event as a component, or recurrent endpoints) or the last known alive date (for 
fatal endpoint) will be used to impute the event date;
5) The above rules are only for general case. If there is additional information available for the
missing date, then the information should be used and the imputation of missing date should be 
treated differently. For example, if an event occurs between two visits and its date is missing, 
then the date in the middle of these visits may be used.
5.1.4
Missing medication stop date
If medication stop date is unknown or is incomplete, the imputation rules are:
1) If only the day field of the drug stop is missing, then the missing date is imputed by using
the 15th of the month;
2) If year and month are missing, then use the next scheduled visit date (using the protocol
specified visit schedule) from the previous last non-missing visit date to replace the missing
drug stop date; 
3) If the drug stop date is completely missing, then:
  a. If patient had fatal AEs (identified as either start or end date is equal to the date of
  death and the AE is flagged as an SAE), handling rules are (in the specified order):
    i. AE end date is not missing: use the AE end date to replace the missing drug
    stop date;
    ii. AE end date is completely missing but AE onset date not missing: use the
    AE onset date to replace the missing drug stop date;
    iii. AE end date is partially missing (only day field is missing): use Novartis


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    standard procedure to impute the AE end date, and then use the imputed AE
    end date to replace the missing drug stop date;
    iv. AE end date is completely missing and AE onset date is partial missing
    (missing the date field only): impute the AE onset date using Novartis
    standard procedure, and then use the imputed AE onset date to replace the
    missing drug stop date;
    v. If both AE onset and end dates are completely missing, then use the last
    previous non-missing visit date plus 35 days to replace the missing drug stop
    date.
  b. If patients had no fatal AEs, handling rules are the same with the case where year
  and month are missing.
5.2
Statistical models
5.2.1
Primary analysis
See Section 2.5.2.
5.2.2
Key secondary analysis
Not applicable.
5.3
Rule of exclusion criteria of analysis sets 
Following tables present a sample of the rules for subject classification in the analysis sets based 
on protocol deviation specifications (Table 5-1) and non-protocol deviation classification 
criteria (Table 5-2). The PDs leading to exclusion of patients from analysis sets may be updated 
prospectively and will be finalized before DB lock.
Table 5-1
Protocol deviations that cause subjects to be excluded
Deviation ID
Description of Deviation
Exclusion in Analyses
INCL04
Index MI event secondary to other medical 
conditions such as anemia, hypotension, 
or an arrhythmia OR thought to be caused 
by coronary vasospasm with documented 
normal coronary arteries
Excluded from PP analysis
INCL05
Index MI is non-spontaneous MI
Excluded from PP analysis
INCL06
LVEF >40% after index MI presentation or 
prior to randomization without symptoms of 
pulmonary congestion 
Excluded from PP analysis
INCL07
Subject with no risk factors
Excluded from PP analysis
INCL08
SBP less than 100 mmHg at randomization 
for patients who received ACE 
inhibitor/ARB during the 24 hours prior to 
randomization.
Excluded from PP analysis
INCL09
SBP less than 110 mmHg at randomization 
for patients who did not receive ACE 
inhibitor/ARB during the 24 hours prior to 
randomization.
Excluded from PP analysis


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Deviation ID
Description of Deviation
Exclusion in Analyses
INCL10
Use of intravenous treatment with 
diuretics, vasodilators, vasopressors 
and/or inotropes during the 24 hours prior 
to randomization.
Excluded from PP analysis
INCL11
Time from presentation to randomization < 
12 hours or  > 7 days
Excluded from PP analysis
EXCL01
Known history of chronic HF at 
randomization
Excluded from PP analysis
EXCL03
Persistent clinical HF at the time of 
randomization
Excluded from PP analysis
EXCL05
Clinically significant right ventricular MI as 
index MI
Excluded from PP analysis
EXCL15
Previous use of LCZ696 or EntrestoTM
Excluded from PP analysis
OTH04
Patients were misrandomized
Excluded from primary and PP analysis
OTH01
Blinding broken locally
Excluded from PP analysis
OTH02
Subject was classified into incorrect 
stratum
Excluded from PP analysis
OTH03
Major GCP violation at site.
Excluded from primary and PP analysis
Table 5-2
Subject classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
SCR
NA
No written informed consent
RAN
NA
Not in SCR; 
Not randomized
FAS
OTH03, OTH04
Not in RAN;
PPS
INCL04, INCL05, INCL06, 
INCL07, INCL08, INCL09, 
INCL10, INCL11, EXCL01, 
EXCL03, EXCL05, EXCL15, 
OTH01, OTH02, OTH03, OTH04
Not in FAS;
SAF
NA
No double-blind study drug taken
5.4
SAS code for Bayesian sensitivity analysis
/* define input data: 
log(HR_pre), HR_pre assumed 0.81;
sepre2 = 4/540 
post-COVID, HR_post assumed 1.00;
sepost2 = 4/184 
i.e. total number of events assumed to be 724, pre-Covid number of events 
assumed to be 540 */
data dat;
input y se2; datalines;
-0.210721 0.007407407
;


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* call proc MCMC with pre-defined mixture prior;
proc mcmc data=dat outpost=postout seed=23 nmc=5000000 ntu=10000 thin = 10
nbi=100000 statistics=(summary interval) diagnostics=none;
ods exclude nobs parameters;
array p[2] (0.5 0.5);
array m[2] (0 0);
array sd[2] (0.147442 2);
parm z loghr;
prior z ~ table(p);
prior loghr ~ normal(m[z], sd=sd[z]);
model y ~ n(loghr, var=se2);
run;
* obtain summary of hazard ratio (posterior);
* including mean, median, 95% interval;
data postout;
set postout;
hr = exp(loghr);
run;
proc means data=postout n mean std median;
run;
proc stdize data=postout pctlmtd=ord_stat outstat=pctls
pctlpts=2.5,97.5;
var hr loghr;
run;
* obtain summary of posterior weights;
proc freq data=postout;
tables z / out=FreqCount;
title 'Posterior mixture weights';
run;
* obtain probability that loghr < 0 (i.e. HR < 1);
data postout2;
set postout;
suc = loghr < 0;
run;
proc means data=postout2 n mean;
run;
6
Reference
Dominguez Islas C, Mander  A, Best N, Turner R. A Bayesian framework for extrapolation 
using mixture priors: challenges and some recommendations. PSI One Day Meeting: 


Novartis
For business use only
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SAP amendment 1 
CLCZ696G2301
Extrapolation, 22 November 2017. Retrieved from https://psiweb.org/docs/default-
source/default-document-library/06-dominguez_psimeeting2.pdf?sfvrsn=cfb6dfdb_0
Lakatos E. Sample sizes based on the log-rank statistic in complex clinical trials. Biometrics 
1988;44:229-41.
Lawless JF. Regression Methods for Poisson Process Data. Journal of the American Statistical 
Association 1987; 82:808-15.
Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial 
infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 
2003;349:1893-906.
Schmidli H, Gsteiger S, Roychoudhury S, O'Hagan A, Spiegelhalter D, Neuenschwander B. 
Robust meta-analytic-predictive priors in clinical trials with historical control information. 
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Biometrics 2000; 56:779-88.


Summary of all amendments to the SAP: 
Date 
Amendment 
Summary 
19-OCT-2020 
Amendment 1 
prior to 
database lock 
(DBL) 
Update introduction for this SAP: Section 1 - Introduction first and 
second paragraphs have been updated.  
 
Change in study design as per study protocol up to v04: Section 
1.1, 2.1, 2.14, 3 - Updated text about the study duration, sample 
size (including sample size re-estimation in protocol v03), and 
interim analyses change as per study protocol v04 
 
 
 
  
 
 
 
 
 
 
  
 
Clarification for the definitions of non-fatal spontaneous MI and non-
fatal stroke: Section 1.2 - Added clarification for non-fatal 
spontaneous MI/stroke definition in the Table 1-2 footnote  
 
 
 
  
 
Clarification for the grouping of stratification factor type of MI: 
Section 2.1 - Added text for clarification of the grouping of 
“NSTEMI” type of MI 
 
Additional analyses due to mis-stratification: Section 2.1 - Added 
analyses for mis-stratification by type of MI/region  
 
Clarification for censoring methods for time-to-event variables: 
Section 2.1, 2.5.3, 2.6.1 - Added/modified censoring methods for 
time-to-event endpoints with a structure for more clarity  
 
Changes as per study protocol v04 for COVID-19 impact: Section 
2.1, 2.3.1, 2.5, 2.5.4, 2.6, 2.6.5, 2.10, 2.11, 2.13 - Added additional 
analyses for potential COVID-19 impact  
 
Clarification of baseline definition: Section 2.1.1 - Updated baseline 
definition  
 
Adding rules for unscheduled visit: Section 2.1.1 - Added rules for 
use of unscheduled visit  
 
Change as per study protocol v02: Section 2.2 - Text added about 
the exclusion of subjects without a valid informed consent from all 
analyses sets  
 


Update of the derivation of subgroups due to refinement / feasibility 
/ scientific reasons: Section 2.2.1 - Updated Table 2-1 definition and 
derivation of subgroups; Updated Table 2-1 footnote for region 
classification to align with the LCZ project standard; Added 
subgroup of number of CV risk factors in Table 2-1  
 
Update of CV medication classification: Section 2.4.2 - Updated the 
classification of CV medications  
 
Clarification for hierarchical testing procedure: Section 2.6.3 - 
Clarified that the components of the primary endpoint are not part of 
the testing procedure  
 
Adding an endpoint in the IPCW analysis: Section 2.6.5 - Added an 
endpoint ((2) time-to-first event of CV death or HF hospitalization) in 
the IPCW analysis  
 
Update AE summaries: Section 2.7.1 - Summaries of AEs have 
been updated  
 
Update AEs of special interest terms: Section 2.7.1 - Updated AEs 
of special interest terms  
 
Update RAAS blockade summaries: Section 2.4.2 - Summaries of 
RAAS blockade and open-label Entresto have been updated  
 
Clarification of central lab data use: Section 2.7.3 - Clarified that 
central lab data will be used for the summary of lab results  
 
Adding abnormal criteria for vital signs: Section 2.7.4 - Added 
abnormal criteria for vital signs  
 
Update renal injury endpoint as per study protocol v03: Section 
2.13.1 - Clarified the definition of renal injury endpoints as 
measured by serum creatinine change from baseline  
 
Adding imputation rules for dates: Section 2.1, 5.1 - Updated 
imputation rules for various types of missing or partially missing 
dates  
 
Update of PD or non-PD criteria for exclusion from analysis sets: 
Section 5.3 - Updated the text and code for the PDs leading to 
exclusion from analysis sets in Table 5-1; Updated the text for non-
PDs in Table 5-2  
18 March 2021 
Amendment 2 
prior to 
database lock 
(DBL) 
Adding definition for initiation or intensification of antihyperglycemic 
medications per protocol requirement before DBL: Sections 1.2, 
2.13.1 - Added the definition of initiation or intensification of 
antihyperglycemic medications  
 
Removing alternative definition of renal composite endpoint (not 
specified in protocol): Sections 1.2, 2.13.1 - Deleted the alternative 
definition of renal composite endpoint 
 
 
 


endpoints days alive out of HF hospitalization through month 6, 
month 12 and through end of study (EOS)  
 
Adding number of CV risk factors Summary: Section 2.3.2.1 - 
Added number of CV risk factors to the summary of CV risk factors 
 
Clarification of definition for time to treatment discontinuation 
analysis: Section 2.4.1 - Update the text for “time to permanent 
discontinuation of study medication not due to death”  
 
Update of study exposure summary: Section 2.4.1 - Updated study 
exposure summary  
 
Clarification of definition of CV death endpoint: Section 2.5.1 - 
Added text for the CV death endpoint definition  
 
Analysis cut-off date: Sections 2.1, 2.5.3, 2.6, 2.13 
 
Adding supportive analyses for primary endpoint: Section 2.5.4 - 
Added alternative definitions for primary endpoint as supportive 
Analyses  
 
Adding a sensitivity analysis for primary endpoint: Sections 2.5.4, 
5.4, 6 - Added a Bayesian sensitivity analysis with robust prior to 
combine potentially COVID-19 affected results with pre- COVID-19 
results 
 
Removing an endpoint from the IPCW analysis to align with 
protocol: Section 2.6.5 - Removed the composite endpoint of HF 
hospitalization or outpatient HF from the IPCW analysis  
 
Update of AE summaries for clarity: Updated text for AE summaries 
Section 2.7.1 
 
Update of AEs of special interest risk names: Section 2.7.1, 2.7.1.1 
- Updated the risk names of AEs of special interest  
 
 
 
  
 
 
  
 
 
 
  
 
Added missing date handling for endpoint event with completely 
missing date: Section 5.1.3 - Added the data handling method for 
event with completely missing event date