Clinical trial NCT02554890
Conditions: Acute Heart Failure
Keywords: Acute Heart Failure reduced ejection fraction NTproBNP Heart failure with reduced ejection fraction (HFREF)
Sponsor: Novartis Pharmaceuticals
Start date: 2016-04-29; Completion date: 2018-07-24
Enrollment: 887 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).

Detailed description:

Arms: arm 1: Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement.

Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan and one tablet of enalapril matching placebo pack). arm 2: Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement.

Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)
Interventions: intervention 1: sacubitril/valsartan (LCZ696) intervention 2: Enalapril intervention 3: sacubitril/valsartan (LCZ696) matching placebo intervention 4: enalapril matching placebo
Intervention descriptions: intervention 1: sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally. intervention 2: Enalapril tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally. intervention 3: matching placebo of sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally. intervention 4: enalapril matching placebo tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Development 
LCZ696 
Clinical Trial Protocol CLCZ696BUS01 / NCT02554890
A multicenter, randomized, double-blind, double dummy, 
parallel group, active-controlled 8-week study to evaluate 
the effect of sacubitril/valsartan (LCZ696) versus enalapril 
on changes in NT-proBNP and safety and tolerability of in- 
hospital initiation of LCZ696 compared to enalapril in 
HFrEF patients who have been stabilized following 
hospitalization for acute decompensated heart failure 
(ADHF). 
Author(s): 
Document type: 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
v02 Clean 
Development phase IIIb/IV 
Document status: 
Final 
Release date: 
05-Oct-2017
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 02-Dec-2013 


 
 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ....................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 11 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Rationale for protocol amendment ........................................................................ 21 
1.3 
Changes to protocol ............................................................................................... 22 
1.4 
Purpose .................................................................................................................. 22 
2 
Study objectives ................................................................................................................. 22 
2.1 
Primary objective(s) ............................................................................................... 22 
2.2 
Secondary objectives ............................................................................................. 23 
 
 23 
3 
Investigational plan............................................................................................................ 24 
3.1 
Study design ........................................................................................................... 24 
3.2 
Rationale of study design ....................................................................................... 25 
 
 25 
3.4 
Rationale for choice of comparator ....................................................................... 26 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 26 
3.6 
Risks and benefits .................................................................................................. 26 
4 
Population .......................................................................................................................... 27 
4.1 
Inclusion criteria .................................................................................................... 28 
4.2 
Exclusion criteria ................................................................................................... 28 
5 
Treatment ........................................................................................................................... 30 
5.1 
Protocol requested treatment ................................................................................. 30 
5.1.1 
Investigational and control treatment .................................................... 30 
5.1.2 
Additional study treatment .................................................................... 31 
5.2 
Treatment arms ...................................................................................................... 31 
5.3 
Treatment assignment, randomization ................................................................... 31 
5.4 
Treatment blinding ................................................................................................. 32 
5.5 
Treating the patient ................................................................................................ 33 
5.5.1 
Patient numbering ................................................................................. 33 
5.5.2 
Dispensing the investigational and comparator treatment .................... 33 


 
 
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5.5.3 
Handling of study treatment .................................................................. 33 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 35 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ......... 37 
5.5.6 
Rescue medication ................................................................................ 38 
5.5.7 
Concomitant treatment .......................................................................... 38 
5.5.8 
Discontinuation of study drug ............................................................... 39 
5.5.9 
Withdrawal of consent .......................................................................... 40 
5.5.10 
Lost to follow-up ................................................................................... 40 
5.5.11 
Emergency breaking of assigned treatment code .................................. 40 
5.5.12 
Study completion and post-study treatment .......................................... 41 
5.5.13 
Early study termination ......................................................................... 41 
6 
Visit schedule and assessments ......................................................................................... 41 
6.1 
Information to be collected on screening failures .................................................. 43 
6.2 
Patient demographics/other baseline characteristics .............................................. 44 
6.3 
Treatment exposure and compliance ..................................................................... 44 
6.4 
Efficacy .................................................................................................................. 44 
6.4.1 
Heart failure signs and symptoms ......................................................... 45 
 
 45 
6.4.3 
Biomarkers ............................................................................................ 45 
6.4.4 
Appropriateness of efficacy measurements ........................................... 46 
6.5 
Safety ..................................................................................................................... 46 
6.5.1 
Physical examination ............................................................................ 46 
6.5.2 
Vital signs .............................................................................................. 47 
6.5.3 
Height, weight and waist/hip circumference ......................................... 47 
6.5.4 
Angioedema .......................................................................................... 47 
6.5.5 
Laboratory evaluations .......................................................................... 47 
6.5.6 
Pregnancy and assessments of fertility .................................................. 48 
6.5.7 
Appropriateness of safety measurements .............................................. 48 
 
 48 
 
 48 
 
 49 
7 
Safety monitoring .............................................................................................................. 49 
7.1 
Adverse events ....................................................................................................... 49 
7.2 
Serious adverse events ........................................................................................... 50 
7.2.1 
Definition of SAE.................................................................................. 50 


 
 
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7.2.2 
SAE reporting ........................................................................................ 51 
7.3 
Reporting of study treatment errors including misuse/abuse ................................. 52 
7.4 
Pregnancy reporting ............................................................................................... 52 
7.5 
Reporting angioedema-like events ......................................................................... 53 
8 
Data review and database management ............................................................................. 53 
8.1 
Site monitoring ...................................................................................................... 53 
8.2 
Data collection ....................................................................................................... 54 
8.3 
Database management and quality control ............................................................ 54 
8.4 
Data Monitoring Committee .................................................................................. 55 
8.5 
Adjudication Committee ........................................................................................ 55 
9 
Data analysis ...................................................................................................................... 56 
9.1 
Analysis sets .......................................................................................................... 56 
9.2 
Patient demographics and other baseline characteristics ....................................... 56 
9.3 
Treatments ............................................................................................................. 57 
9.4 
Analysis of the primary variable(s) ....................................................................... 57 
9.4.1 
Variables ............................................................................................... 57 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 57 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 58 
9.4.4 
Supportive analyses ............................................................................... 58 
9.5 
Analysis of secondary 
 variables .................................................. 58 
9.5.1 
Secondary variables ............................................................................... 58 
 
 58 
9.5.3 
Other safety variables ............................................................................ 61 
 
 61 
9.5.5 
Pharmacokinetics .................................................................................. 61 
9.5.6 
Pharmacogenetics and pharmacogenomics ........................................... 61 
9.5.7 
Biomarkers ............................................................................................ 62 
9.5.8 
PK/PD ................................................................................................... 62 
9.6 
Interim analyses ..................................................................................................... 62 
9.7 
Sample size calculation .......................................................................................... 62 
10 Ethical considerations ........................................................................................................ 63 
10.1 
Regulatory and ethical compliance ........................................................................ 63 
10.2 
Informed consent procedures ................................................................................. 63 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 63 
10.4 
Publication of study protocol and results ............................................................... 64 
11 Protocol adherence ............................................................................................................ 64 


 
 
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11.1 
Protocol Amendments ........................................................................................... 64 
12 References ......................................................................................................................... 64 
13 Appendix 1: Clinically notable laboratory values ............................................................. 67 
14 Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.5 mEq/L) ....................................................................................................... 68 
15 Appendix 3: Guidelines for the management of blood pressure ....................................... 69 
16 Appendix 4: Guidelines for the management of renal dysfunction ................................... 70 
 71 
 
 
List of tables 
Table 1-1 
Adverse reactions occurring at an incidence of >5% of patients in 
the double-blind period of PARADIGM-HF were as follows: ............. 20 
Table 5-1 
Investigational and comparator treatment ............................................. 30 
Table 5-2 
Treatment Dose Levels ......................................................................... 30 
Table 5-3 
Dose titration schedule based on SBP ................................................... 35 
Table 6-1 
Assessment schedule ............................................................................. 42 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 52 
Table 9-1 
Sample size and power for various rate of reduction in 
sacubitril/valsartan group given alpha =0.05: ...................................... 62 
 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 25 
Figure 3-2 
36 hour washout design ......................................................................... 27 


 
 
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List of abbreviations 
ACE 
angiotensin converting enzyme 
ACEI 
angiotensin converting enzyme inhibitor 
ADHF 
acute decompensated heart failure 
AE 
adverse event 
AF 
atrial fibrillation 
AHF 
acute heart failure 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance model 
ANP 
arial natriuretic peptide 
ARB 
angiotensin receptor blocker 
ARNI 
angiotensin receptor neprilysin inhibitor 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
b.i.d. 
twice a day 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
BP 
blood pressure 
Bpm 
beats per minute 
CHF 
chronic heart failure 
CFR 
US Code of Federal Regulations 
CDS 
Core Data Sheet (for marketed drugs) 
COPD 
Chronic obstructive pulmonary disease 
CPO 
Country Pharma Organization 
CRA 
clinical research associate (site monitor) 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRTD 
Cardiac resynchronization therapy device 
CSR 
Clinical Study Report 
CTL 
Clinical Trial Leader 
CV 
cardiovascular 


 
 
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DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
Echo 
echocardiogram 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
cGMP 
cyclic guanosine monophosphate 
EOS 
end of study 
ER 
emergency room 
HF 
heart failure 
HfrEF 
heart failure with reduced ejection fraction 
hs-Troponin 
high sensitivity troponin 
HTN 
hypertension 
IA 
interim analysis 
ICH 
International Conference on Harmonization of Technical   Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
investigator notification 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
 
 
LFT 
Liver function test (raised serum transaminases and/or bilirubin levels) 
LVAD 
Left ventricular assist device 
LVEF 
Left ventricular ejection fraction 
LVESV 
left ventricular end systolic volume 
LVH 
left ventricular hypertrophy 


 
 
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MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial infarction 
mm Hg 
millimeter mercury 
MUGA 
multi gated acquisition scan 
NEP 
neutral endopeptidase 
NEPi 
neutral endopeptidase inhibitor 
NP 
natriuretic peptide 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
PCI 
percutaneous coronary intervention 
 
 
QoL 
Quality of Life 
RAAS 
renin angiotensin aldosterone system 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
ULN 
upper limit of normal 
USPI 
United States prescribing information/package insert 


 
 
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Glossary of terms 
 
 
Assessment 
A procedure used to generate data required by the study 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the trial 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
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.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include protocol- 
specified concomitant background therapies when these are 
standard treatments in that indication 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 
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. 
Period 
A subdivision of a cross-over study 
Premature subject/patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival 
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), active drug run-ins or background therapy 
Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment for any reason; may or may not 
also be the point/time of premature patient withdrawal 
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 


 
 
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drug being tested in the study 


 
 
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Protocol summary 
 
 
Protocol number 
CLCZ696BUS01 
Title 
A multicenter, randomized, double-blind, double-dummy, parallel group, 
active-controlled 8-week study to evaluate the effect of sacubitril/valsartan 
(LCZ696) versus enalapril on changes in NT-proBNP and safety and 
tolerability of in-hospital initiation of sacubitril/valsartan compared to enalapril 
in HFrEF patients who have been stabilized following hospitalization for acute 
decompensated heart failure (ADHF) 
Brief title 
In-hospital initiation of sacubitril/valsartan vs. enalapril to assess changes in 
NT-proBNP through 8 weeks of treatment following an ep isode of acute 
decompensated heart failure. 
Sponsor and 
Clinical Phase 
Novartis 
Phase IIIb/IV 
Investigation type 
Interventional 
Study type 
Multicenter, randomized, double-blind, parallel group, active-controlled 
Purpose and 
rationale 
The purpose of this study is to assess the effect of in-hospital initiation of 
sacubitril/valsartan tablets vs. enalapril on time averaged proportional change 
in NT-proBNP in patients hospitalized for acute decompensated heart failure 
(ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) 
≤ 40%). 
Hospitalization for acute decompensated heart failure identifies patients at 
increased risk of death and re-hospitalization following discharge. This 
increased risk justifies intervention with novel treatment strategies initiated 
prior to hospital discharge to improve patient outcomes. 
Primary 
Objective(s) 
The primary objective of this study is to assess the effect of in-hospital 
initiation of sacubitril/valsartan tablets vs. enalapril on the time-averaged 
proportional change of NT-proBNP from baseline in patients who have been 
stabilized following hospitalization for acute decompensated heart failure and 
reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%). 
Weeks 4 and 8 will be included in the analysis (primary analysis time point). 
Secondary 
Objectives 
To examine the effect of sacubitril/valsartan tablets vs. enalapril on change  
in: 
• 
The proportional change in NT-proBNP from baseline to Week 8 
• 
Incidence of symptomatic hypotension during 8 weeks of treatment 
• 
Incidence of hyperkalemia (Potassium >5.5 mEq/L) during 8 weeks of 
treatment 
• 
Incidence of angioedema during 8 weeks of treatment 
• 
Biomarkers: high sensitivity-Troponin (hs-Troponin), urinary cGMP at 4 
and 8 weeks; and BNP:NT-proBNP ratio 


 
 
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Study design 
This study will use a randomized, double-blind, double-dummy, 
active-controlled, parallel group design. Eligible patients hospitalized 
for ADHF will be randomized no earlier than 24 hours and up to ten days of 
presentation, while still hospitalized. At the time of randomization, patients will 
have been stabilized, defined for this study as: 
• 
SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no 
symptomatic hypotension; 
• 
No increase (intensification) in i.v. diuretic dose within the last 6 
hours prior to randomization; 
• 
No i.v. inotropic drugs for 24 hours prior to randomization; 
• 
No i.v. vasodilators including nitrates within the last 6 hours prior to 
randomization 
All patients will need to meet all other inclusion and none of the exclusion 
criteria. 
Patients will be randomized to sacubitril/valsartan or enalapril. All patients 
randomized to sacubitril/valsartan will require a 36-hour wash-out from 
previous ACEi treatment prior to first dose of active study treatment. All 
randomized patients in the trial will remain hospitalized for observation for 6 
hours following the third dose of study medication. See section 3.1 for more 
details. 
At the end of the 8-week treatment period, all patients will enter a 4 -week 
follow up period on open label sacubitril/valsartan. 
Population 
The study population will consist of male and female patients, ≥ 18 years of 
age, admitted to hospital for acute decompensated heart failure. The goal is 
to randomize a total of approximately  882 patients to  sacubitril/valsartan   or 


 
 
N o v arti s  
A m e n d e d Pr ot o c ol V er si o n 0 2 ( Cl e a n)  
C o nfi d e nti al  
P a g e 1 3  
Pr ot o c ol N o. C L C Z 6 9 6 B U S 0 1  
 
 
 
 
e n al a pril i n a 1: 1 r ati o i n a p pr o xi m at el y 1 7 0 c e nt er s i n t h e U nit e d St at e s. At 
t h e ti m e of r a n d o mi z ati o n, p ati e nt s will h a v e b e e n st a bili z e d, d efi n e d f or t hi s 
st u d y a s:  
•  
S B P ≥1 0 0 m m H g f or t h e pr e c e di n g 6 h o ur s pri or  t o 
r a n d o mi z ati o n; n o s y m pt o m ati c h y p ot e n si o n  
•  
N o i n cr e a s e (i nt e n sifi c ati o n) i n i. v. di ur eti c d o s e wit hi n l a st 6 
h o ur s pri or t o  r a n d o mi z ati o n 
•  
N o i. v. i n otr o pi c dr u g s f or 2 4 h o ur s pri or t o  r a n d o mi z ati o n 
•  
N o i. v. v a s o dil at or s i n cl u di n g nitr at e s wit hi n l a st 6 h o ur s pri or  t o 
r a n d o mi z ati o n; 
All p ati e nt s will n e e d t o m e et all ot h er i n cl u si o n a n d n o n e of t h e e x cl u si o n 
crit eri a.  
I n clu si o n crit eri a  
P ati e nt s eli gi bl e f or i n cl u si o n i n t hi s st u d y h a v e t o f ulfill all of t h e f oll o wi n g 
crit eri a:  
1.  P o s s e s s t h e c a p a cit y t o pr o vi d e writt e n i nf or m e d c o n s e nt w hi c h m u st b e 
o bt ai n e d b ef or e a n y a s s e s s m e nt i s  p erf or m e d.  
2.  P ati e nt s ≥ 1 8 y e ar s of a g e, m al e or  f e m al e. 
3.  C urr e ntl y h o s pit ali z e d f or A D H F. P ati e nt s wit h a di a g n o si s of a c ut e h e art 
f ail ur e  h a d  t o  h a v e  s y m pt o m s  a n d  si g n s  of  fl ui d  o v erl o a d  (i. e.  j u g ul ar  
v e n o u s  di st e nti o n,  e d e m a  or  r al e s  o n  a u s c ult ati o n  or  p ul m o n ar y  
c o n g e sti o n o n  c h e st x -r a y) at ti m e of h o s pit ali z ati o n.  
4.  Eli gi bl e p ati e nt s will b e r a n d o mi z e d n o e arli er t h a n 2 4 h o ur s a n d u p t o t e n 
d a y s  aft er  pr e s e nt ati o n  w hil e  still  h o s pit ali z e d  a s  l o n g  a s  m e et  t h e  
f oll o wi n g d efi niti o n of st a bl e st at u s:  
 S B P ≥1 0 0 m m H g f or t h e pr e c e di n g 6 h o ur s pri or t o r a n d o mi z ati o n;  n o 
s y m pt o m ati c  h y p ot e n si o n  
 N o i n cr e a s e (i nt e n sifi c ati o n) i n i. v. di ur eti c d o s e wit hi n l a st 6 h o ur s 
pri or t o  r a n d o mi z ati o n 
 N o i. v. i n otr o pi c dr u g s f or 2 4 h o ur s pri or t o  r a n d o mi z ati o n 
 N o i. v. v a s o dil at or s i n cl u di n g nitr at e s wit hi n l a st 6 h o ur s pri or t o 
r a n d o mi z ati o n 
5.  L V E F ≤4 0 %  wit hi n  t h e  p a st  6  m o nt h s  (i n cl u di n g  c urr e nt  h o s pit ali z ati o n) 
u si n g  e c h o c ar di o gr a p h y,  m ulti  g at e d  a c q ui siti o n  s c a n  ( M U G A),  C T  
s c a n ni n g, M RI or v e ntri c ul ar a n gi o gr a p h y pr o vi d e d n o s u b s e q u e nt st u d y 
d o c u m e nt e d a n E F of  > 4 0 %.  
6.  El e v at e d N T -pr o B N P  ≥  1 6 0 0 p g/ m L  O R  B N P  ≥4 0 0  p g/ m L  d uri n g  c urr e nt 
h o s pit ali z ati o n  
E x cl u si o n crit eri a  
P ati e nt s f ulfilli n g a n y of t h e f oll o wi n g crit eri a ar e n ot eli gi bl e f or i n cl u si o n i n 
t hi s  st u d y.  N o  a d diti o n al  e x cl u si o n s  m a y b e  a p pli e d  b y t h e  i n v e sti g at or,  i n  
or d er t o e n s ur e t h at t h e st u d y p o p ul ati o n will b e r e pr e s e nt ati v e of all eli gi bl e 
p ati e nt s.  
1. C urr e ntl y t a ki n g s a c u bitril/ v al s art a n t a bl et s or a n y u s e wit hi n t h e p a st 3 0 
d a y s.  


 
 
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2. Enrollment in any other clinical trial involving an investigational agent or 
investigational device. 
3. History of hypersensitivity, known or suspected contraindications, or 
intolerance to any of the study drugs, including ACEIs, ARBs, or 
Sacubitril (NEP inhibitor) 
4. Patients with a known history of angioedema related to previous ACE 
inhibitor or ARB therapy. 
5. Requirement of treatment with both ACE inhibitor and ARB. 
6. eGFR < 30 ml/min/1.73 m2 as measured by the simplified Modification of 
Diet in Renal Disease (MDRD) formula at screening. 
7. Serum potassium > 5.2 mEq/L at screening. 
8. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, 
carotid or other major CV surgery; percutaneous coronary intervention 
(PCI) or carotid angioplasty, within one month prior to Visit 1. 
9. Primary cause of dyspnea due to non-cardiac, non-heart failure causes 
such as acute or chronic respiratory disorders 
10. Intended coronary or carotid artery disease revascularization within the 6 
months after Visit 1. 
11. Implantation of a cardiac resynchronization therapy device (CRTD) within 
the prior 3 months from Visit 1or intent to implant a CRTD. 
12. History of heart transplant or patients who are on a transplant list or with 
left ventricular assistance device (LVAD). 
13. Isolated right HF due to severe pulmonary disease. 
14. Documented untreated ventricular arrhythmia with syncopal episodes 
within the 3 months prior to Visit 1. 
15. Symptomatic bradycardia or second or third degree heart block without a 
pacemaker. 
16. Presence of hemodynamically significant mitral, aortic, or hypertrophic 
cardiomyopathy. 
17. History of malignancy of any organ system (other than localized basal cell 
carcinoma of the skin), treated or untreated, within the past year with a 
life expectancy of less than 1 year. 
18. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or 
increased ammonia levels, if performed), or history of cirrhosis with 
evidence of portal hypertension such as varices. 
19. 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 hCG laboratory test. 
20. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, including women whose career, lifestyle, 
or sexual orientation precludes intercourse with a male partner and 
women whose partners have been sterilized by vasectomy or other 
means, UNLESS they are using two birth control methods. The two 
methods can be a double barrier method (if accepted by the local 
regulatory authority and ethics committee) or a barrier method plus a 
hormonal method 
• 
Adequate barrier methods of contraception include: diaphragm, 
condom (by the partner), intrauterine device (copper or hormonal), 
sponge or spermicide. Hormonal contraceptives include any 


 
 
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marketed contraceptive agent that includes an estrogen and/or a 
progesterone agent. 
• 
Reliable contraception should be maintained throughout the study 
and for 7 days after study drug discontinuation. 
• 
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 six months of spontaneous 
amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 
20 pg/mL or have had surgical bilateral oophorectomy (with or 
without hysterectomy) 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. 
Investigational and 
reference therapy 
All eligible patients will be randomized to receive either sacubitril/valsartan or 
enalapril. The following study treatment will be provided for the 8 -week 
double blind double dummy treatment period: 
• 
sacubitril/valsartan tablets + matching placebo or enalapril tablets + 
matching placebo. 
Open-label, sponsor-provided sacubitril/valsartan tablets will be provided for 
the open label extension. 
Efficacy 
assessments 
Primary: 
Time-averaged proportional change from baseline in NT-proBNP. Weeks 4 
and 8 will be included in the analysis. 
Secondary: 
Proportional change in NT-proBNP from baseline to Week 8 
Biomarkers: hs-Troponin, urinary cGMP and BNP to NT-proBNP ratio 


 
 
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Safety 
assessments 
 
 
Incidence of symptomatic hypotension 
Incidence of hyperkalemia (serum potassium ≥5.5 mEq/l) 
Incidence of angioedema In addition, safety will be assessed through  
physical exam, vital signs, laboratory evaluations, other adverse events and 
serious adverse events. The Data Monitoring Committee (DMC) will monitor 
safety. 
Data analysis 
The primary hypothesis to be tested is that the ratio of the geometric means  
of 
NT-Pro 
BNP 
(average 
of Weeks 
4 
and 
8/baseline) 
for 
the 
sacubitril/valsartan tablets and enalapril groups are equal (H0) versus the 
ratio of the geometric means of NT -Pro BNP are not equal (Ha). For NT- 
proBNP, the time-averaged proportional change from baseline in a  
logarithmic scale will be analyzed using an analysis of covariance (ANCOVA) 
model using data from Weeks 4 and 8 with treatment as a fixed effect factor 
and the logarithmic baseline biomarker value as a covariate. The estimated 
treatment effects in terms of ratios of geometric means, based on the least- 
squared means from the ANCOVA model, and the corresponding two -sided 
95% confidence intervals will be provided. Baseline is Week 0. 
For NT-proBNP at Week 8, a proportional change from baseline in a 
logarithmic scale will be analyzed using an ANCOVA model with treatment as 
a fixed effect factor and the logarithmic baseline biomarker value as a 
covariate. The estimated treatment effects in terms of ratios of geometric 
means, based on the least-squared means from the ANCOVA model, and the 
corresponding two-sided 95% confidence intervals will be provided. Baseline 
is Week 0. Week 4 will be used if the Week 8 value is missing. 
 
 
Incidences of symptomatic hypotension, hyperkalemia and angioedema will 
be calculated, along with relative risk of sacubitril/valsartan vs. enalapril and 
95% confidence intervals of the relative risk. 
For biomarkers including BNP to NT-proBNP ratio, hs-Troponin, and urinary 
cGMP, the time-averaged proportional change from baseline in a logarithmic 
scale will be analyzed using an ANCOVA model using the data from Weeks 4 
and 8 with treatment as a fixed effect factors and the logarithmic baseline 
biomarker value as a covariate For each of Weeks 4 and 8 the estimated 
treatment effects in terms of ratios of geometric means, based on t he least- 
squared means from the ANCOVA model, and the corresponding two-sided 
95% confidence intervals will be provided. Baseline is Week 0. 
For BNP to NT-proBNP ratio and urinary cGMP at Weeks 1 and 2, a 
proportional change from baseline in a logarithmic scale will be analyzed 
using an ANCOVA model with treatment as a fixed effect factor and the 


 
 
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logarithmic baseline biomarker value as a covariate, using observed data. For 
each of Weeks 1 and 2 the estimated treatment effects in terms of ratios of 
geometric means, based on the least-squared means from the ANCOVA 
model, and the corresponding two-sided 95% confidence intervals will be 
provided. Baseline is Week 0. 
Analyses of the secondary variables will be based on the full analysis set. 
The assessment of safety will be based primarily on the frequency of adverse 
events, SAEs, and laboratory abnormalities. Safety analyses will be 
performed based on the Safety Set. There will be no inferential analyses of 
the safety data. 
Assuming a significance level of 0.05 and 85% power, a sample size of 882 
patients would be needed to detect an 18% reduction in the geometric mean 
of the time-averaged proportional change from baseline (average of Weeks 4 
and 8) in NT-proBNP for the sacubitril/valsartan treatment group assuming a 
value of 0.95 for the enalapril group, a common standard deviation of 0.85 
and a 25% rate of missing/non-evaluable samples. 


 
 
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1 
Introduction 
1.1 
Background 
Heart failure is a major public health issue. More than 5 million Americans have heart failure 
(HF) and treatment costs for HF are approximately $31 billion annually (Go et al 2014). 
Outcomes for patients after a hospitalization for HF remain disappointingly poor. The 1 -year 
mortality rate after a HF hospitalization is 20-30%, and this number has been relatively 
unchanged over the past decade (Chen et al 2011, Loehr et al 2008). 
The current state of treatments for patients hospitalized with acute heart failure (AHF) is 
focused around maintaining previously established guideline directed medical therapy, 
optimizing volume status, and initiating beta-blockers if indicated (Yancy et al 2013, Gattis et 
al 2004). Unfortunately, recent clinical trials employing a variety of ad ditional in-hospital 
interventions have failed to improve post-discharge outcomes (Binanany et al 2005, Konstam 
et al 2007, Massie et al 2010, O’Connor et al 2011). Thus, therapeutic options to improve 
post-discharge survival free of recurrent HF hospitalizations for patients hospitalized for AHF 
are limited. 
In addition, while intravenous diuretics are nearly universally required for symptom relief 
during a HF hospitalization (Gheorghiade et al 2005), they activate the renin-angiotensin- 
aldosterone system (RAAS) and sympathetic nervous system and may provoke renal 
dysfunction (Felker et al 2012). Activation of the RAAS plays a fundamental role in the 
pathophysiology of HF (Braunwald 2013, Givertz 2001), and although therapies to block 
adverse neurohormonal activation are well established and improve clinical outcomes in 
chronic HF with reduced ejection fraction  (Yancy et al 2013, McMurray et al 2012), they  
have not been extensively tested among patients hospitalized with AHF. Further reducing 
RAAS activation during the period following a HF hospitalization may hold promise to 
change the trajectory of poor post-discharge outcomes for patients with HF. 
Volume expansion and congestion during AHF leads to the synthesis and release of counter - 
regulatory natriuretic peptides from the myocardium: A-type natriuretic peptide (ANP) 
responding predominantly to atrial distention and B-type natriuretic peptide (BNP) to 
ventricular wall stress. The precursor molecule of BNP is a propeptide (proBNP108) that  
when cleaved, results in the generation of the biologically active BNP and the release in the 
circulation of a biologically inert aminoterminal fragment called N-terminal prohormone of 
Brain Natriuretic Peptide (NT-proBNP). This fragment is a largely stable peptide that can be 
measured in serum. Both BNP and NT-proBNP are useful to aid the diagnosis or exclusion of 
HF (Yancy et al 2013). The PROTECT study was a small study ( N=151) that demonstrated 
that NT-proBNP guided therapy was superior to standard of care in reducing total 
cardiovascular events, improved quality of life and impact on cardiac remodeling in patients 
with chronic reduced ejection fraction (Januzzi 2011). A larger on-going study is looking to 
evaluate whether treatment directed therapy based on NT-proBNP levels will provide benefit 
to patients compared to standard of care in patients with reduced ejection fraction (Felker 
2014). 


 
 
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Patients developing an AHF episode are known to have markedly elevated levels of BNP and 
NT-proBNP, which are reduced following adequate treatment and normalization of their 
cardiac decompensation. In the RELAX AHF trial, it was shown that patients that have a 
higher NT-proBNP level during an AHF hospitalization have a worse prognosis (Metra et al. 
2013). Therefore, it is important to evaluate therapeutic strategies that can lead to superior 
reductions in NT-proBNP in patients hospitalized due to an AHF episode. 
Sacubitril/valsartan combination tablet is an orally available, first in class, combination of 
sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin receptor blocker that targets 
complementary pathways, RAAS inhibition via an Angiotensin II receptor blockade and 
natriuretic peptide augmentation via neprilysin inhibition. This novel agent may also hold 
promise in modifying the poor outcomes currently observed after a hospitalization for AHF, 
especially in the initial high-risk post-hospitalization period. 
 
Preliminary studies 
Sacubitril/valsartan, which is known in prior trials as LCZ696, has been evaluated for safety 
and efficacy in patients with chronic heart failure. The PARAMOUNT study was a 
randomized, double-blind, active-controlled phase 2 trial of 308 patients with HF with 
preserved ejection fraction (Left ventricular ejection fraction (LVEF) ≥45%) (Solomon et al 
2012). Patients enrolled in the study received sacubitril/valsartan tablets titrated to 97/103 mg 
twice daily or valsartan titrated to 160 mg twice daily. The primary end point of the study was 
change in NT-proBNP levels from baseline to 12 weeks. NT-proBNP levels were  
significantly reduced at 12 weeks in the sacubitril/valsartan group compared with the  
valsartan group (sacubitril/valsartan: baseline, 783 pg/mL [95% CI 670 to 914], 12 weeks 605 
pg/mL [95% CI512-714]; valsartan: baseline, 862 pg/mL [95% CI 733 -1012], 12 weeks  835 
pg/mL [95% CI 710-981]; ratio: sacubitril/valsartan /valsartan, 0.77, 95% CI 0.64 to 0.92, 
p=0.005. The sacubitril/valsartan combination was well tolerated and had a similar adverse 
effect profile to valsartan. The PARAGON-HF trial is now enrolling 4300 similar patients 
with chronic HF with preserved ejection fraction (LVEF ≥ 45%) to test whether the favorable 
effect of sacubitril/valsartan combination tablet in reducing NT-proBNP seen in 
PARAMOUNT translates into a reduction in the composite end point of cardiovascular 
morbidity and total (first and recurrent) HF hospitalizations. 
The PARADIGM-HF study was a large randomized, double-blind, active-controlled trial of 
8442 patients with symptomatic, chronic HF with reduced ejection fraction (LVEF ≤ 40%) 
(McMurray et al 2013, McMurray et al 2014). Patients enrolled in the study started in a single 
blind sequential run-in phase with enalapril 10 mg twice daily and after a washout period of  
36 hours, went on to sacubitril/valsartan combination tablet at 97/103 mg daily to assess for 
safety and tolerability. Those patients who completed the run -in phase were then randomized 
and received sacubitril/valsartan combination tablet titrated to 97/103 mg twice daily or 
enalapril 10 mg twice daily. The trial was stopped prematurely after a median follow-up of 27 
months upon the recommendation of the data safety monitoring board due to compelling 
evidence in favor of sacubitril/valsartan. Patients receiving sacubitril/valsartan combination 
tablet, compared to enalapril, were noted to have reduced risk of the primary outcome of 
composite of death from cardiovascular causes or hospitalization for HF (HR0.80, 95% CI 
0.73-0.87). The hazard ratio for all-cause mortality was 0.84 (95% CI, 0.76-0.93) and for 


 
 
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hospitalization for HF was 0.79 (95% CI 0.71-0.89) (McMurray et al 2014). In PARADIGM- 
HF, 8385 patients had a baseline NT-proBNP obtained. Results were consistent with the 
primary composite endpoint regardless of whether the NT-proBNP was less than or equal to 
the median values compared to higher than median values (USPI Entresto, figure 4). 
Additionally, a subset of patients had biomarkers obtained at baseline, visit 3 (end of enalapril 
run-in), visit 5 (end of sacubitril/valsartan combination tablet run-in), 4 weeks after 
randomization, and at 8 months after randomization. The ratio of NT -proBNP to baseline 
levels was 25% lower in the sacubitril/valsartan combination tablet group compared to the 
enalapril group at 4 weeks and 8 months post-randomization (both p<0.0001). Conversely, 
BNP levels were approximately 23% higher in the sacubitril/valsartan combination tablet 
group compared to the enalapril group at 4 weeks and 8 months post-randomization (both 
p<0.0001). These findings are consistent with NT-proBNP not being a substrate of neprilysin, 
whereas BNP is a substrate of neprilysin; levels of BNP reflect the action of the drug whereas 
NT-proBNP levels reflect the effect of the sacubitril/valsartan combination on the heart 
[PARADIGM-HF data on file, [Packer 2014]]. 
 
Table 1-1 
Adverse reactions occurring at an incidence of >5% of patients in the 
double-blind period of PARADIGM-HF were as follows: 
 
Sacubitril/valsartan (N=4203) 
% 
Enalapril (N=4220) 
% 
Hypotension 
18 
12 
Hyperkalemia 
12 
14 
Cough 
9 
13 
Dizziness 
6 
5 
Renal failure/acute renal failure 
5 
5 
 
 
Angioedema occurred at rate of 0.5% in the sacubitril/valsartan arm compared to 0.2% in the 
enalapril arm (ENTRESTO USPI). 
The combination of sacubitril/valsartan was evaluated in a multicenter, randomized, double- 
blind, and parallel group design in heart failure patients with reduced ejection fraction to 
assess the safety and tolerability of two different titration regimens (NCT01922089). Patients 
were stratified on low RAAS inhibition (whether they were ACEi/ARB naïve or receiving 
≤10 mg daily of enalapril or ≤ 160 mg daily of valsartan (or equivalent doses of other 
ACEi/ARBs)) or high RAAS inhibition stratum. This high RAAS inhibition stratum was 
defined as receiving > 10 mg daily of enalapril or > 160 mg daily of valsartan (or equivalent 
doses of other ACEi or ARBs). The patients underwent dosing with 50 mg BID during the 
open-label run-in period of 5 days, and then were randomized to titration of the  target dose  
of 97/103 mg twice daily over 6 weeks (conservative up-titration) compared to three weeks 
(condensed up-titration). 540 patients entered the run-in period and 498 were randomized.  
The primary endpoint was the proportion of patients experiencing pre-specified  adverse 
events (AEs) and pre-specified laboratory assessment outcomes. The results were presented at 
the European Society of Cardiology Heart Failure meeting in 2015. The combination of 
sacubitril/valsartan demonstrated an acceptable safety and tolerability profile regardless of the 


 
 
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up-titration regimen. After excluding non-adverse events discontinuations or death-related 
discontinuations, >76% of patients achieved and maintained the target dose of 97/103 twice 
daily for 12 weeks. Achievement of target dose was possible even in patients who required 
dose interruption or down-titration during the study period, and rates of AEs were generally 
lower than in the PARADIGM-HF trial. Hypotension occurred in 9.7% of the condensed 
regimen compared to 8.4% in the conservative regimen; renal dysfunction occurred in 7.3%  
of condensed compared to 7.6% in the conservative regimen, hyperkalemia occurred in 7.7% 
in the condensed regimen compared to 4.4% in the conservative regimen and angioedema 
occurred in 0.0% in the condensed regimen compared to 0.8% in the conservative regimen. 
ENTRESTO™ (sacubitril/valsartan) received FDA approval on 07July2015. It is indicated to 
reduce the risk of cardiovascular death and hospitalization for heart failure in patients with 
chronic heart failure (NYHA class II-IV) and reduced ejection fraction. It is usually 
administered in conjunction with other heart failure therapies in place of an ACE inhibitor or 
other ARB. The approved dosages are 24/26 mg, 49/51 mg, and 97/103 mg twice daily. 
During the prior clinical studies 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 
mg, 100 mg and 200 mg, respectively. 
The present study will be the first study to examine sacubitril/valsartan combination tablet 
administration during ADHF and whether it can safely mitigate the adverse neuro -hormonal 
activation that persists and contributes to the unacceptably high adverse event rate currently 
observed in the first months after hospitalization for ADHF as determined by the effect on 
NT-proBNP in this patient population. Importantly, although it is likely that clinical events 
(i.e., death, hospitalizations, etc.) will occur in the patients randomized in the present study, 
there is not enough statistical power to assess the effect on these hard clinical outcomes and 
therefore this trial will not include differences in the rate of mortality or HF hospitalizations  
as part of the primary or secondary endpoints. These endpoints will only be analyzed for the 
purpose of safety evaluation. 
 
1.2 
Rationale for protocol amendment 
Amendment 2 (05Oct2017) 
On the basis of blinded review of the projected aggregated (enalapril and sacubitril/valsartan 
treatment groups combined) rate of missing samples for NTproBNP, this rate exceeds the 
initial trial assumption of 10%. The sample size has been increased to 882 patients in order to 
preserve the originally intended power. 
Given interest in the effect of sacubitril/valsartan on NTproBNP after titration to dose level 3, 
a secondary endpoint has been added. 
 
 


 
 
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Amendment 1 (28Jul2016) 
The protocol inclusion criteria have been modified to be more closely aligned with clinical 
practice in the United States where patients with acute decompensated heart failure are often 
rapidly stabilized and transitioned from intravenous to oral diuretic therapy so as to move 
efficiently to outpatient care, with close follow-up. The protocol has been modified to include 
patients who are at least 24 hours from hospital presentation versus 48 hours. This change was 
instituted to allow sites to randomize stabilized patients who otherwise might be discharged 
earlier than 48 hours. In addition, the window of eligibility, which had been set at 5 days, has 
been extended to 10 days to permit inclusion of patients who have longer hospitalizations (e.g. 
due to initial diagnostic uncertainty). 
Because a substantial proportion of patients who are stabilized with medical therapy for acute 
decompensation heart failure are asymptomatic with a systolic blood pressure that remains 
predominantly within the range of 100 – 110 mm Hg, the inclusion  criterion  regarding 
systolic blood pressure has been lowered to ≥100 mmHg. The SBP stabilization period was 
also changed from 24 hours to 6 hours because a 6 hour window is considered an adequate 
period of time to establish stability. 
 
1.3 
Changes to protocol 
Changes to specific sections in the protocol are shown in the track changes version of the 
protocol using the strike through font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities. 
The changes described in this amendment require IRB/IEC approval prior to implementation. 
In addition, since the changes herein do affect the informed consent, sites will be required to 
update and submit for approval a revised informed consent that takes into account the changes. 
 
1.4 
Purpose 
The purpose of this study is to assess the effect of in-hospital initiation of sacubitril/valsartan 
vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been 
stabilized following hospitalization for acute decompensated heart failure (ADHF) and 
reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%). 
 
2 
Study objectives 
2.1 
Primary objective(s) 
The primary objective of this study is to assess the effect of in-hospital initiation of 
sacubitril/valsartan vs. enalapril on the time-averaged proportional change of NT-proBNP 
from baseline in patients who have been stabilized following hospitalization for ADHF and 
reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%). Weeks 4 and 8 
will be included in the analysis (primary analysis time point). 


 
 
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2.2 
Secondary objectives 
To examine the effect of sacubitril/valsartan vs. enalapril on: 
• The proportional change in NT-proBNP from baseline to Week 8 
• Incidence of symptomatic hypotension during 8 weeks of treatment 
• Incidence of hyperkalemia (Potassium >5.5 mEq/L) during 8 weeks of treatment 
• Incidence of angioedema during 8 weeks of treatment 
• Biomarkers: hs-Troponin (high sensitivity), urinary cGMP and BNP to NT-proBNP ratio 
at 4 and 8 weeks 
 


 
 
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3 
Investigational plan 
3.1 
Study design 
This study will use a randomized, double-blind, double-dummy, active-controlled, parallel 
group design. Eligible patients hospitalized for ADHF will be randomized no earlier than 24 
hours and up to ten days of presentation while still hospitalized. 
At the time of randomization, patients will have been stabilized, defined for this study as: 
• SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic 
hypotension 
• No increase (intensification) in i.v. diuretic dose within last 6 hours prior to 
randomization 
• No i.v. inotropic drugs for 24 hours prior to randomization 
• No i.v. vasodilators including nitrates within last 6 hours prior to randomization 
 
All patients will need to meet all other inclusion and none of the exclusion criteria. 
In order to provide for a necessary 36 hour washout of prior ACEi treatment prior to receiving 
sacubitril/valsartan (known as LCZ696 in prior trials), the supplied blinded study drug for 
those allocated to sacubitril/valsartan will be placebo only until the 3rd dose. Because the  
study is blinded, ALL patients, regardless of randomization arm, need to remain  in  the 
hospital for six hours after they have received their 3 rd dose of study medication. Please see 
Figure 3-2. 
Patients will be randomized to sacubitril/valsartan or enalapril. Initial dose will be determined 
by the blood pressure at the time of randomization. Study treatment will be titrated t o the 
Level #3 target doses of sacubitril/valsartan 97/103 mg bid and enalapril 10 mg bid. Titration 
will be based on blood pressure at the time of the visit. Dose adjustments will only be allowed 
if indicated per protocol defined safety and tolerability criteria and investigator judgement. 
At the end of the 8-week treatment period ALL patients will need to have a 36 hour washout 
from study treatment prior to starting the open label extension to ensure that the blinding of  
the core study is maintained. To facilitate this washout, patients should take their final dose of 
study drug on the morning of their week 8 visit and then begin open label sacubitril/valsartan 
after 36 hours in the evening of week 8 visit + one day. 
All patients will start open label treatment on sacubitril/valsartan at their final dosing level 
during double blind treatment. However, at an investigator’s judgement, starting dose may be 
adjusted by one dose level up or down. 
The intent of the open-label phase is to have the patients up-titrated to the desired dose level 
#3 (97/103 mg sacubitril/valsartan) based on clinical need and investigator judgement. 


 
 
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Figure 3-1 
Study Design 
 
3.2 
Rationale of study design 
Hospitalization for ADHF identifies patients at increased risk of death and re-hospitalization 
following discharge. This increased risk justifies intervention with novel treatment strategies 
initiated prior to hospital discharge to improve patient outcomes. Both  the PARAMOUNT  
and PARADIGM-HF trials demonstrated reductions in the NT-proBNP compared to the 
comparator enalapril and valsartan, respectively, in both the chronic reduced ejection fraction 
and preserved ejection fraction heart failure patients. PARADIGM-HF demonstrated 
reductions in the NT-proBNP values seen at both 4 weeks and 8 months post randomization in 
the arm receiving the combination of the sacubitril/valsartan compared to the enalapril arm. In 
the current protocol, the primary endpoint of NT-proBNP will be evaluated at both the 4 and 8 
week intervals to better assess the short-term benefit/risk ratio of sacubitril/valsartan  
compared to enalapril in patients who have been stabilized from an ADFH hospitalization in 
the setting of reduced ejection fraction. 
The need for a 36-hour wash-out period is required per the FDA approved USPI label because 
there is a potential for increased risk for angioedema in patients who receive both an ACE 
inhibitor and the combination of sacubitril/valsartan. The requirement to stop the ARB is 
because there is an ARB contained within sacubitril/valsartan combination. The open-label 
period of 4 weeks provides the opportunity for every patient to receive sacubitril/valsartan and 
evaluate the change in NT-proBNP and other biomarkers in patients who had been previously 
receiving enalapril, while still being monitored for safety outcomes. 
 


 
 
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3.4 
Rationale for choice of comparator 
Treatment with ACEI has been well established as the standard of care for RAAS blockade 
and is recommended by treatment guidelines as a 1A recommendation for all patients with 
CHF and reduced LVEF, unless ACEI-intolerant. As a well-studied ACEI in heart failure, 
enalapril has been selected as the comparator for this study with a target dose of 10 mg BID 
The 10 mg BID dose was the same target dosage studied in the SOLVD study and is the dose 
that was chosen   in the PARADIGM-HF trial. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
 
3.6 
Risks and benefits 
All patients randomized to the sacubitril/valsartan treatment arm will be given matching 
placebo doses of both sacubitril/valsartan and enalapril on the day of randomization to fulfill 
the requirement for a 36 hour washout prior to sacubitril/valsartan treatment initiation. The 
first active dose of sacubitril/valsartan treatment will be the third dose of study drug received 
after randomization. The 36 hour wash out period is required to minimize the interaction 
between an ACEi and sacubitril in potentiating the development of angioedema. Patients 
randomized to the enalapril treatment arm do not require a washout, but will receive 
sacubitril/valsartan matching placebo in addition to active enalapril starting on the day of 
randomization. 
Since this is a double blind study, all study patients must remain in the hospital for at least 6 
hours following the third dose of study medication even though the 36 hour wash out is only 
required for patients randomized to sacubitril/valsartan. This will allow for the first dose of 
active sacubitril/valsartan (third dose of study medication) to be administered in the hospital 
and will ensure that the blind is maintained. 
All patients will be allowed to continue receiving the rest of their background cardiovascular 
(CV) medications. The risk to patients in this trial will be minimized by compliance with the 
eligibility criteria and close clinical monitoring. A Data Monitoring Committee (DMC) will 
also monitor the study for all safety considerations, since this population represents a patient 
population who are being initiated on study drug during the same hospitalizat ion for 
admission for acute decompensated heart failure. 


 
 
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Figure 3-2 
36 hour washout design 
 
 
 
RANDOMIZATION (0 hr) 
1st Dose 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RANDOMIZATION (0 hr) 
1st Dose 
Active Drug 
12 hrs post 
randomization 
2nd Dose 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 hrs post 
randomization 
2nd Dose 
Active Drug 
24 hrs post 
randomization 
3rd Dose 
Active Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 hrs post 
randomization 
3rd  Dose 
Active Drug 
 
All patients will be allowed to continue receiving the rest of their background cardiovascular 
(CV) medications. The risk to patients in this trial will be minimized by compliance with the 
eligibility criteria and close clinical monitoring. A Data Monitoring Committee (DMC) will 
also monitor the study for all safety considerations, since this population represents a patient 
population who are being initiated on study drug during the same hospitalization for 
admission for acute decompensated heart failure. 
 
4 
Population 
The study population will consist of male and female patients, ≥ 18 years of age, presenting to 
the hospital for acute decompensated heart failure. The goal is to randomize a total of 
approximately 882 patients to sacubitril/valsartan or enalapril in a 1:1 ratio in approximately 
170 centers in the United States. At the time of randomization, patients will have been 
stabilized, defined for this study as: 
• SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic 
hypotension 
• No increase (intensification) in i.v. diuretic dose within last 6 hours prior to 
randomization 
• No i.v. inotropic drugs for 24 hours prior to randomization 
• No i.v. vasodilators including nitrates within last 6 hours prior to randomization; 
All patients will need to meet all other inclusion and none of the exclusion criteria. 
Last dose of previous ACEi 
sacubitril/valsartan 
Screening 
36 hour washout for sacubitril/valsartan treatment arm 
6 hour 
observation 
enalapril 
Last dose of previous ACEi 


 
 
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4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Possess the capacity to provide written informed consent which must be obtained before 
any assessment is performed. 
2. Patients ≥ 18 years of age, male or female. 
3. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to 
have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales 
on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization. 
4. Eligible patients will be randomized no earlier than 24 hours and up to ten days after 
presentation while still hospitalized as long as meet the following definition of stable 
status: 
• SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no 
symptomatic hypotension 
• No increase (intensification) in i.v. diuretic dose within last 6 hours prior to 
randomization 
• No i.v. inotropic drugs for 24 hours prior to randomization 
• No i.v. vasodilators including nitrates within last 6 hours prior to randomization 
 
5. LVEF ≤40% within the past 6 months (including current hospitalization) using 
echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or  
ventricular angiography, provided no subsequent study documented an EF of >40%. 
6. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization. 
 
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 investi gator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days. 
2. Enrollment in any other clinical trial involving an investigational agent or 
investigational device. 
3. History of hypersensitivity, known or suspected contraindications, or intolerance to any 
of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor). 
4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB 
therapy. 
5. Requirement of treatment with both ACE inhibitor and ARB. 
6. eGFR < 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in 
Renal Disease (MDRD) formula at screening. 
7. Serum potassium > 5.2 mEq/L at screening. 


 
 
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8. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other 
major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, 
within one month prior to Visit 1. 
9. Primary cause of dyspnea due to non-cardiac, non-heart failure causes such as acute or 
chronic respiratory disorders. 
10. Intended coronary or carotid artery revascularization within the 6 months after Visit 1. 
11. Implantation of a cardiac resynchronization therapy device (CRTD) within the prior 3 
months from Visit 1or intent to implant a CRTD. 
12. History of heart transplant or patients who are on a transplant list or with left 
ventricular assistance device (LVAD). 
13. Isolated right HF due to severe pulmonary disease. 
14. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 
months prior to Visit 1. 
15. Symptomatic bradycardia or second or third degree heart block without a pacemaker. 
16. Presence of hemodynamically significant mitral, aortic or hypertrophic obstructive 
cardiomyopathy. 
17. History of malignancy of any organ system (other than localized basal cell carcinoma 
of the skin), treated or untreated, within the past year with a life expectancy of less than 
1 year. 
18. Known hepatic impairment (as evidenced by total bilirubin > 3 mg/dL, or increased 
ammonia levels, if performed), or history of cirrhosis with evidence of portal 
hypertension such as varices. 
19. 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 
hCG laboratory test. 
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, including women whose career, lifestyle, or sexual orientation 
precludes intercourse with a male partner and women whose partners have been 
sterilized by vasectomy or other means, UNLESS they are using two birth control 
methods. The two methods can be a double barrier method (if accepted by the local 
regulatory authority and ethics committee) or a barrier method plus a hormonal method. 
• Adequate barrier methods of contraception include: diaphragm, condom (by the 
partner), intrauterine device (copper or hormonal), sponge or spermicide. 
Hormonal contraceptives include any marketed contraceptive agent that includes 
an estrogen and/or a progesterone agent. 
• Reliable contraception should be maintained throughout the study and for 7 days 
after study drug discontinuation. 
• 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 six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL 
and estradiol < 20 pg/mL or have had surgical bilateral oophorectomy (with or 


 
 
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without hysterectomy) 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. 
 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational and control treatment 
 
Table 5-1 
Investigational and comparator treatment 
All eligible patients will be randomized to receive either sacubitril/valsartan or enalapril. The 
following study treatment will be provided: 
 
 
Treatment 
Minimum 
dose 
Maximum 
dose 
Frequency 
Admin. 
Route 
sacubitril/valsartan 
24/26 mg 
97/103 mg 
BID 
oral 
sacubitril/valsartan matching 
placebo 
oral 
Enalapril 
2.5 mg 
10 mg 
BID 
oral 
Enalapril matching placebo 
oral 
 
 
Table 5-2 
Treatment Dose Levels 
 
Dose Level 
sacubitril/valsartan 
Enalapril 
1 
24/26 mg BID 
2.5 mg BID 
2 
49/51 mg BID 
5.0 mg BID 
3 
97/103 mg BID 
10 mg BID 
Both sacubitril/valsartan and enalapril and their matching placebos will be packaged and 
labeled by the sponsor in accordance with the US Code of Federal Regulation s governing 
handling of investigational treatments, and will be dispensed by the study physician. 
Matching placebo will also be needed for sacubitril/valsartan combination tablet and matching 
placebo for the enalapril for the first day of treatment to allow for the 36-hour washout 
required for patients randomized to the sacubitril/valsartan treatment arm. 
Each participating hospital will be provided with a central supply kit containing dose levels 1 
and 2 and their matching placebos. Bottles will be numbere d and assigned via an Interactive 
Web Response System (IWRS). On the day of randomization (visit 2), the IWRS system will 
assign both a hospital kit and a patient kit. 
Treatment for the day of randomization will be provided to the patients from the hospital kit. 
Treatment for the second day of dosing onward will be provided from the patient kit which 
patients will take home upon discharge. 


 
 
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Patients not tolerating the target dose of sacubitril/valsartan 97/103 mg bid or enalapril 10 mg 
bid will be titrated down to the lower dose level (including active medication and matching 
placebos), at the investigator’s discretion, based on the defined safety and tolerability criteria. 
Sacubitril/valsartan dose or enalapril dose levels may be increased to the targeted desired dose 
level #3 of 97/103mg twice daily or enalapril 10 BID on an every 2 week basis or earlier if 
based on clinical need and investigator judgement. 
Patients not tolerating the target dose level #3 of sacubitril/valsartan 200 mg BID or enalapril 
10 mg BID will be titrated down to the lower dose level (including active medication and 
matching placebos), at the investigator’s discretion, based on the defined safety and 
tolerability criteria. 
This study is designed as a double-blind, double-dummy trial to ensure the blinding during the 
entire course of the study. To maintain the blinding, patients will be required to take their 
assigned active treatment tablet along with placebo matching the opposite treatment twice 
daily. 
All study sites will be provided with a Treatment Manual describing the treatment packaging 
and treatment instructions. 
 
5.1.2 
Additional study treatment 
 
Treatment 
# of 
patients 
Minimum 
dose 
Maximum 
dose 
Frequency 
Admin. 
Route 
Open-label 
sacubitril/v 
alsartan 
882 
Dose level 
#1 (24/26 
mg) 
Dose level 
#3 (97/103 
mg) 
BID 
oral 
 
 
Open-label sacubitril/valsartan will be packaged and labeled by the sponsor in accordance 
with the US Code of Federal Regulation governing handling of investigational treatments, and 
will be dispensed by the study physician. Open-label treatment will be provided for a 4-week 
follow up. 
All patients will start open label treatment on sacubitril/valsartan at their final dosing level 
during double blind treatment. However, at an investigator’s judgement, starting dose may be 
adjusted by one dose level up or down. 
The intent of the open-label phase is to have the    patients up-titrated to the desired dose level 
#3 (200 mg sacubitril/valsartan) based on clinical need and investigator judgement. 
 
5.2 
Treatment arms 
Patients will be randomized in a 1:1 ratio to either sacubitril/valsartan or enalapril. 
 
5.3 
Treatment assignment, randomization 
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 
randomization list will be produced by or under the responsibility of Novartis D rug Supply 


 
 
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Management using a validated system that automates the random assignment of treatment 
arms to randomization numbers in the specified ratio. 
Eligible patients will be randomized no earlier than 24 hours after presentation at the hospital 
and no later than within ten days of admission, while still hospitalized, via IWRS to one of the 
treatment arms. The investigator or his/her delegate will contact the IWRS after confirming 
that the patient fulfills all the study entry criteria. The IWRS will assign a randomization 
number to the patient, which will be used to link the patient to a treatment arm and will 
specify which bottle from the centralized hospital supply the patient will be dosed for the first 
day and a unique medication number for the first package of investigational treatment to be 
dispensed to the patient. The initial dose will be determined by the patient’s blood pressure at 
the time of the call to the IWRS. 
The randomization numbers will be generated using the following procedure to ensu re that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IWRS 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 validat ed system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Initial dose at randomization will be determined by systolic blood pressure (SBP). See Table 
5-3. 
Dose adjustments to lower dose levels may be made at any time at both scheduled and 
unscheduled visit only if clinically indicated for blood pressure control/tolerability reasons. 
Dose adjustments to increase dose levels may be made at any tim e at both scheduled and 
unscheduled visits based on clinical need or investigator judgement. 
Subsequent supplies of study drug will be assigned in the following manner. The investigator 
or his or her delegate will call the IWRS and provide the patient’s number. The IWRS will ask 
the caller whether there is a change in the dose level of the study drug. If the caller indicates 
that there is no change in the dose level, the IWRS will provide the unique medication 
numbers of the study drug with the same dose le vel that was dispensed at the previous 
dispensing. If the caller indicates that the dose level has changed since the last dispensing, the 
IWRS will ask the caller which dose level should be dispensed. The caller will enter the dose 
level to dispense or whether no study drug should be dispensed (in case of study drug 
withdrawal). If applicable, the IWRS will provide the unique medication numbers for the  
study drug supplies that should be dispensed at the new dose level. 
 
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: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study with the exception 
of the IWRS provider generating the randomization code, members of the DMC and the 
independent biostatistician assigned to the DMC. (2) The identity of the treatments will be 


 
 
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concealed by the use of investigational treatments that are identical in packaging, labeling, 
and schedule of administration, appearance, taste and odor. 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.11) and at the 
conclusion of the study. 
 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the 4-digit site 
number (e.g., 0501, 0502 etc.) assigned by Novartis and a 5-digist sequential number assigned 
by the investigator (e.g., 00001, 00002, etc.). Hence a 9 -digit study patient identification 
number, e.g., 050100001. Once assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number  
by the investigator. The investigator or his/her staff will contact the IWRS and provide the 
assigned patient study identification number along with the requested identifying information 
for the patient to register them into the IWRS. The site will enter this number on the electronic 
case report form (eCRF) in the electronic data capture system (EDC). 
 
5.5.2 
Dispensing the investigational and comparator treatment 
Each study site will be supplied by Novartis with investigational and comparator treatment in 
packaging of identical appearance. Each hospital will be provided a kit for Day 1 of treatment, 
from which all patients will be provided their first 2 doses. This kit will include dose levels 1 
and  2  and  their matching placebos. Since  the  first  day of  treatment  is  placebo only for 
patients randomized to the sacubitril/valsartan arm in order to facilitate the required 36-hour 
washout, the bottles assigned for the sacubitril/valsartan treatment arm will all contain 
placebos. Patients will receive their first 2 doses from the centralized hospital supply. The  
third dose of treatment will be provided from the patient supply that will be sent home with  
the patient upon discharge. 
The investigational and control treatment packaging will have a 2 -part label. A unique 
randomization number is printed on each part of this label which corresponds to one of the 2 
treatment arms and a dose level. Investigator staff will identify the investigational treatment 
package(s) to dispense to the patient by contacting the IWRS 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. 
 
5.5.3 
Handling of study treatment 
 
5.5.3.1 
Handling of investigational and comparator treatment 
Investigational and comparator 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 investigational and comparator 
treatment should be stored according to the instructions specified on the labels. Clinical 


 
 
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supplies are to be dispensed only in accordance with the protocol. Medication labels will 
include storage conditions but no information about the patient except for the medication 
number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational and comparator treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by field monitors during site visits or remotely and at the 
completion of the trial. Patients will be asked to return all unused investigational or 
comparator treatment and packaging at the end of the study or at the time of discontinuation  
of treatment. 
At the conclusion of the study, and as appropriate during the course o f the study, the 
investigator will return all unused investigational and comparator treatment, packaging, drug 
labels, and a copy of the completed drug accountability log according to the instructions 
provided by Novartis or its agents. 
 
5.5.3.2 
Handling of other study treatment 
Each study site will be supplied by Novartis with open -label sacubitril/valsartan for the 4- 
week open-label follow up period. The IWRS will need to be called to receive drug shipments 
prior to dispensing. 
The open-label sacubitril/valsartan packaging will have a 2-part label. Investigator staff will 
identify the treatment package(s) to dispense to the patient by contacting the IWRS 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. 
Open-label sacubitril/valsartan 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 open-label sacubitril/valsartan 
treatment should be stored according to the instructions specified on the labels. Clinical 
supplies are to be dispensed only in accordance with the protocol. Medication labels will 
include storage conditions but no information about the patient except for the medication 
number. 
The investigator must maintain an accurate record of the shipment and dispensing of open- 
label sacubitril/valsartan treatment in a drug accountability log. Monitoring of drug 
accountability will be performed by field monitors during site visits or remotely and at the 
completion of the study. Patients will be asked to return all unused open-label treatment and 
packaging at the end of the study or at the time of discontinuation of treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused open-label treatment, packaging, drug labels, and a copy of 
the completed drug accountability log according to the instructions provided by Novartis or its 
agents. 


 
 
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5.5.4 
Instructions for prescribing and taking study treatment 
All medication for the duration of the study will be provided by Novartis. Eligible patients  
will be randomized via IWRS to either sacubitril/valsartan or enalapril. Patients randomized  
to the sacubitril/valsartan arm will receive sacubitril/valsartan matching placebo for the first 
day of treatment to fulfill the required 36 -hour wash-out period (in addition to enalapril 
matching placebo). Patients randomized to enalapril will not require a washout and will 
receive active treatment on the first day of treatment, in addition to sacubitril/valsartan 
matching placebo. The first day of dosing will be provided from a centralized hospital supply 
containing dose levels 1 and 2 and matching placebos. 
From the second day of treatment (third dose), patients will be provided with sufficient 
medication to last until the next scheduled visit. In order to adequately blind  the  study, 
patients will be required to take a total of two tablets (one tablet from the sacubitril/valsartan / 
sacubitril/valsartan matching placebo pack and one tablet from the enalapril/enalapril 
matching placebo pack) twice a day for the duration of the study. 
Initial dose at randomization will be determined by systolic blood pressure (SBP). 
• All patients with a systolic blood pressure (SBP) of ≥100 to ≤120 mm Hg will start at 
Dose level #1 (2.5 mg Enalapril or 24/26 mg sacubitril/valsartan, BID). 
• Patients with a SBP ≥ 120 mm Hg will start at dose level #2 (5 mg enalapril or 49/51 
mg sacubitril/valsartan, BID). 
• Patients will be titrated to the next dose level at Weeks 1 and 2 (Visits 3 and 4) with 
the goal of reaching the target dose for dose level #3 (10 mg enalapril or 97/103 mg 
sacubitril/valsartan, BID) by week 2 (Visit 4). 
• Patients should be titrated to the next dose level at week 1 only if their SBP is >110 
mm Hg and at week 2 if their SBP is > 100 mm Hg. 
Dose titration will proceed according to the following table: 
 
Table 5-3 
Dose titration schedule based on SBP 
 
Visit 
Previous dose 
level 
Systolic Blood 
pressure mm Hg* 
Start/remain/tit 
rate to: Dose 
level # 
Baseline (Visit 2) 
N/A 
≥ 100 
1 
N/A 
≥120 
2 
1 
<110 
1 
1 Week (Visit 3)** 
1 
≥110 
2 
2 
<110 
2 
2 
≥110 
3 
1 
<100 
1 
2 weeks (Visit 4) 
1 
≥100 
2 
2 
<100 
2 
2 
≥100 
3 


 
 
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Visit 
Previous dose 
level 
Systolic Blood 
pressure mm Hg* 
Start/remain/tit 
rate to: Dose 
level # 
1 
<100 
1 
4 Weeks (Visit 5) 
1 
≥100 
2 
2 
<100 
2 
2 
≥100 
3 
1 
<100 
1 
6 Weeks (Visit 6) 
1 
≥100 
2 
2 
<100 
2 
2 
≥100 
3 
 
**Up titration may be done prior to the week 1 visit for patients who were started at dose  
level 1 who were previously on high dose RAS blockade (˃10 mg enalapril  total daily dose  
or > 160 mg valsartan  total daily dose or equivalent doses of other ACEi or ARB). 
Dose adjustments to lower dose levels may be made at any time at both scheduled and 
unscheduled visits only if indicated for blood pressure control/tolerability reasons. 
Study medication should be taken with a glass of water with or without food. If the patient 
misses taking any study drug dose, he/she should take it as soon as possible, unless 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 dosage prescribed and dispensed to the patient and all dose changes during the study must 
be recorded in the IWRS and on the Dosage Administration Record eCRF. 
The investigator should 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 should be instructed to contact the investigator 
if he/she is unable to take the study treatment as prescribed for any reason. 
All patients that complete 8 weeks of treatment will proceed with a 4 -week follow up on 
open-label sacubitril/valsartan. All patients will have the wash out in order to maintain the 
blinding of the core study. To facilitate this washout, patients should take their final dose of 
study drug on the morning of their week 8 visit and then begin open label sacubitril/valsartan 
after 36 hours in the evening of week 8 visit + one day. All patients will start open label 
treatment on sacubitril/valsartan at their final dosing level during double blind treatment. 
However, at an investigator’s judgement, starting dose may be adjusted by one dose level up 
or down. 
The intent of the open-label phase is to have the patients up-titrated to    the desired dose level 
#3 (200 mg sacubitril/valsartan) based on clinical need and investigator judgement. 


 
 
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5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Every attempt should be made to maintain patients on the target study drug dose level for as 
long a duration as possible throughout the study. If, however, in the opinion of the 
investigator, a patient is unable to tolerate the protocol-specified target dose, the investigator 
should consider whether dose adjustments of concomitant medications may rectify the 
situation before reducing the dose of study treatment. If adjustment of the concomitant 
medications is not possible or does not alleviate the side effects of concern, the investigator 
may down-titrate the dose of the study drug to the previous dose level. If needed, the study 
drug may be stopped completely, but the patient should continue to attend the study visits and 
be followed until the completion of the study. Patients may restart their current dose of study 
drug following an interruption of treatment, based on investigator judgment. 
Study drug dose level adjustments should be mainly based on overall safety and tolerability 
with special focus on hyperkalemia, symptomatic hypotension 
 
 
 
Adjustment of study drug dose level 
If necessary, the patient may be down-titrated to the next lower dose level. The patient may 
continue receiving the lower dose level for a recommended period of 1 to a maximum of 4 
weeks. Re-challenge to titrate back up to the target dose level should be attempted at 2 weeks. 
It must be noted that the desired dose of study medication is the highest dose ( dose level #3), 
but patient tolerability and safety must be taken into account. 
If the tolerability issues are not alleviated despite down -titration by one dose level, the 
investigator may lower the study drug dose further to the next lower level for 1 to a maximum 
of 4 weeks, up to temporary withdrawal of the study drug. Again, once stable, the patient 
should be re-challenged with up-titration to the next higher dose level in an attempt to bring 
back the patient gradually to the target study drug dose level (dose level #3). The investigator 
may choose the next dose level for down - or up-titration according to his or her clinical 
judgment. The IWRS should be contacted to register any changes in the patient’s study drug 
dose level, including in cases of temporary and permanent withdrawal 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 of study medication (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, but reasons for not getting 
to dose level #3 need to be clearly described in the eCRF. 
 
Study drug restart after temporary treatment interruption 
Study drug should be reintroduced in those who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator. 


 
 
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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 up to dose level 3 every 1 to 4 weeks, as per the investigator’s judgment. Patients re - 
started on the study drug will retain their original randomization and study identification 
numbers. Should the patient not tolerate the re-start study drug dose level, he/she may be 
down-titrated again (if appropriate) or discontinue the study medication. 
Study visits should occur as close as possible to the pre-defined visit schedule. The timeframe 
between the regular visits should be maintained as scheduled, irrespective of the number of 
unscheduled visits that may be performed in between, according to the visit and time schedule 
described in Table 6-1. 
Any changes in the study drug dose level, including temporary/permanent withdrawal or re - 
start of the study drug, must be recorded on the Dosage Administration Record eCRF and 
registered in the IWRS. 
In case of pregnancy discovered during the study, the patient should be instructed to stop 
taking the study drug immediately. 
 
5.5.6 
Rescue medication 
Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to 
investigators in the appendices. Patients may receive open -label (non-study medications) 
ACEIs and/or ARBs during the study ONLY if the study medication has been discontinued 
either temporarily or permanently. A 36 hour wash-out period is required when switching 
from or to an ACE inhibitor. Use of rescue medication must be recorded in the eCRF. 
 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into t he study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after informed consent must be recorded on the Concomitant medications or 
Surgeries and Medical Procedures eCRF. 
 
ACEIs and ARBs: 
Patients’ pre-study ACEIs/ARBs will be replaced with the study medication. 
The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient is 
receiving study medication. If the investigator believes that addition of an ACEI or ARB is 
necessary, then study drug must be discontinued. Study medication should be stopped 36 
hours prior to addition of open-label ACEI. If not already treated with aldosterone antagonist, 
consideration should be given to adding this therapy rather than an ACEI or and ARB, while 
monitoring renal function. 


 
 
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Other heart failure and cardiovascular medication 
If a patient’s condition warrants any change in concomitant heart failure or cardiovascular 
medications, changes may be made at the investigator’s discretion. 
Oral diuretics may be used and may be adjusted throughout the study duration at the  
discretion of the investigator. 
 
Medications known to raise potassium levels 
Potassium sparing diuretics, potassium supplements, aldosterone antagonists, and any other 
medications known to raise potassium levels should be used with caution while the patient is 
receiving study medication due to the increased possibility of occurrence of hyperkalemia. 
Potassium levels should be monitored regularly especially in those who are receiving these 
medications. 
Concomitant administration of renin inhibitors, such as aliskiren, is prohibited. 
 
Phosphodiesterase-5 (PDE-5) inhibitors 
PDE-5 inhibitors should be used with caution while the patient is receiving study medicatio n 
due to the increased possibility of occurrence of hypotension. 
 
Nesiritide and intravenous nitrates 
The concomitant admission of sacubitril/valsartan with nesiritide and intravenous nitrates has 
not been studied. Concomitant use of nesiritide will not be permitted during the study. 
 
Other medications 
Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to avoid 
interference with study drug absorption. 
 
5.5.8 
Discontinuation of study drug 
Patients may voluntarily discontinue the study drug for any reason at any time. 
Study drug must be discontinued under the following circumstances: 
• Withdrawal of consent 
• Pregnancy 
• Use of prohibited concomitant medication 
• Any protocol deviation that constitutes a risk to the patient 
• Investigator believes that continuation of study drug may be detrimental to the patient’s 
well-being 
 
Study medication may be discontinued at the investigator’s discretion if any of the following 
occur: 
• Any severe suspected drug related AE 


 
 
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• Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator to determine if 
it constitutes a reason for discontinuation of study medication. 
• Depending on the serum potassium, blood pressure, or eGFR, patients may need to have 
their study drug dose or the dose of another concomitant medication reduced or 
discontinued; or, if appropriate, have potentially contributing agents adjusted. Refer to 
appendices for treatment guidelines for hyperkalemia, hypotension or renal dysfunction, 
respectively. 
In the case of study drug discontinuation, patients should remain in the trial and attend follow- 
up visits. If the patient refuses, he/she should be contacted by telephone to obtain follow-up 
health status information in place of protocol-specified visits unless the patient expressly 
refuses such contacts. 
The investigator must notify the IWRS of any study drug discontinuation and record it on the 
drug administration eCRF. 
 
5.5.9 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 
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 assessm ents 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 sites must request permission from patients who withdraw 
consent for a final telephone contact for patient health status. 
At the time a patient withdraws consent, the investigator must make every effort to determine 
the primary reason for this decision and record this information. Study drug 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. 
 
5.5.10 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls,  
registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred. 
 
5.5.11 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. 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 IWRS. 
When the investigator contacts the system to break a treatment code for a patient, he/she must 


 
 
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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 Clinical Trial Lead 
(CTL) that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place in case of an 
emergency. The investigator will inform the patient how to contact his/her backup in cases of 
emergency when he/she is unavailable. The investigator will provide protocol number, study 
treatment name if available, patient number, and instructions for contacting Novartis Country 
Pharma Organization CPO (or any entity to which it has delegated responsibility for 
emergency code breaks) to the patient in case an emergency treatment code break is required 
at a time when the investigator and backup are unavailable. 
 
5.5.12 
Study completion and post-study treatment 
At the end of study visit, patients will be asked to return all remaining study drug. The 
investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
When the patient has completed all scheduled study assessments, the investigator must call 
the IWRS to record the patient completion in the IWRS. 
 
5.5.13 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should 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 
All assessments are listed in Table 6-1. Assessments that are to be reported in the clinical 
database are marked with an ‘x’. Assessments that will only be reported in the source 
documentation are marked with a ‘s’. Patients should be seen for all visits on the designated 
day or as close to it as possible. 
The screening period may begin following an admission to hospital for ADHF. Clinical 
assessments performed during a patient’s hospitalization, prior to signing of informed consent, 
may be used for Visit 1/Screening. Eligible patients may be randomized once it is confirmed 
that they meet all inclusion criteria and none of the exclusion criteria. 
 
Patients may be contacted for safety evaluations for 30 days after the last dose of the 4 -week 
open-label follow-up period. Documentation of attempts to contact the patient should be 
recorded in the source documentation. 


 
 
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Unscheduled visits for safety/medication evaluation/unscheduled assessments are permitted at 
any time during the study. 
 
 
Table 6-1 
Assessment schedule 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Phase 
screening 
Treatment 
4 week 
f/u- 
titration 
4 week 
f/u 
Week 
1 
2 
4 
6 
8 
10 
~12 
Day 
-10 to -1 
1 
7 
14 
28 
42 
56 
70 
84 
Informed consent 
s 
Inclusion/exclusion 
criteria 
x 
x 
Demography/ 
medical history 
x 
Heart failure and CV 
disease history 
x 
ECG 
x 
Physical exam 
s 
s    
(cardiac 
related 
only) 
s 
s 
Height 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Waist/hip 
circumference 
x 
HF signs and 
symptoms and 
NYHA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HF and CV 
medications 
x 
x8 
x 
x 
x 
x 
x 
x 
Conmeds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AE/SAE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test 
x 
x4 
x 
x 
x 
Plasma BNP or NT- 
proBNP 
x9 
x 
x 
x 
x 
x 
x 
Plasma/serum 
biomarkers1 
x 
x 
x 
x 
x 
x 
Spot urine 
biomarkers2 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
Chemistry 
x 
x 
x 
x 
x 
x 
x6 
x 


 
 
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Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Phase 
screening 
Treatment 
4 week 
f/u- 
titration 
4 week 
f/u 
Week 
1 
2 
4 
6 
8 
10 
~12 
Day 
-10 to -1 
1 
7 
14 
28 
42 
56 
70 
84 
Hematology 
x 
x 
x 
Hemoglobin A1C 
x 
IWRS call 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Randomization 
x 
Dispense treatment 
x 
x 
x 
x 
x 
x5 
x 
Drug accountability 
x 
x 
x 
x 
x 
x 
x 
Angioedema 
assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study completion – 
randomized 
treatment 
x 
Study completion – 
open label period 
x 
Post study 
completion follow 
up3 
s3 
1 includes cardiac, renal, and drug mechanism of action biomarkers 
2 include urinary markers such as cGMP. 
3Health status phone call 4 weeks after study completion (16 weeks). 
4Urine pregnancy test will be done at Visit 2 at the local laboratory. 
5At week 8, patients will receive open label sacubitril/valsartan and be instructed to not take study 
medication on the day of the final visit in order to fulfill the washout requirement 
6Limited chemistry panel.
 
 
8CV medications will be recorded at time of hospital discharge. 
9 BNP or NT-proBNP will be assessed at Visit 1 via local laboratory. NT-proBNP will be assessed 
via central laboratory for Visits 2-9. 
 
6.1 
Information to be collected on screening failures 
All patients who have signed informed consent but are not randomized will have the study 
completion page for the screening visit, 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 source data. 


 
 
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6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, ethnicity and source of patient referral. Relevant medical 
history/current medical condition data includes data collected up to the point in which 
informed consent is signed. Where possible, diagnoses and not symptoms, will be recorded. 
HF medications will be recorded in eCRFs separately from other medications. Likewise, 
detailed HF history and other relevant CV medical history will be recorded on eCRFs 
separately from other medical history. 
 
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 care giver. This information should be captured in the 
source document at each visit. Patient compliance should be at least 80% during the double - 
blind treatment period. The investigator and/or study personnel will counsel the patient if 
compliance is below 80%. Study drug accountability will also be determined by the site 
monitor while performing routine site visits and at the completion of the study. 
Duration of double-blind study drug exposure will be calculated based upon the start and stop 
dates recorded in the eCRF. 
 
6.4 
Efficacy 
The efficacy end points are: 
Primary: 
Time-averaged proportional change from baseline in NT-proBNP. Weeks 4 and 8 will be 
included in the analysis. 
Secondary: 
• The proportional change in NT-proBNP from baseline to Week 8 
• Biomarkers: hs-Troponin, urinary cGMP and BNP to NT-proBNP ratio 


 
 
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6.4.1 
Heart failure signs and symptoms 
Signs and symptoms of heart failure will be reviewed by the investigator at all visits during  
the study. The signs and symptoms evaluation may include, but are not limited to, paroxysmal 
nocturnal dyspnea, fatigue, edema, dyspnea at rest, dyspnea upon effort, orthopnea, rales, 
jugular venous distention, presence of a third heart sound. NYHA classification will be 
assessed and scored at each visit. 
 
 
 
6.4.3 
Biomarkers 
BNP or NT-proBNP will be obtained in all patients by using the local laboratory at Visit 1 to 
determine eligibility. NT-proBNP will be obtained in all patients using the central laboratory 
at Visits 2, 3, 4, 5 and 7  (randomization, weeks 1, 2, 4, and  8),       and at the end of the  open 
label extension, Visit 9 (Week 12). 
In addition, biomarker measurements will be obtained from serum and plasma samples at 
Visits 2, 3, 4, 5, 7 and 9 (randomization, 2, 4, 8 and 12 weeks), to determine effects of 
treatment on biomarkers of CV, CHF or renal risk. Spot urine will be collected at Visits 2, 3, 4, 
5, 7 and 9 (randomization, weeks 1, 2, 4, 8 and 12) to measure urinary cGMP. 
The selected biomarkers to be studied will be those believed to be relevant to the 
pathophysiology of the disease processes of heart failure and renal dysfunction. Biomarkers 
studies may include, but are not limited to those accessing cardiac and renal benefit or 
biomarkers related to the study drug mechanism of action such as: 
• Neurohormones BNP and NT-proBNP 
• hs-Troponin (will not be measured at Week 2) 


 
 
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• urinary cGMP 
Evaluation of Neprilysin measurement at baseline as a predictor of clinical outcome may be 
added depending on availability of a validated assay and sample handling requirements. The 
list may be changed or expanded further as new relevant biomarkers may be discovered  
during this study and after its completion. As such, serum and plasma will be bio -banked for 
analysis of yet to be identified diagnostic biomarkers. Details of sample collection, handling 
and shipment will be provided to investigators in the laboratory manual. 
 
6.4.4 
Appropriateness of efficacy measurements 
The selected efficacy variables for this study including changes in NT-proBNP and other 
biomarkers concentrations, as well as heart failure signs and symptoms are standard for the 
evaluation of therapeutic agents in a heart failure population. 
 
6.5 
Safety 
 
 
 
• Incidence of symptomatic hypotension 
• Incidence of hyperkalemia (Potassium >5.5 meq/l) 
• Incidence of angioedema 
Safety assessments will consist of monitoring and recording of all adverse events and serious 
adverse events, evaluation of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations. 
 
6.5.1 
Physical examination 
A complete physical exam will be performed at Visits 1, 7 and 9 (screening, weeks 8 and 12). 
It will include the examination of general appearance, skin, neck, eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, and vascular and neurological 
examinations. If indicated based on medical history, and/or symptoms, rectal, external 
genitalia, breast and pelvic exams will be performed. The Visit 4 (Week 2) physical exam will 
only be a cardiac care exam. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of the study drug must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings made after informed consent which meet the definition of an 
adverse event must be recorded on the Adverse Event eCRF. 


 
 
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6.5.2 
Vital signs 
Vital signs will be assessed at every visit. This will include blood pressure and pulse 
measurements. BP will be measured using a standard sphygmomanometer with an  
appropriate sized cuff and the non-dominant arm in the sitting position after 5 minutes of rest. 
Every effort should be made to use the same arm for the patient for all vital signs assessments 
and where possible, the same person doing the assessment. 
 
6.5.3 
Height, weight and waist/hip circumference 
Height in centimeters if possible will be measured at Visits 1 and 2. Body weight to the 
nearest 0.1 kg without shoes, will be measured at all visits. Waist/hip circumference to the 
nearest centimeter will be measured at Visit 1. 
 
6.5.4 
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. Although, the mechanism is not fully understood, bradykinin has  been  
implicated as the putative mediator. Therefore, medications that raise the levels  of  
endogenous bradykinin by inhibiting the enzymes responsible for its breakdown, such as ACE, 
aminopeptidase P, and NEP, may result in this potentially dangerous side effect. All suspected 
cases of angioedema, regardless of suspected causality, must be reported. The Angioedema 
Assessment forms must be completed and the Clinical Trial Lead or their designee must be 
notified. 
If the angioedema event meets SAE criteria, the investigator must ensure that an SAE form is 
completed and submitted to Novartis Drug Safety and Epidemiology. 
 
6.5.5 
Laboratory evaluations 
The local hospital laboratory will be used for all laboratory evaluations required to determine 
eligibility. If eligibility laboratory assessments were not done during the patient’s 
hospitalization, samples should be collected and sent to the local laboratory. A central 
laboratory will be used for analysis of all collected specimens from baseline through the final 
visit. Details on the collections, shipment of samples and reporting of results by the central 
laboratory will be provided to investigators in the laboratory manual. Results fr om the local 
hospital laboratory will be recorded in the laboratory evaluations eCRF. 
Clinically notable laboratory findings are defined in Appendix 1. 
Local laboratory assessments may be performed on an as-needed basis for unscheduled visits. 
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator in the Comments screen of the patient's eCRF and 
additional laboratory evaluations should be performed, as judged appropriate by the 
investigator. If the laboratory abnormality induces clinical signs or symptoms, or requires 
therapeutic intervention, then the diagnosis or medical condition must be entered on the AEs 
screen  of  the  patient's  eCRF.  If  the  laboratory  abnormality is  the  primary  reason  for an 


 
 
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unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then the 
procedure for rapid notification of SAEs must be followed. Likewise, if the laboratory 
abnormality leads to discontinuation from the study drug (temporarily or permanently), the 
patient must be followed until the abnormality resolves or until it is judged to be permanent. 
This investigation may include continued monitoring by repeat laboratory testing or by 
performing additional laboratory tests as deemed necessary by the investigator or the Novartis 
medical monitor. 
 
6.5.5.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured at Visits 1 (local lab), 2 and 7 (central lab). Hemoglobin A1c 
will be measured at Visit 2 (central lab). 
 
6.5.5.2 
Clinical chemistry 
Assessments required for eligibility that need to be measured at Visit 1 include creatinine, 
potassium, and total bilirubin. Blood urea nitrogen (BUN), glucose, creatinine, total bilirubin, 
AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium ,  
total protein, albumin, uric acid, and lipid profile will be measured at Visits 2, 3, 4, 5, 7 and 9 
(central lab). 
 
6.5.5.3 
Urinalysis 
Dipstick-test determination of specific gravity, pH, blood, total protein, bilirubin, ketones, and 
leukocytes will be measured at Visit 2 (central lab). If dipstick is positive, a qualitative 
microscopic determination, including white blood cells high power field (WBCs/HPF) and red 
blood cells high power field (RBCs/HPF) will be performed. 
 
6.5.6 
Pregnancy and assessments of fertility 
All female patients of childbearing potential will have a serum pregnancy t est (hCG) 
performed at Visit 1 (local lab) and Visits 5, 7 and 9 (central lab). In addition, these patients 
will have a urine pregnancy test conducted in the hospital laboratory at Visit 2. If any of these 
tests are positive at Visits 1 and 2, the patient should not be enrolled in t he trial. If a patient 
should become pregnant during the trial, the patient may remain in the trial for follow-up  
visits but must discontinue study drug. 
 
6.5.7 
Appropriateness of safety measurements 
The majority of safety assessments selected for this study are standard for the evaluation of 
patients with heart failure. 
 


 
 
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7 
Safety monitoring 
7.1 
Adverse events 
Study drug includes the investigational drug under evaluation and the comparator drug or 
placebo that is given during any phase of the study. Medical conditions/diseases present 
before informed consent are only considered AEs if they worsen after informed consent. 
Abnormal laboratory values or test results constitute AEs only if they induce clinical sig ns or 
symptoms, are considered clinically significant, or require therapy. 


 
 
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The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test, or other assessments. 
All AEs must be recorded on the Adverse Events CRF with the following information. 
1. the severity grade [mild, moderate, severe] 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2.2. 
All AEs should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e. further observation only); study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this AE; concomitant medication 
given; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The 
action taken to treat the AE should be recorded on the Adverse Event CRF. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should 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. 
Novartis may request additional information on specific adverse events of interest and may 
make requests to perform additional diagnostic tests to further assess the safety profile of the 
study medications. Such information may include diagnostic procedure reports, disch arge 
summaries, autopsy reports, and other relevant information that may help in assessing the 
reported adverse event. All additional information will be de-identified prior to collection by 
Novartis or its agents. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
 
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: 


 
 
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• 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, i.e. 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 hypothetic ally might have 
caused death if more severe . 
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 . 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per section 7.2.2. 
 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode, regardless of when the event occurs. This report must be submitted within 24 hours 
of the investigator receiving the follow-up information. An SAE that is considered completely 
unrelated to a previously reported one should be reported separately as a new event. 
In addition if required by the local health authority or ethics committee, the investigator 
should report all expected and unexpected serious adverse events to these authorities and also 
inform the institutional review board at the study institution. 


 
 
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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the local 
Novartis Drug Safety and Epidemiology (DS&E) Department. The telephone number of the 
contact persons in the local department of DS&E, specific to the site, are listed in the 
investigator folder provided to each site. The original copy of the SAE Report Form and the 
fax confirmation sheet must be kept with the case report form documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, wheth er the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If a SAE is unexpected, i.e., the event is not previously documented in the Investigator’s 
Brochure (new occurrence) and is suspected to be related to the Novartis study drug, this 
event is considered a Suspected Unexpected Serious Adverse Reaction (SUSAR). A 
DS&E associate may urgently require further information from the investigator for Health 
Authority reporting purposes. In general, it is Novartis policy to unblind SUSARs for 
regulatory reporting. If the unblinding shows that the Novartis drug is involved, Novartis 
will issue an Investigator Notification (IN) to inform all investigators participating in any 
study with the same drug that this SUSAR has been reported. In addition, SUSARs will be 
collected and reported to the competent authorities and relevant ethics committees as per 
United States regulatory requirements in the USA. 
An external independent DMC will be appointed and will review efficacy and safety data of 
the ongoing trial on a regular basis. DMC opinion and recommendations will be notified by 
Novartis as soon as possible to the competent authorities and the ECs where they qualify for 
expedited reporting. 
 
7.3 
Reporting of study treatment errors including misuse/abuse 
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 
 
 
7.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 


 
 
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the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
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. 
 
7.5 
Reporting angioedema-like events 
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 and communicate this report 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. 
Occasionally, the investigator may be contacted by the Novartis regarding AEs that were 
reported on behalf of patients that may resemble an angioedema -like event. The investigator 
or his/her delegated staff must complete the required report forms and supply the required 
medical records for such events, regardless of whether the investigator views the event in 
question as angioedema or not. 
All angioedema reports will be forwarded to an angioed ema adjudication committee by 
Novartis for assessment. 
Submission of an angioedema report is not a substitution for the submission of a SAE report. 
If an angioedema-like event satisfies the definition of a SAE, the investigator must submit a 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event. 
 
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 (e)CRFs with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
monitor. Additionally, a central analytics organization may analyze data & id entify risks & 


 
 
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trends for site operational parameters, and provide reports to Novartis Clinical Teams to assist 
with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by  
the patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm  
their consistency with the eCRF entries. Novartis monitoring standards require  full  
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the (e)CRFs are performed according to the 
study-specific monitoring plan. No information in 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 Electronic 
Case Report Forms (eCRFs) using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
review of the data by the CRO working on behalf of Novartis. Prior to database lock, 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 a CD-ROM or paper 
copies of the patient data for archiving at the investigational site. 
 
8.3 
Database management and quality control 
CRO staff working on behalf of Novartis, review the data entered into the eCRFs 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 CRO staff who 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 WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and AEs will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
the designated CRO. 


 
 
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Randomization codes and data about all study drug dispensed to the patient and all dosage 
changes will be tracked using an Interactive Voice Response System (IWRS). The system will 
be supplied by a vendor, who will also manage the IWRS database. The IWRS database will 
be sent electronically to the designated CRO. 
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis. The 
occurrence of reportable 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 by joint written agreement between the Head 
of Biometrics and the Medical Unit Head. 
 
8.4 
Data Monitoring Committee 
An external data monitoring committee (DMC) independent of Novartis will be appointed to 
review the incidence of the pre-specified clinical events including major cardiac  events, 
serious adverse events, the rate and distribution of adverse events , and relevant laboratory 
findings on an ongoing basis. If it is deemed necessary for internal decision making due to 
patient safety, an interim analysis will be conducted by an independent statistical group. 
The membership of the DMC and the responsibilities of the DMC and Novartis will be 
defined in a separate document entitled ‘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, procedure to address conflicts of interest and statistical monitoring guidelines. 
 
8.5 
Adjudication Committee 
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. There will 
be a separate eCRF for angioedema events. 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 and communicate 
this report 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. 
Occasionally, the investigator may be contacted by the Novartis regarding AEs that were 
reported on behalf of patients that may resemble an angioedema -like event. The investigator 
or his/her delegated staff must complete the required report forms and supply the required 
medical records for 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 assessment. 


 
 
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Submission of an angioedema report is not a substitution for the submission of a SA E report. 
If an angioedema-like event satisfies the definition of a SAE, the investigator must submit a 
SAE report in addition to the Adjudication Questionnaire for an Angioedema-like Event. 
 
9 
Data analysis 
A designated Contract Research Organization will perform the statistical analysis. 
It is planned that the data from all centers that participate in this protocol will be combined, so 
that an adequate number of subjects will be available for analysis. 
Unless otherwise specified, all statistical tests will be conducted against a two-sided 
alternative hypothesis, employing a significance level of 0.05. 
Efficacy, safety, and other data will be summarized. For continuous variables, summary 
statistics (mean, standard deviation, median, 25th and 75th percentiles, interquartile range, 
minimum, and maximum) at each time point and for change from baseline to each time point 
will be reported by treatment group. 
 
9.1 
Analysis sets 
The following patient sets will be used for the statistical reporting and analyses: 
The Randomized Set will consist of all randomized patients. 
The Full Analysis Set (FAS) will consist of all randomized patients with the exception for 
those patients who have not been qualified for randomization and have not received study 
drug, but have been inadvertently randomized into the study. Following the intent-to-treat 
principle, patients will be  analyzed  according  to  the  treatment  to  which  they  were 
assigned  at randomization.  Efficacy  variables  will  be  analyzed  based  on  the  FAS   as  
the  primary set. 
The Safety Set (SAF) will consist of all randomized patients who received at least one dose of 
study drug. Patients will be included in the analysis according to the treatment actually 
received. The Safety Set will be used for the analyses of safety variables. 
The Per-Protocol (PP) set will be a subset of the FAS which will consist of the patients who 
do not have major deviations from the protocol procedures in the double-blind study stage. 
Major protocol deviations will be pre-specified prior to unblinding treatment codes for 
analyses. This supplemental efficacy set will be used to support the primary analysis results. 
 
9.2 
Patient demographics and other baseline characteristics 
Baseline value is defined as the last non-missing assessment prior to the first dose of 
randomized study medication, including the matching placebos, unless specified otherwise in 
the protocol. 
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years), 
sex, race, ethnicity, weight, height, body mass index (BMI), category of prior CHF 
medication, prior HF hospitalization, NYHA class, NT-proBNP, BNP, and vital signs. BMI 


 
 
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will be calculated as weight (kg) / height2 (m2) from the collected height and weight at Visit 1 
(Screening Visit). Continuous variables will be summarized using n, mean, standard deviation, 
median, 25th and 75th percentiles, interquartile range, minimum, and maximum. Geometric 
means will be used to summarize the NT-proBNP results. Categorical variables will be 
summarized using frequency and percentage. 
The Randomized Set and FAS will be the patient sets for the above analyses. 
 
9.3 
Treatments 
The overall duration on the double-blind study drug will be summarized by treatment group 
using mean, standard deviation, median, 25th and 75th percentiles, interquartile range, 
minimum, and maximum. Additionally, the number and percentage of patients will be 
summarized by treatment group for duration category. 
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date will be summarized by therapeutic class, preferred term, and treatment 
group. 
The number and percentage of patients on different HF background medications will be 
tabulated by treatment at baseline and during the double-blind stage. 
The Safety Set will be used for the above analyses. 
 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Variables 
The primary efficacy variable is the time-averaged proportional change from baseline in NT- 
proBNP. Weeks 4 and 8 will be included in the analysis (primary analysis time point). 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary hypothesis to be tested is that the ratio of the geometric means of NT -proBNP 
(average of Weeks 4 and 8/baseline) for the sacubitril/valsartan and enalapril groups are equal 
(H0) versus the ratio of the geometric means of NT-proBNP are not equal (Ha). 
For NT-proBNP, the time-averaged proportional change from baseline in a logarithmic scale 
will be analyzed using an analysis of covariance (ANCOVA) model using data from Weeks 4 
and 8 with treatment as a fixed effect factor and the logarithmic baseline biomarker value as a 
covariate The estimated treatment effect in terms of ratios of geometric means, based on the 
least-squared means from the ANCOVA model, and the corresponding two -sided 95% 
confidence intervals will be provided. Baseline is Week 0. 
The change from baseline log-transformed NT-proBNP will be calculated as log (post-dose 
value) – log (baseline value). Geometric means (presented as a ratio to baseline) will be 
calculated by exponentially back-transforming the LS means based on the ANCOVA model. 


 
 
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9.4.3 
Handling of missing values/censoring/discontinuations 
The analysis will be performed based on all available data in the FAS and based on likelihood 
method with an assumption of missing at random for missing data. 
 
9.4.4 
Supportive analyses 
T-tests comparing treatment groups using change from log (baseline) to log (Week 8) values 
and log (Week 4) values will be performed. 
In addition to the primary analysis, the primary efficacy variable will also be analyzed using 
the same analysis model in the PP Set as supportive. 
 
9.5 
Analysis of secondary and exploratory variables 
9.5.1 
Secondary variables 
For NT-proBNP at Week 8, a proportional change from baseline in a logarithmic scale will be 
analyzed using an ANCOVA model with treatment as a fixed effect factor and the logarithmic 
baseline biomarker value as a covariate. The estimated treatment effects in terms of ratios of 
geometric means, based on the least-squared means from the ANCOVA model, and the 
corresponding two-sided 95% confidence intervals will be provided. Baseline is Week 0 . 
Week 4 will be used if the Week 8 value is missing. 
Incidences of symptomatic hypotension, hyperkalemia and angioedema will be calculated, 
along with the relative risk of sacubitril/valsartan vs. enalapril and 95% confidence intervals  
of the relative risk. 
For biomarkers including BNP to NT-proBNP ratio, hs-Troponin, and urinary cGMP, the 
time-averaged proportional change from baseline in a logarithmic scale will be analyzed using 
an ANCOVA model using the data from Weeks 4 and 8 with treatment as a fixed effect factor 
and the logarithmic baseline biomarker value as a covariate. The estimated treatment effects  
in terms of ratios of geometric means, based on the least-squared means from the ANCOVA 
model, and the corresponding two-sided 95% confidence intervals  will  be  provided. 
Baseline is Week 0. 
For BNP to NT-proBNP ratio and urinary cGMP at Weeks 1 and 2, a proportional change 
from baseline in a logarithmic scale will be analyzed using an ANCOVA model with 
treatment as a fixed effect factor and the logarithmic baseline biomarker value as a covariate. 
For each of Weeks 1 and 2 the estimated treatment effects in terms of ratios of geometric 
means, based on the least-squared means from the ANCOVA model, and the corresponding 
two-sided 95% confidence intervals will be provided. Baseline is Week 0. 
Analyses of the secondary variables will be based on the FAS. 
 


 
 
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9.5.3 
Other safety variables 
The safety and tolerability assessments are listed below: 
• AEs and SAEs 
• Sitting systolic, diastolic BP, and pulse pressure 
• Heart rate 
• Laboratory values 
The assessment of safety will be based primarily on the frequency of adverse events, SAEs, 
and laboratory abnormalities. Other safety data will be summarized as appropriate. 
The incidence of treatment-emergent adverse events (new or worsened) will be summarized 
by primary system organ class, preferred term, severity, and relationship to study drug. In 
addition, the incidence of death, SAEs, and AEs leading to discontinuation will be 
summarized separately by primary system organ class and preferred term. 
Laboratory data will be summarized by presenting shift tables using  extended  reference 
ranges (baseline to most extreme post-baseline value), by presenting summary statistics of   
raw data and change from baseline values (mean, median, standard deviation, 25th and 75th 
percentiles, interquartile range, minimum and maximum) and by the flagging of  notable 
values in data listings. 
Data from other tests (e.g., ECG or vital signs) will be listed, notable values will be flagged, 
and any other information collected will be listed as appropriate. 
Safety analyses will be performed based on the Safety Set. There will be no inferential 
analyses of the safety data. 
 
 
9.5.5 
Pharmacokinetics 
Not Applicable. 
 
9.5.6 
Pharmacogenetics and pharmacogenomics 
Not applicable. 


 
 
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9.5.7 
Biomarkers 
See Sections 9.4 and Section 9.5 for a description of the methods used to analyze the 
biomarkers.  Any other biomarkers collected but not specifically mentioned in Sections 9.4 or 
9.5 will be analyzed in the same manner. 
 
9.5.8       PK/PD 
Not applicable. 
 
9.6 
Interim analyses 
No interim analysis is planned. 
 
9.7 
Sample size calculation 
Assuming a significance level of 0.05 and 85% power, a sample size of 882 patients would be 
needed to detect an 18% reduction in the geometric mean of the time-averaged proportional 
change from baseline (average of Weeks 4 and 8) in NT-proBNP for the sacubitril/valsartan 
treatment group assuming a value of 0.95 for the enalapril group, a common standard 
deviation of 0.85 and a 25% rate of missing/non-evaluable samples. The estimates are based 
on the day 5 to day 14 data from the RELAX -AHF study. The standard deviation estimate is 
supported by data from PARADIGM. 
The assumption of a 18% reduction in the geometric mean for NT-proBNP for the 
sacubitril/valsartan treatment group vs. the enalapril group is consistent with NT-proBNP 
results seen in PARADIGM (26% and 25% relative reduction of sacubitril/valsartan vs. 
enalapril at Week 4 and Month 8 respectively), PARAMOUNT (23% relative of 
sacubitril/valsartan vs. valsartan at Week 12) and RELAX-AHF (19% relative reduction of 
serelaxin vs. placebo at Day 2). 
 
Table 9-1 
Sample size and power for various rate of reduction in 
sacubitril/valsartan group given alpha =0.05: 
 
Change 
Common 
Relative reduction in 
Change in GM for 
Power 
Non- 
Total sample 
in GM for 
enalapril 
SD 
GM for 
sacubitril/valsartan 
sacubitril/valsartan 
group 
evaluable 
rate 
size after 
adjusting for 
group compared to 
non- 
enalapril group 
evaluable 
rate 
.95 
.85 
15% 
.81 
85% 
10% 
1096 
.95 
.85 
15% 
.81 
90% 
10% 
1280 
.95 
.85 
18% 
.78 
85% 
10% 
736 
.95 
.85 
18% 
.78 
90% 
10% 
860 
.95 
.85 
18% 
.78 
85% 
25% 
882 
.95 
.85 
20% 
.76 
85% 
10% 
582 
.95 
.85 
20% 
.76 
90% 
10% 
680 


 
 
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10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with  
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Decla ration 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), IRB/IEC-approved informed consent, or, if applicable, 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 should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should 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 (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the 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 should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree t hat 
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 
should not be entered in the study. 
In the event that Novartis wants to perform testing on the samples that are not described in  
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained. 
 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should 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 


 
 
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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 
Novartis assures that 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. 
 
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 sho uld be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs. 
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. All significant protocol deviations will be recorded and reported in the CSR. 
 
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 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in section 7 Safety Monitoring should be followed. 
 
12 
References 
Binanay C, Califf RM, Hasselblad V, O’Connor CM, Shah MR, Sopko G, Stevenson LW, 
Francis GS, Leier CV and Miller LW. Evaluation study of congestive heart failure and 
pulmonary artery catheterization effectiveness: the ESCAPE trial. Journal American Medical 
Association 2005;294:1625-33. 
Braunwald E. Heart failure. Journal American College Cardiology Heart Failure 2013;1:1-20. 


 
 
Novartis 
Amended Protocol Version 02 (Clean) 
Confidential 
Page 65 
Protocol No. CLCZ696BUS01 
 
 
 
Chen J, Normand SL, Wang Y, and Krumholz HM. National and regional trends in heart 
failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. Journal 
American Medical Association. 2011;306:1669-78. 
Felker GM, et al. Rationale and Design of the GUIDE-IT study. Journal American College 
Cardiology Heart Failure 2014;2:457-65. 
Felker GM and Mentz RJ. Diuretics and Ultrafiltration in Acute Decompensated Heart Failure. 
Journal American College of Cardiology 2012;59:2145-2153. 
Gattis WA, O’Conner CM, Gallup DS, Hasselblad V and Gheorghiade M. Predischarge 
initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the 
Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart 
Failure (IMPACT-HF) trial. Journal American College of Cardiology 2004;43:1534-41. 
Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, Massie BM, Roland E, 
Targum S, Collins SP, Filippatos G and Tavazzi L. Acute heart failure syndromes: current 
state and framework for future research. Circulation 2005;112:3958-68. 
Givertz MM. Manipulation of the renin-angiotensin system. Circulation 2001;104:E14-8. 
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MF, Dai S, Ford ES, Fox 
CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, 
Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, 
Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, 
Mussolino ME, Meumar RW, Nichol G, Pandey DK, Paynter, NP, Reeves MJ, Sorlie, Stein J, 
Towfighi A, Turan TN, Virani SS, Wong ND, Woo D and Turner MB. Heart disease and 
stroke statistics – 2014 update: A report from the American Heart Association. Circulation 
2014;129:e28-e292. 
Januzzi JL Jr, Rehman SU, Mohammed AA, Bhardwaj A, Barajas L, Barajas J, Kim HN, 
Baggish AL, Weiner RB, Chen-Tournoux A, Marshall JE, Moore SA, Carlson WD, Lewis 
GD, Shin J, Sullivan D, Parks K, Wang TJ, Gregory SA, Uthamalingam S, Semigran MJ. Use 
of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with 
chronic left ventricular systolic dysfunction. Journal American College of Cardiology 
2011;58:188. 
Konstam MA, Gheorghiade M, Burnett JC, Jr., Grinfeld L, Maggioni AP, Swedberg K, 
Udelson JE, Zannad F, CookT, Ouyang J, Zimmer C and Orlandi C. Effects of oral tolvaptan 
in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. Journal 
American Medical Association 2007;297:1319-31. 
Loehr LR, Rosamond WE, Change PP, Folsom AR and Chambless LE. Heart Failure 
Incidence and Survival (from the Atherosclerosis Risk in Communities Study). The American 
Journal of Cardiology 2008;101:1016-1022. 
Massie BM, O’Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Weatherley BD, 
Cleland JG, Givertz MM, Voors A, DeLucca P, Mansoor GA, Salerno CM, Bloomfield DM 
and Dittrich HC. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. The 
New England Journal of Medicine 2010;363:1419-28. 


 
 
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McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau J, Shi VC, 
Solomon SD, Swedberg K and Zile MR. Dual angiotensin receptor and neprilysin inhibition 
as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic 
heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to 
Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM- 
HF).. European Journal of Heart Failure 2013;15:1062-73. 
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz M, Rizkala AR, Rouleau JL, Shi VC, 
Solomon SD, Swedberg K and Zile MR. Baseline characteristics and treatment of patients in 
Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and 
morbidity in Heart Failure trial (PARADIGM-HF). European Journal of Heart Failure 2014. 
McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi 
VC, Solomon SD, Swedberg K and Zile MR. Angiotensin–Neprilysin Inhibition versus 
Enalapril in Heart Failure. New England Journal of Medicine 2014;371:993-1004. 
McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, 
Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GYH, Maggioni AP, 
Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, 
Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A. ESC Guidelines for the diagnosis 
and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and 
Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. 
Developed in collaboration with the Heart Failure Association (HFA) of the ESC. European 
Heart Journal 2012;33:1787-1847. 
Metra M. et al. Effect of Serelaxin on cardiac, renal and hepatic biomarkers in the Relaxin in 
Acute Heart Failure  (RELAX-AHF) Development Program, Correlation with Outcomes. 
Journal of the American College of Cardiology 2013;61:196-206 
O'Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, 
Heizer GM, Komajda M, Massie BM, McMurray JJV, Nieminen MS, Reist CJ, Rouleau JL, 
Swedberg K, Adams KF, Anker SD, Atar D, Battler A, Botero R, Bohidar NR, Butler J, 
Clausell N, Corbalán R, Costanzo MR, Dahlstrom U, Deckelbaum LI, Diaz R, Dunlap ME, 
Ezekowitz JA, Feldman D, Felker GM, Fonarow GC, Gennevois D, Gottlieb SS, Hill JA, 
Hollander JE, Howlett JG, Hudson MP, Kociol RD, Krum H, Laucevicius A, Levy WC, 
Méndez GF, Metra M, Mittal S, Oh B-H, Pereira NL, Ponikowski P, Tang WHW, Tanomsup 
S, Teerlink JR, Triposkiadis F, Troughton RW, Voors AA, Whellan DJ, Zannad F and Califf 
RM. Effect of Nesiritide in Patients with Acute Decompensated Heart Failure. New England 
Journal of Medicine 2011;365:32-43. 
Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, 
Takeuchi M, Gong J, Lefkowitz M, Packer M and McMurray JJV. The angiotensin receptor 
neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 
double-blind randomised controlled trial. Lancet 2012;380:1387-1395. 
von Lueder TG, Sangaralingham SJ, Wang BH, Kompa AR, Atar D, Burnett JC, Jr. and Krum 
H. Renin-angiotensin blockade combined with natriuretic peptide system augmentation: novel 
therapeutic concepts to combat heart failure. Circulation Heart Failure2013;6:594-605. 


 
 
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Yancy C, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, 
Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, 
McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, 
Tsai EJ and Wilkoff BL. 2013 ACCF/AHA Guideline for the Management of Heart Failure: 
A Report of the American College of Cardiology Foundation/American Heart Association 
Task Force on Practice Guidelines. Circulation 2013;128:e240-e327. 
 
13 
Appendix 1: Clinically notable laboratory values 
Clinically notable laboratory abnormalities for selected tests based on a percent c hange from 
baseline: 
 
Hematology 
RBC count 
>50% increase, >20% decrease 
Hemoglobin 
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
 
Blood Chemistry 
ALT (SGPT) 
>150% increase 
AST (SGOT) 
>150% increase 
BUN 
>50% increase 
Creatinine 
>50% increase 
Total bilirubin 
>100% increase 
CPK 
>300% increase 
Alkaline phosphatase >100% increase 
Potassium 
>20% increase, >20% decrease 
Chloride 
>10% increase, >10% decrease 
Calcium 
>10% increase, >10% decrease 
Uric acid 
>50% increase 


 
 
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14 
Appendix 2: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.5 mEq/L) 
General principles 
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken. 
Any patient who experiences a potassium level ≥ 5.5 mEq/L confirmed by repeated testing 
after randomization requires regular, repeated checks of potassium concentration (beyond that 
prescribed in the protocol) until it is clear that the potassium concentration is stable and not 
rising into the range of concern (≥ 5.5 mEq/L). 
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below and the investigator’s clinical judgement. Hyperkalemia should be followed 
until resolution. 
Recommended corrective action for management of hyperkalemia 
Serum potassium > 5.3 and less than or equal to 5.5 mEq/L 
• Confirm potassium concentration in a non-hemolyzed sample 
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.) 
• Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents: 
• Aldosterone antagonists (if they are believed to be the most likely cause of hyperkalemia) 
• Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 
• Potassium supplements, e.g., potassium chloride 
• Salt substitutes 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors 
• Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and 
Septra® (trimethoprim/sulfamethoxazole fixed combination) 
• Herbal Supplements: 
• For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum officinale), 
horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian 
ginseng, hawthorn berries 
• Repeat serum potassium measurement within 3 to 5 days 
• If serum potassium remains > 5.3 and ≤ 5.5 mEq/L, regularly monitor serum potassium 
levels to ensure stability (suggested once monthly) 


 
 
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• Consider down-titration of study medication, according to investigator’s medical 
judgment. 
 
Serum potassium > 5.5 and < 6.0 mEq/L 
• Confirm potassium concentration in a non-hemolyzed sample 
• Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment. 
• Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mEq/L 
• Repeat serum potassium measurement after 2-3 days 
• If serum potassium < 5.5 mEq/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days 
 
Serum potassium greater than or equal to 6.0 mEq/L 
• Immediately discontinue study drug 
• Confirm potassium concentration in a non-hemolyzed sample 
• Urgently evaluate patient and treat hyperkalemia as clinically indicated 
• Apply all measures outlined for serum potassium > 5.3 and < 6.0 mEq/L 
• If serum potassium < 5.5 mEq/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days 
 
15 
Appendix 3: Guidelines for the management of blood 
pressure 
Guidelines 
1. Investigator should monitor blood pressure closely 
2. If symptomatic hypotension occurs: 
a. Correct any treatable cause, e.g. hypovolemia 
b. If hypotension persists, any antihypertensive drug and non-disease-modifying drugs, 
such as diuretics, CCBs, nitrates, and α-blockers, should be down-titrated or 
stopped first before down-titration of the study drug is considered 
3. If hypotension persists, the study drug should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medication adjustment guidelines described in 
Section 5.5.5 should be adhered to as much as possible. 


 
 
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16 
Appendix 4: Guidelines for the management of renal 
dysfunction 
General principles: 
Glomerular filtration rate in HF patients depends on intrinsic ren al function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, 
renal dysfunction may develop or may deteriorate in some patients after study drug 
administration. These recommendations have been developed to guide the investigators in 
managing patients with renal dysfunction after randomization. 
Two types of response to serum creatinine increase are described: 
Surveillance situation 
 
the investigator will check for 
potentially reversible causes of renal dysfunction such as: 
• Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect creatininemia 
• Volume decrease, including that resulting from excessive dosing of diuretics 
• Urinary infection 
• Urinary tract obstruction 
• Study medication 
 
Action situation 
If a patient eGFR decreases by ≥ 40% from baseline (or if serum creatinine concentration rises 
above 3 mg/dL (265 µmol/L), the investigator will check for potentially reversible causes of 
renal dysfunction (see above). 
If the investigator judges that study medication has to be stopped, he/she will have to contact 
the Novartis medical monitor or his/her designee. Thereafter, serum creatinine assessments 
will have to be repeated at least each week until levels return to acceptable value s. If study 
medication was stopped, every effort will be done to restart it again, according to clinical 
conditions. 


 
 
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SAP_001.pdf: 
Clinical Development 
LCZ696/Sacubitril/Valsartan/Entresto®
CLCZ696BUS01 / NCT02554890
A multicenter, randomized, double-blind, double dummy, 
parallel group, active-controlled 8-week study to evaluate 
the effect of sacubitril/valsartan (LCZ696) versus enalapril 
on changes in NT-proBNP and safety and tolerability of in- 
hospital initiation of LCZ696 compared to enalapril in 
HFrEF patients who have been stabilized following 
hospitalization for acute decompensated heart failure 
(ADHF) 
Statistical Analysis Plan (SAP) 
Author: 
CRO Statistician, 
 
Statistician, Novartis, 
 
Document type: 
SAP Documentation 
Document status: 
Final 2.0, Amendment 1 
Release date: 
20-Aug-2018
Number of pages: 
49 
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) 
27- 
Sep- 
2016 
Prior 
to 
DB 
Lock 
Creation of 
Final 
Version 
NA – First Version 
NA 
20- 
Aug- 
2018 
Prior 
to 
DB 
Lock 
Creation of 
Amendment 
1 
1. Updated to align with protocol 
version 02 (amended protocol) 
dated 05-Oct-2017: sample size 
increase; addition of secondary 
endpoint (proportional change in 
NT-proBNP from baseline to Week 
8);
 
 
2. Clarified baseline definition for 
safety labs and biomarkers 
 
 
3. Added sensitivity analysis for 
primary endpoint based on “strict” 
baseline definition (i.e., collection 
date:time < first dose date:time) 
4. Modified definition of treatment 
emergent AEs and flagging of 
deaths in listing to remove “28 
days post last dose of study 
treatment” lag time 
 
 
 
6. Clarified that biomarker samples 
from patients who withdraw 
consent will not be analyzed by the 
central laboratory 
7. Removed “on treatment” 
terminology and “28 days post last 
dose of study treatment” lag time 
(from the open-label phase 
definition) 
8. Clarified coding dictionary 
versions to be utilized 
1. Section 1 
Introduction; Section 
1.1 Study Design; 
Section 1.2 Study 
Objectives and 
Endpoints; Section 
2.7.1 Secondary 
Endpoints; Section 
2.7.2 Statistical 
Hypothesis, Model, 
and Method of 
Analysis;
 
 
2. Section 2.1.1 
General Definitions 
3. Section 2.5.4 
Supportive Analyses; 
Section 4 Change to 
Protocol Specified 
Analyses 
4. Section 2.8.1.2 
General Rules for AE 
Reporting; Section 
2.8.2 Deaths 
 
6. Section 2.12 
Biomarkers 
7. Section 2.1.1 
General Definitions 
8. Section 2.3.4 
Demographics and 
Other Baseline 
  
Characteristics; 
 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
9. Clarified that analyses of BNP and 
NT-proBNP values will be based 
on samples processed/assessed by 
the central laboratory 
10. Clarified definitions for double- 
blind, open-label, and pooled 
phases, and changed terminology 
from “treatment phase” to “study 
phase” 
 
 
 
 
 
 
 
 
 
13. Clarified that date of last contact 
will be determined from the Date 
of Last Contact field on the Study 
Completion/Exit eCRF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.4.2 Prior, 
Concomitant and Post 
Therapies; Section 
2.8.1.1 Coding of AEs 
9. Section 2.1.1 
General Definitions; 
Section 2.12 
Biomarkers 
10. Section 2.1.1 
General Definitions 
 
 
13. Section 2.1.1 
General Definitions 
 
 
 
 
 
 
 
 
 
17. Section 2.7.1 
Secondary Endpoints; 
Section 2.7.2 
Statistical Hypothesis, 
Model, and Method of 
Analysis; Section 4 
Change to Protocol 
Specified Analyses 
18. Section 2.5.4 
Supportive Analyses; 
Section 4 Change to 
Protocol Specified 
Analyses 
  
 
 


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Date 
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point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
 
 
17. Specified the following biomarkers 
as secondary endpoints: UcGMP to 
urinary creatinine ratio, BNP, and 
NT-proBNP to BNP ratio 
18. Replaced supportive analysis of the 
primary endpoint consisting of 
summary statistics and t-test p- 
values for comparing treatment 
groups on the proportional change 
from baseline in a logarithmic scale 
at Weeks 4 and 8 with ANCOVA 
at Weeks 4 and 8 
 
 
 
 
 
 
 
 
 
 
 
21. Modified the Safety Set definition 
to remove the word ‘active’ so that 
inclusion in the Safety Set is not 
restricted to patients who received 
at least one dose of active study 
treatment 
22. Clarified that duration of exposure 
during the double-blind phase is 
calculated from the date of first 
study treatment (not date of first 
active study treatment); added 
summary of patient dose level and 
titration data by visit and systolic 
blood pressure using visit-specific 
cut-off values from dose titration 
 
 
 
 
 
 
 
 
 
 
 
21. Section 2.2 
Analysis Sets; Section 
4 Change to Protocol 
Specified Analyses 
22. Section  2.4.1 
Study 
Treatment/Compliance 
23. Section 5.6 Rule of 
Exclusion Criteria of 
Analysis Sets 
24. Section 2.2.1 
Subgroup of Interest 
25. Section 2.3.1 
Patient Disposition 
26. Section 2.3.4 
Demographics and 
Other Baseline 
Characteristics 
27. Section 2.3.3 
Index Hospitalization 
28. Section 2.3.4 
Demographics and 
Other Baseline 
Characteristics 
29. Section 5.4.1 
Notable Vital Sign 
Values 
30. Section 2.8.4.4 HF 
Signs and Symptoms 
  
schedule 
 


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Date 
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point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
23. Updated rules of exclusion criteria 
of analysis sets based on final 
review of PDs and associated final 
PD documentation (VAP Module 3 
v3.0 dated 15Aug2018) 
24. Combined <30 and 30 – <45 
baseline eGFR subgroups into <45 
subgroup due to low number of 
patients in <30 subgroup 
25. Added disposition categories for 
patients who prematurely 
discontinued study treatment 
during double-blind and open-label 
phases that exclude deaths; 
removed disposition categories for 
patients who completed the double- 
blind and open-label phases as 
these are covered in the study 
completion tables; removed 
disposition category for patients 
who were not randomized 
26. Added source of patient referral 
and summary (continuous and 
categorical) of NT-proBNP and 
BNP values from local laboratory 
to demographic and baseline 
characteristics table; removed 
Pooled column and broke out 
Open-Label Sacubitril/Valsartan 
column by randomized treatment 
group for all demographic and 
baseline data tables 
27. Clarified that summary of index 
hospitalization data will only be 
treatment group (and not also by 
open-label and pooled 
sacubitril/valsartan) 
28. Added categorical summary of 
number of hospitalizations for HF 
within past 12 months (excluding 
index hospitalization) 
29. Modified notable vital signs criteria 
30. Clarified that HF Signs and 
31. Section 2.7.2 
Statistical Hypothesis, 
Model, and Method of 
Analysis; Section 
2.8.1.4 Adverse 
Events of Special 
Interest/Grouping of 
AEs; Section 2.8.4.6 
Angioedema 
32. Section 2.8.1.3 AE 
Summaries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
40. Section 2.5.4 
Supportive Analyses 
41. Section 2.4.2 
Prior, Concomitant 
and Post Therapies 
42. Section 2.3.1 
Patient Disposition 
43. Section 2.3.4 
Demographics and 
  
Symptoms will be summarized at 
 


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Date 
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Reason for 
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Outcome for update 
Section and title 
impacted (Current) 
all visits (not just Randomization 
and Week 8) 
31. Clarified that separate 
summaries/analyses of angioedema 
data, including AEs related to 
angioedema, will be produced – 
one based on all angioedema and 
the other based on positively 
adjudicated angioedema; added a 
summary of key characteristics of 
positively adjudicated angioedema 
32. Added an AE overview table 
(number and percentage of patients 
in various AE categories) and two 
SAE tables (occurring with 
frequency ≥0.5%; by seriousness 
criteria) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Baseline 
Characteristics 
44. Section 2.3.4 
Demographics and 
Other Baseline 
Characteristics 
45. Section  2.4.1 
Study 
Treatment/Compliance 
 
 
 
 
48. Section 2.7.2 
Statistical Hypothesis, 
Model, and Method of 
Analysis; Section 4 
Change to Protocol 
Specified Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
52. Section 2.2 
Analysis Sets; Section 
4 Change to Protocol 
Specified Analyses 
 
  
  


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Date 
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Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
 
 
 
 
 
 
 
40. Added a descriptive summary of 
patient evaluability for primary 
endpoint analysis based on NT- 
proBNP values 
41. Removed reference to diuretics 
being combined into a single dose 
equivalent for purposes of the 
diuretic dose summaries during the 
index hospitalization and at post- 
randomization visits 
42. Modified categories for study 
completion at Weeks 8 and 12 
43. Added variable “Time from 
presentation to randomization 
(days)” to summary of disease 
characteristics 
44. Added variables “ACEi naïve”, 
“ARB naïve”, and “ACEi/ARB 
naïve” to summary of disease 
characteristics 
45. Added variable “Dispensed dose 
level 3 by Week 6” to dose level by 
visit summary 
 
 
 
 
 
 
  
 


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Date 
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point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
48. Added Weeks 4 and 8 to the 
analysis of change from baseline in 
biomarkers defined as secondary 
endpoints; clarified that analysis of 
hs-Troponin T will not be 
performed at Week 2 since it is not 
measured at Week 2 
 
 
 
 
 
 
 
 
52. Modified PPS definition to clarify 
that major protocol deviations will 
exclude patients from the PPS 
regardless of the study phase in 
which they occur 
 
 
54. Implemented various minor 
clarifications, including those 
reflected in updated version of 
  
DCTs dated 12-Dec-2017 
 


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Table of contents 
Table of contents ................................................................................................................. 9 
List of abbreviations .......................................................................................................... 11 
1 
Introduction ....................................................................................................................... 13 
1.1 
Study design ........................................................................................................... 13 
1.2 
Study objectives and endpoints.............................................................................. 14 
2 
Statistical methods ............................................................................................................. 15 
2.1 
Data analysis general information ......................................................................... 15 
2.1.1 
General definitions ................................................................................ 15 
2.2 
Analysis sets .......................................................................................................... 18 
2.2.1 
Subgroup of interest .............................................................................. 18 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 18 
2.3.1 
Patient disposition ................................................................................. 18 
2.3.2 
Protocol deviations ................................................................................ 21 
2.3.3 
Index hospitalization ............................................................................. 21 
2.3.4 
Demographics and other baseline characteristics.................................. 21 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 24 
2.4.1 
Study treatment / compliance ................................................................ 24 
2.4.2 
Prior, concomitant and post therapies ................................................... 25 
2.5 
Analysis of the primary objective .......................................................................... 26 
2.5.1 
Primary endpoint ................................................................................... 26 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 26 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 27 
2.5.4 
Supportive analyses ............................................................................... 27 
2.6 
Analysis of the key secondary objective ................................................................ 27 
2.7 
Analysis of secondary objectives ........................................................................... 27 
2.7.1 
Secondary endpoints ............................................................................. 27 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 28 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 28 
2.8 
Safety analyses ....................................................................................................... 28 
2.8.1 
Adverse events ...................................................................................... 29 
2.8.2 
Deaths .................................................................................................... 30 
2.8.3 
Laboratory data ..................................................................................... 30 
2.8.4 
Other safety data.................................................................................... 31 
2.9 
Pharmacokinetic endpoints .................................................................................... 36 
2.10 
PD and PK/PD analyses ......................................................................................... 36 


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 36 
 
 36 
 
 36 
2.12 
Biomarkers ............................................................................................................. 37 
 
 37 
2.14 
Interim analysis ...................................................................................................... 42 
3 
Sample size calculation ..................................................................................................... 42 
4 
Change to protocol specified analyses ............................................................................... 42 
5 
Appendix ........................................................................................................................... 44 
5.1 
Imputation rules ..................................................................................................... 44 
5.1.1 
Study treatment ..................................................................................... 44 
5.1.2 
AE date imputation ............................................................................... 44 
5.1.3 
Concomitant medication date imputation ............................................. 44 
5.2 
AEs coding/grading ............................................................................................... 45 
5.3 
Laboratory parameters derivations ........................................................................ 45 
5.3.1 
Laboratory grading ................................................................................ 45 
5.3.2 
Notable laboratory values...................................................................... 46 
5.4 
Vital signs .............................................................................................................. 46 
5.4.1 
Notable vital sign values ....................................................................... 46 
5.5 
Statistical models ................................................................................................... 47 
5.5.1 
Primary analysis .................................................................................... 47 
5.5.2 
Key secondary analysis ......................................................................... 47 
5.6 
Rule of exclusion criteria of analysis sets .............................................................. 48 
6 
Reference ........................................................................................................................... 49 


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List of abbreviations 
ACEi 
Angiotensin Converting Enzyme Inhibitors 
ADHF 
Acute Decompensated Heart Failure 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ARB 
Angiotensin Receptor Blocker 
ATC 
Anatomical Therapeutic Chemical 
bid 
bis in diem/twice a day 
BMI 
Body Mass Index 
BNP 
B-type Natriuretic Peptide 
CCU 
Coronary Care Unit 
cGMP 
cyclic Guanosine 3',5'-Monophosphate 
CHF 
Chronic Heart Failure 
CKD 
Chronic Kidney Disease 
CRO 
Contract Research Organization 
CRT-P 
Cardiac resynchronization therapy – no ICD 
CRT-D 
Cardiac resynchronization therapy – with ICD 
CSR 
Clinical Study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCT 
Data Collection Tool 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
HCTZ 
Hydrochlorothiazide 
HF 
Heart Failure 
HS 
High Sensitivity 
ICD 
Implantable Cardioverter Defibrillator 
ICU 
Intensive Care Unit 
i.v. 
Intravenous 
IVCD 
Intraventricular Conduction Delay 
IWRS 
Interactive Web Response System 
 
 
KM 
Kaplan Meier 
LBB 
Left Bundle Branch 
LCZ696 
Sacubitril/Valsartan 
LS 
Least squares 
LVAD 
Left Ventricular Assist Device 
LVEF 
Left Ventricular Ejection Fraction 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 


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NT-proBNP 
N-terminal Prohormone of B-type Natriuretic Peptide 
NYHA 
New York Heart Association 
PD 
Pharmacodynamic 
 
 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Set 
 
 
PT 
Preferred Term 
RBB 
Right Bundle Branch 
RS 
Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SOC 
System Organ Class 
SS 
Safety Set 
 
 
TEAE 
Treatment-emergent Adverse Event 
TFLs 
Tables, Figures, Listings 
TIA 
Transient Ischemic Attack 
 
 
UcGMP 
Urinary cGMP 
VAD 
Ventricular Assist Device 
WHO 
World Health Organization 


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1 
Introduction 
The statistical analysis plan (SAP) will outline in detail the analyses planned in the protocol. 
The analyses will be used to generate the Clinical Study Report (CSR). The SAP is based on 
protocol version 02 (Amended protocol) dated 05-Oct-2017 and the data collection tool (DCT) 
version 14.0 dated 12-Dec-2017. 
 
1.1 
Study design 
This study will use a randomized, double-blind, double-dummy, active-controlled, parallel 
group design. Eligible patients hospitalized for acute decompensated heart failure (ADHF) will 
be randomized no earlier than 24 hours and up to ten days of presentation while still hospitalized. 
A total of approximately 882 patients randomized to sacubitril/valsartan or enalapril in a 1:1 
ratio is planned with no stratification. 
At the time of randomization, patients will have been stabilized, defined for this study as: 
• Systolic blood pressure (SBP) ≥ 100 mmHg for the preceding 6 hours prior to 
randomization; no symptomatic hypotension 
• No increase (intensification) in intravenous (i.v.) diuretic dose within last 6 hours prior 
to randomization 
• No i.v. inotropic drugs for 24 hours prior to randomization 
• No i.v. vasodilators including nitrates within last 6 hours prior to randomization 
All patients will need to meet all other inclusion and none of the exclusion criteria. 
In order to provide for a necessary 36 hour washout of prior angiotensin converting enzyme 
inhibitors (ACEi) treatment prior to receiving sacubitril/valsartan (known as LCZ696 in prior 
trials), the supplied blinded study drug for those allocated to sacubitril/valsartan will be placebo 
only until the 3rd dose. Because the study is blinded, all patients, regardless of randomization 
arm, need to remain in the hospital for six hours after they have received their 3rd dose of study 
medication. 
Initial dose will be determined by the blood pressure at the time of randomization. Study 
treatment will be titrated to the Level #3 target doses of sacubitril/valsartan 97/103 mg (bis in 
diem/twice a day) bid and enalapril 10 mg bid. Titration will be based on blood pressure at the 
time of the visit. Dose adjustments will only be allowed if indicated per protocol defined 
safety/tolerability criteria and investigator judgement. At the end of the 8-week treatment period, 
all patients will need to have a 36 hour washout from study treatment prior to starting the open- 
label extension to ensure that the blinding of the core study is maintained. To facilitate this 
washout, patients should take their final dose of study drug on the morning of their week 8 visit 
and then begin open label sacubitril/valsartan after 36 hours in the evening of week 8 visit + 
one day. All patients will start open label treatment on sacubitril/valsartan at their final dosing 
level during double blind treatment. However, at an investigator’s judgement, starting dose may 
be adjusted by one dose level up or down. 
Eligible patients will be randomized no earlier than 24 hours after presentation at the hospital 
and no later than within ten days of admission, while still hospitalized, via interactive web 


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response system (IWRS) to one of the treatment arms. The investigator or his/her delegate will 
contact the IWRS after confirming that the patient fulfills all of the study entry criteria. The 
IWRS will assign a randomization number to the patient, which will be used to link the patient 
to a treatment arm and will specify which bottle from the centralized hospital supply the patient 
will be dosed for the first day and a unique medication number for the first package of 
investigational treatment to be dispensed to the patient. 
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 IWRS provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s). 
The primary time point will be Weeks 4 and 8. 
There are no interim analyses planned. 
1.2 
Study objectives and endpoints 
The primary objective of this study is to assess the effect of in hospital initiation of 
sacubitril/valsartan vs. enalapril on the time-averaged proportional change of N-terminal 
prohormone of B-type natriuretic peptide (NT-proBNP) from baseline in patients who have 
been stabilized following hospitalization for ADHF and reduced ejection fraction (left 
ventricular ejection fraction [LVEF] ≤ 40%). Weeks 4 and 8 will be included in the analysis 
(primary analysis time point). 
 
The secondary objectives of this study are to examine the effect of sacubitril/valsartan vs. 
enalapril on: 
• The proportional change in NT-proBNP from baseline to Week 8 
• Incidence of symptomatic hypotension during 8 weeks of treatment 
• Incidence of hyperkalemia (Potassium >5.5 mEq/L) during 8 weeks of treatment 
• Incidence of angioedema during 8 weeks of treatment 
• Biomarkers: hs-Troponin (high sensitivity), urinary cyclic Guanosine 3’,5’- 
Monophosphate (cGMP) and B-type natriuretic peptide (BNP) to NT-proBNP ratio at 4 
and 8 weeks 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
, a Novartis-designated Contract Research Organization 
(CRO) will be performing all analyses outlined in this SAP. SAS® version 9.3 (or higher) will 
be used for all analyses. 
Data from all centers that participate in this protocol will be combined, so that an adequate 
number of patients will be available for analysis. 
Unless otherwise specified, for continuous data, the mean, standard deviation, median, first and 
third quartile, interquartile range, and minimum and maximum values will be presented. For 
categorical data, frequencies and percentages will be presented. All statistical tests will be 
conducted against a two-sided alternative hypothesis, employing a significance level of 0.05. 
All data will be provided in listings in addition to summaries described below. 
 
2.1.1       General definitions 
Study treatment 
Patients will receive either sacubitril/valsartan or enalapril during the first 8 weeks of the study. 
Study treatment will refer to either of these two drugs. 


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Baseline 
For safety labs and biomarkers, baseline is defined as the last non-missing assessment collected 
<3 hours from the first dose of study treatment, including matching placebos. For patients not 
treated, baseline is defined as the last non-missing assessment prior to or on the date of 
randomization. BNP and NT-proBNP values will be based on clinical laboratory samples 
processed and assessed by the central laboratory. 
For other assessments, including those for which assessment time is collected (ECGs, HF Signs 
and Symptoms, and pregnancy tests), baseline is defined as the last non-missing assessment 
prior to or on the start date of study treatment (randomization date for patients not treated), 
including matching placebos. 
Date of first administration of study treatment 
Double-blind phase: The date of first administration of study treatment in the double-blind 
phase is defined as the first date a dose of study treatment is administered and recorded on the 
Dose Administration (Visit 2) electronic case report form (eCRF). 
Open-label phase: The date of first administration of study treatment in the open-label phase is 
defined as the first date a dose of sacubitril/valsartan is administered in the open-label phase 
and recorded on the Dose Administration (Visit 7) eCRF. 
Pooled phase: The date of first administration of study treatment in the pooled phase is defined 
as the first date a dose of sacubitril/valsartan is administered either in the double-blind phase or 
open-label phase. 
Date of last administration of study treatment 
Double-blind phase: The date of last administration of study treatment in the double-blind phase 
is defined as the last date a dose of study treatment is administered in the double-blind phase 
and recorded on the Dose Administration (Visit 7) eCRF, or earlier if prematurely discontinued 
and recorded on the Early Investigational Product Permanent Discontinuation eCRF. 
Open-label phase: The date of last administration of study treatment in the open-label phase is 
defined as the last date of sacubitril/valsartan is administered in the open-label phase and 
recorded on the Drug Administration eCRF. 
Pooled phase: The date of last administration of study treatment in the pooled phase is defined 
as the last date of sacubitril/valsartan administered either in double-blind phase or open-label 
phase. 
Study day 
The study day describes the day of the assessment relative to the date of randomization. 
The study day will be calculated as the difference between the date of assessment and the date 
of randomization plus 1. If the date of assessment is prior to the date of randomization, the study 
day will be negative and will be calculated as the difference between the date of the assessment 
and the date of randomization. 


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Double-blind phase 
Assessments performed at Weeks 1, 2, 4, 6, or 8 (including, but not limited to, vital signs) are 
assigned to the double-blind phase for summarization purposes. Unscheduled assessments are 
not assigned to a study phase for purposes of by-visit summaries. 
For summarization of adverse events [AEs], medications, protocol deviations, notable vital 
signs and laboratory abnormalities, and symptomatic hypotension by study phase, an 
assessment during the double-blind phase is defined as any assessment obtained in the following 
time interval: 
Date of randomization (or date of first administration of study treatment, as appropriate) through 
the date of the Week 8 visit, inclusive. For patients without a Week 8 visit, a projected Week 8 
visit date will be derived relative to their randomization date. 
An ‘active treatment’ assessment is defined for sensitivity analyses starting with the first dose 
of study treatment in patients randomized to enalapril and the third dose of study treatment in 
patients randomized to sacubitril/valsartan. 
Open-label phase 
Assessments performed at Weeks 10 or 12 (including, but not limited to, vital signs) are 
assigned to the open-label phase for summarization purposes. Unscheduled assessments are not 
assigned to a study phase for purposes of by-visit summaries. 
For summarization of AEs, medications, protocol deviations, notable vital signs and laboratory 
abnormalities, and symptomatic hypotension by study phase, an assessment during the open- 
label phase is defined as any assessment obtained in the following time interval: 
After the date of the Week 8 visit. For patients without a Week 8 visit, a projected Week 8 visit 
date will be derived relative to their randomization date. 
Patients who died, withdrew consent, or were lost to follow-up prior to or on their projected 
Week 8 visit date will be excluded from the open-label phase. 
Pooled phase 
An assessment during the pooled phase is defined as any assessment obtained in the double- 
blind phase for patients randomized to sacubitril/valsartan, or any assessment obtained in the 
open-label phase regardless of randomized treatment arm. 
Last contact 
The date of last contact will be determined from the Date of Last Contact field on the Study 
Completion/Exit eCRF. 
Year, month and week 
For reporting purposes, the rules below will be followed to convert a year, month and week to 
days. 
1 year = 365.25 days 
1 month = 30.3475 days 
1 week = 7 days 


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1 day = 24 hours 
 
2.2 
Analysis sets 
The following analysis data sets will be used in the analyses: 
Randomized Set (RS): The RS will consist of all randomized patients. 
Full Analysis Set (FAS): The FAS will consist of all randomized patients with the exception 
for those patients who have not been qualified for randomization and have not received study 
treatment, but have been inadvertently randomized into the study. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment to which they were assigned at 
randomization. Efficacy variables will be analyzed based on the FAS as the primary set. 
Safety Set (SS): The SS will consist of all randomized patients who have received at least one 
dose of study treatment. Patients will be included in the analysis according to the treatment 
actually received. The SS will be used for the analyses of safety variables. 
Per-Protocol Set (PPS): The PPS will be a subset of the FAS, which will consist of the patients 
who do not have major deviations from the protocol procedures. Major protocol deviations will 
be pre-specified prior to unblinding treatment code for analysis. This supplemental analysis set 
will be used to support the primary analysis results. 
 
2.2.1 
Subgroup of interest 
The following subgroups will be analyzed for the primary objective and the secondary objective 
for AEs of special interest: 
1. Age group (<65, ≥65 years) and (<75, ≥75 years) 
2. Ejection fraction categories prior to randomization (>40%, >30% - 40%, >20% - 30%, 
≤20%) 
3. Prior use of ACEi/ARB (at the time of hospitalization) 
4. Baseline quartiles of NTproBNP (randomization sample) 
5.   Baseline eGFR (<45, 45 - <60, ≥60 ml/min/1.73 m2) 
6.   Systolic blood pressure at randomization (<110, ≥110 mm Hg) 
See Sections 2.5 and 2.7 for further details on the primary and secondary objectives, 
respectively. 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
All patients will be used for the summary of patient disposition. The following categories will 
be summarized: 
• Number of patients who were screened 
• Primary reason for not continuing to double-blind phase 


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o Investigator decision 
o Subject/Guardian decision 
o Screen failure 
o Adverse event 
o Pregnancy 
o Study terminated by sponsor 
o Technical problems 
o Death 
• Number of patients who were randomized 
• Number and percentage of patients who were treated 
• Number and percentage of patients who prematurely discontinued study treatment 
during double-blind phase 
• Number and percentage of patients who prematurely discontinued study treatment 
during double-blind phase, excluding deaths 
• Number and percentage of patients who prematurely discontinued study treatment 
during open-label phase 
• Number and percentage of patients who prematurely discontinued study treatment 
during open-label phase, excluding deaths 
• Reasons for premature discontinuation of study treatment (separately for double-blind 
phase and open-label phase) 
o Adverse event 
o Death 
o Protocol deviation 
o Investigator decision 
o Subject/Guardian decision 
o Lost to follow-up 
o Technical problems 
o Pregnancy 
o Withdrawal of consent 
o Noncompliance with study treatment 
o Study terminated by sponsor 
• Study  duration  in  months  [(date  of  last  contact/death  –  date  of     randomization 
+1)/30.3475] 


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A separate summary for study completion will be presented and the FAS will be used. The 
following categories will be summarized at Week 8 by treatment group, open-label and pooled 
sacubitril/valsartan: 
• Patients who received at least one dose of study treatment 
• Patients who did not receive at least one dose of study treatment 
• Patients with known vital status at Week 8 
o Dead prior to opening of projected Week 8 visit window 
o Completed Week 8 visit after opening of projected Week 8 visit window 
o Any visit/contact with visit date after opening of projected Week 8 visit window 
o Vital status recorded with last known alive date after opening of projected Week 
8 visit window 
• Patients with unknown vital status at Week 8 
o Lost to follow-up prior to opening of projected Week 8 visit window 
o Withdrawal of informed consent to any follow-up prior to opening of projected 
Week 8 visit window 
The following categories will be summarized at Week 12 by treatment group, open-label and 
pooled sacubitril/valsartan: 
• Patients who received at least one dose of study treatment 
• Patients who did not receive at least one dose of study treatment 
• Patients with known vital status at Week 12 
o Dead 
o Visit 
 In person with patient 
 Telephone (or video) contact with patient 
 Known alive through other contact with patient or contact with party 
other than patient 
 Other contact with patient (mail, email, text, social media, etc.) 
• Patients with unknown vital status at Week 12 
o Lost to follow-up 
o Withdrawal of informed consent to any follow-up 
Additionally, listings of inclusion/exclusion criteria, screening disposition, reason for 
withdrawal of consent and study treatment disposition will be provided. 
Any visit that did not occur per protocol will be listed with the reason it was not done. 


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2.3.2 
Protocol deviations 
The number and percentages of protocol deviations by category will be summarized by study 
phase (see Section 2.1.1 for study phase definitions). Additionally, a listing of protocol 
deviations during the study will also be presented. The RS will be used. 
 
2.3.3 
Index hospitalization 
The number and percentages of the following information about patients and their index 
hospitalization visit will be summarized by treatment group. The RS will be used. 
• Patient in shock (No, Yes, Unknown) 
• Patients receiving following treatment from index hospitalization to randomization 
o Vasopressor (No, Yes, Unknown) 
o Inotrope (No, Yes, Unknown) 
o Nitroprusside (No, Yes, Unknown) 
o Nesiritide (No, Yes, Unknown) 
o Patient cared for in Intensive Care Unit (ICU) (No, Yes, Unknown) 
The number and percentage (categorical variables) and descriptive statistics (continuous data) 
for information on patient index hospitalization discharge will be summarized by treatment 
group. The RS will be used. 
• Duration of index hospitalization stay in days [(date:time of discharge – date:time of 
arrival)/(3600*24)] 
• Discharge disposition (Home or with family/friends, Rehabilitation facility, Skilled 
nursing facility, Death, Unknown) 
• Discharge weight (kg) 
• New York Heart Association (NYHA) class (I, II, III, IV, Not done) 
• Patient experienced worsening heart failure since randomization (No, Yes, Unknown) 
• Patient cared for in ICU (No, Yes, Unknown) 
o Number of nights in ICU since randomization 
• Patient treated with any of the following medication classes since randomization 
(Intravenous inotrope, Intravenous vasopressor, Nitroprusside, No, Unknown) 
• Patient took third dose of double-blind study treatment (No, Yes) 
All information relating to the index hospitalization will be listed. 
2.3.4 
Demographics and other baseline characteristics 
Demographics, baseline characteristics, and disease history are collected at the screening visit. 
Descriptive  summaries  and/or  listings  will  be  provided.  The  number  and        percentage 


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(categorical variables) and descriptive statistics (continuous data) for the information below 
will be summarized by treatment group for both double-blind and open-label patients. 
The    FAS    will    be    used. 
Demographics and baseline characteristics 
Demographic variables include: 
• Age (years), age group (<65 years and ≥65 years; <75 years and ≥75 years) 
• Sex (Male, Female) 
o Child bearing status (Able to bear children, Premenarche, Post-menopausal [per- 
protocol >12 months], Sterile-of child bearing age) 
• Race (Caucasian, Black, Asian, Native American, Pacific Islander, Unknown, Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Source of patient referral (Physician’s own practice, Physician referral, Advocacy group, 
ER or hospital, Friend/family member, Patient database, Unknown, Other) 
Baseline characteristic variables include: 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) (kg/m2) [= weight (kg)/height (m)2 from screening visit 1] 
o BMI categories (<20, 20 - <25, 25 - 30, >30  kg/m2) 
• Smoking history (Former, Current, Never) 
• Heart rate (bpm) 
• Bundle branch block (or Intraventricular Conduction Delay [IVCD]) present (No, Yes) 
o Bundle branch block type (Left bundle branch [LBB] block, Right bundle branch 
[RBB block], Non-specific intraventricular conduction delay) 
• NT-proBNP (pg/mL), separately for values based on clinical laboratory samples 
processed and assessed by the central and local laboratories 
o  NT-proBNP categories (<450, 450 - <900, 900 - <1600, 1600 - <3200, 3200 - 
<7400, 7400 - <10000, ≥10000 pg/mL) 
• BNP (pg/mL), separately for values based on clinical laboratory samples processed and 
assessed by the central and local laboratories 
o BNP categories (<100, 100 - <225, 225 - <400, 400 - <800, 800 - <1850,   1850 
- <2500, ≥2500 pg/mL) 
Disease characteristics 
Disease characteristic variables include: 


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• Category of prior chronic heart failure (CHF) medication (ACEi, Angiotensin Receptor 
Blocker [ARB], Beta blocker, Aldosterone antagonist, Ivabradine, Hydralazine, Nitrates 
[long lasting], Digoxin, Diuretic) 
• ACEi naïve (No, Yes); ARB naïve (No, Yes); ACEi/ARB naïve (No, Yes) 
• History of HF prior to qualifying HF event (No, Yes, Unknown) 
• Number of hospitalizations with primary diagnosis of HF within past 12 months not 
including index hospitalization 
o Number of hospitalizations categories (0, 1, 2, ≥3, Not Applicable) 
• Total number of hospitalizations for any reason within past 12 months 
• NYHA classification 30 days prior to index hospitalization (I, II, III, IV, Unknown) 
• Ejection fraction (%) 
o Ejection fraction categories (>40%, >30% - 40%, >20% - 30%, ≤20%) 
• Time from presentation to randomization (days) 
Cardiovascular history 
Cardiovascular history will be summarized. The following disease information will be collected: 
• Hypertension (No, Yes, Unknown) 
• Transient Ischemic Attack (TIA) (No, Yes, Unknown) 
• Stroke (No, Yes, Unknown) 
• Peripheral vascular disease (No, Yes, Unknown) 
• Chronic renal insufficiency [eGFR <60 ml/min/1.73m2 on testing >30 days prior to 
index hospitalization] (No, Yes, Unknown) 
o Chronic Kidney Disease (CKD) stage (CKD stage 3 [eGFR 30 - 59], CKD stage 
4 [eGFR 15 - 29], CKD stage 5 [eGFR <15 or dialysis]) 
• Arrhythmia (No, Yes, Unknown) 
o Arrhythmia type (Atrial fibrillation, Atrial flutter, Supraventricular tachycardia, 
Ventricular tachycardia) 
• Pacemaker/Implantable Cardioverter Defibrillator (ICD) (No, Yes, Unknown) 
o Device type (Pacemaker [conventional], Cardiac resynchronization therapy – no 
ICD [CRT-P], Cardiac resynchronization therapy – with ICD [CRT-D], ICD 
only [single/dual], Other, Unknown) 
• Moderate to severe valvular heart disease (No, Yes, Unknown) 
o Heart disease type (Mitral regurgitation, Aortic regurgitation, Aortic stenosis, 
Tricuspid regurgitation) 
• Prior valvular heart surgery (No, Yes, Unknown) 


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o Valvular surgery type (Mitral, Aortic, Tricuspid, Pulmonic) 
Non-Cardiovascular Medical History 
Non-cardiovascular medical history and ongoing conditions will be summarized and listed. The 
summaries will be presented by primary system organ class (SOC), preferred term (PT) and 
treatment group for both double-blind and open-label patients. Non-cardiovascular medical 
history and ongoing conditions will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) terminology (v19.0 or later). 
Surgeries and Medical Procedures 
Surgeries and medical procedures will be listed, including the reason, start date and end date. 
Surgeries and medical procedures will be coded using MedDRA terminology (v19.0 or later). 
 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The SS will be used for all analyses associated with study treatment and medications, unless 
otherwise specified. 
 
2.4.1 
Study treatment / compliance 
The duration of double-blind study treatment phase is defined as: 
Duration (days) = (date of last study treatment in double-blind study phase – date of first study 
treatment) +1 
The first date of study treatment is recorded on the Dose Administration (Visit 2) eCRF. 
The duration of the open-label study treatment phase is defined as: 
Duration (days) = (date of last study treatment in open-label study phase – date of first study 
treatment in open-label phase) +1 
The duration of the pooled phase (sacubitril/valsartan in double-blind phase and/or 
sacubitril/valsartan in open-label phase) is defined as: 
Duration (days) = (date of last study treatment of sacubitril/valsartan [any phase] – date of 
first study treatment of sacubitril/valsartan [any phase]) +1 
Summary statistics will be displayed for the duration of double-blind study treatment, duration 
of open-label study treatment and duration of pooled sacubitril/valsartan by phase. 
The durations will also be categorized into weekly time intervals (<7 days, 7 - <14 days, 14  - 
<21 days, …, etc.). The number and percentage of patients in each category will be presented 
by phase. 
Total patient-days of exposure will also be summarized by phase. 
In addition, the number and percentages of each dose level dispensed by visit will be 
summarized by treatment group and open-label sacubitril/valsartan. The number and percentage 
of the maximum dose levels dispensed will also be presented by treatment group and open-label 
sacubitril/valsartan. Similarly, the up-titrated doses, down-titrated doses and unchanged doses 
will be summarized by visit, treatment group and open-label sacubitril/valsartan. The  number 


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and percentage of patients who were dispensed dose level 3 by Week 6 will be summarized by 
treatment group. 
An additional summary of patient dose level and titration data will be generated by visit and 
systolic blood pressure using the visit-specific systolic blood pressure cut-off values from the 
dose titration schedule. 
All information on dose administration will be listed. 
 
2.4.2 
Prior, concomitant and post therapies 
Non-HF Medications 
Prior and concomitant non-HF medications will be coded according to the World Health 
Organization (WHO) Drug Reference List (v15.3 or later). Prior and concomitant medications 
are mutually exclusive, as defined below: 
• Prior medications are defined as any medication with an end date prior to the first dose 
of study treatment 
• Concomitant medications are defined as any medications taken on or after the start of 
study treatment. Prior medications that are ‘ongoing’ at the time of the first study 
treatment or whose end date is after first study treatment will be considered a 
concomitant medication 
The number and percentage of patients with concomitant medications that started after study 
treatment will be summarized by Anatomical Therapeutic Chemical (ATC) class, preferred 
term and study phase (refer to Section 2.1.1 for study phase definitions). All medications will 
be listed. 
HF Medications 
Medication names are provided for ACEi, ARB, beta blocker and other antiplatelets and will 
be coded using the WHO Drug Reference List (v15.3 or later) and the preferred term will be 
displayed for these categories. 
The number and percentages of prior HF medications at screening will be summarized by 
treatment group, open-label and pooled sacubitril/valsartan. Similarly, the HF medications 
collected at randomization will be summarized by treatment group, open-label and pooled 
sacubitril/valsartan. A descriptive summary for the total daily dose of each medication (for 
which doses are collected) will also be presented. These summaries will also be presented using 
the FAS. 
The number and percentages of HF medications collected post randomization will be 
summarized by study phase (see Section 2.1.1 for study phase definitions). The overall 
summary will be presented. The following medications will be summarized: Beta blocker, 
Ivabradine, Hydralazine, Nitrites (long acting), Calcium channel blocker, Potassium, Digoxin, 
Statin, 
Furosemide, 
Torsemide, 
Bumetanide, 
Hydrochlorothiazide 
(HCTZ), 
Diuril 
(chlorothiazide), Metolazone, Spironolactone and Eplerenone. 
Additionally, a descriptive summary for the total daily dose of each diuretic taken post 
randomization will be presented by visit, treatment group and open-label  sacubitril/valsartan; 


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these include: Furosemide, Torsemide, Bumetanide, HCTZ, Diuril (chlorothiazide), 
Metolazone, Spironolactone and Eplerenone. 
HF Medications at Index Hospitalization Discharge 
The number and percentages of HF medications at the index hospitalization discharge will be 
summarized by treatment group, open-label and pooled sacubitril/valsartan. The following 
medications will be summarized: Beta blocker, Ivabradine, Hydralazine, Nitrites (long acting), 
Calcium channel blocker, Potassium, Digoxin and Statin. Additionally, the number and 
percentages of each daily diuretic and/or potassium taking during the index hospitalization 
collected at discharge, the route (when applicable) and total daily dose will be summarized by 
treatment group, open-label and pooled sacubitril/valsartan. 
These summaries will also be presented using the FAS. 
Post Randomization Non-study Drug ACEi/ARB 
Any ACEi and/or ARB taken after randomization will be listed. 
 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is the time-averaged proportional change from baseline in NT-proBNP. 
Weeks 4 and 8 will be included in the analysis (primary analysis time point). The analysis of 
the primary endpoint will be based on the FAS. 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary hypothesis to be tested is the ratio of the geometric means of NT-proBNP (average 
of Weeks 4 and 8/baseline) for the sacubitril/valsartan and enalapril treatment groups are equal 
(H0) versus the ratio of the geometric means of NT-proBNP are not equal (Ha). 
For NT-proBNP, the time-averaged proportional change from baseline in a logarithmic scale 
will be analyzed using an analysis of covariance (ANCOVA) model using data from Weeks 4 
and 8 with treatment as a fixed effect factor and the logarithmic baseline biomarker value as a 
covariate. 
The values from Weeks 4 and 8 will be averaged and the change from baseline in log- 
transformed NT-proBNP will be calculated as follows: 
log (average post dose value) – log (baseline value) 
The estimated treatment effect in terms of ratios of geometric means, based on the least-squares 
(LS) means from the model, and the corresponding two-sided 95% confidence intervals will be 
presented. 
The geometric means (presented as a ratio to baseline) will be calculated by exponentially back 
transforming the LS means based on the ANCOVA model as follows: 
exp (LS mean) 


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2.5.3 
Handling of missing values/censoring/discontinuations 
The analysis will be performed based on all available data in the FAS and based on likelihood 
method with an assumption of missing at random for missing data. 
 
2.5.4 
Supportive analyses 
The primary endpoint will be analyzed in the FAS using the same analytical approach as 
described in Section 2.5.2; however, baseline will be defined as the last non-missing NT- 
proBNP assessment with collection date:time < first dose date:time. 
For NT-proBNP at Weeks 4 and 8, a proportional change from baseline in a logarithmic scale 
will be analyzed using an ANCOVA model with treatment as a fixed effect factor and the 
logarithmic baseline biomarker value as a covariate. For each visit, the estimated treatment 
effects in terms of ratios of the geometric means based on the LS means from the model and 
the corresponding two-sided 95% confidence intervals produced from the model will be 
presented. The geometric mean will be calculated by exponentially back transforming the LS 
means. 
The primary endpoint will also be analyzed in the PPS using the same analytical approach as 
described in Section 2.5.2. 
In addition, a binary outcome variable will be created for patients achieving a 25%, 50% and 
75% decline in NT-proBNP (0-no, 1-yes) and a logistic regression model will be fit. The odds 
ratio, 95% confidence interval and p-value will be provided. The outcome variable will be 
achieving a decline in NT-proBNP and the predictor of response will be treatment group. 
A descriptive summary of patient evaluability for the primary endpoint analysis based on NT- 
proBNP values will be presented by treatment group. 
 
2.6 
Analysis of the key secondary objective 
No key secondary objective. 
 
2.7 
Analysis of secondary objectives 
All analyses will be performed on the FAS, unless otherwise specified. 
 
2.7.1 
Secondary endpoints 
Secondary endpoints include the following: 
• The proportional change in NT-proBNP from baseline to Week 8 
• Incidence of symptomatic hypotension during 8 weeks of treatment 
• Incidence of hyperkalemia (potassium >5.5 mEq/L) during 8 weeks of treatment 
• Incidence of angioedema during 8 weeks of treatment 
• Biomarkers: hs-Troponin T (high sensitivity), urinary cGMP (UcGMP), UcGMP to 
urinary creatinine ratio, BNP, NT-proBNP to BNP ratio, and BNP to NT-proBNP ratio 
at 4 and 8 weeks 


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2.7.2 
Statistical hypothesis, model, and method of analysis 
For NT-proBNP at Week 8, a proportional change from baseline in a logarithmic scale will be 
analyzed using an ANCOVA model with treatment as a fixed effect factor and the logarithmic 
baseline biomarker as a covariate. The estimated treatment effects in terms of ratios of 
geometric means, based on the LS means from the ANCOVA model, and the corresponding 
two-sided 95% confidence intervals will be provided. Baseline is Week 0. Week 4 will be used 
if the Week 8 value is missing. 
The incidence of symptomatic hypotension up to Week 8 will be calculated by treatment group. 
The relative risk (sacubitril/valsartan vs. enalapril) and the 95% confidence interval will also be 
presented. Similarly, the incidence of hyperkalemia, all angioedema, and positively adjudicated 
angioedema during the 8 week double-blind phase and the relative risk (sacubitril/valsartan vs. 
enalapril) will be summarized. Additionally, medication change, lowest documented systolic 
blood pressure and lowest documented diastolic blood pressure will be summarized by 
treatment group for symptomatic hypotension. The highest potassium value documented for 
hyperkalemia will also be summarized by treatment group. 
For biomarkers including BNP, BNP to NT-proBNP ratio, NT-proBNP to BNP ratio, hs- 
Troponin T, UcGMP, and UcGMP to urinary creatinine ratio, the time-averaged proportional 
change from baseline in a logarithmic scale will be analyzed using an ANCOVA model using 
data from Weeks 4 and 8 with treatment group as a fixed effect factor and the logarithmic 
baseline biomarker value as a covariate. 
Similar to the primary endpoint, the values from Weeks 4 and 8 will be averaged and the change 
from baseline will be calculated. 
The estimated treatment effect in terms of ratios of geometric means, based on the LS means 
from the model, and the corresponding two-sided 95% confidence intervals will be presented. 
The geometric means (presented as a ratio to baseline) will be calculated by exponentially back 
transforming the LS means based on the ANCOVA model. 
For biomarkers including BNP, BNP to NT-proBNP ratio, NT-proBNP to BNP ratio, UcGMP, 
and UcGMP to urinary creatinine ratio at Weeks 1, 2, 4 and 8, a proportional change from 
baseline in a logarithmic scale will be analyzed using an ANCOVA model with treatment as a 
fixed effect factor and the logarithmic baseline biomarker value as a covariate. For each visit, 
the estimated treatment effects in terms of ratios of the geometric means based on the LS means 
from the model, and the corresponding two-sided 95% confidence intervals produced from the 
model will be presented. Similarly, the geometric mean will be calculated by exponentially back 
transforming the LS means based on the ANCOVA model. This analysis will also be performed 
for hs-Troponin T at Weeks 1, 4, and 8 (note that hs-Troponin T is not measured at Week 2). 
 
2.7.3 
Handling of missing values/censoring/discontinuations 
The analysis will be performed based on all available data in the FAS and based on likelihood 
method with an assumption of missing at random for missing data. 
 
2.8 
Safety analyses 
All safety analyses will be performed on the SS unless otherwise specified. 


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2.8.1 
Adverse events 
 
2.8.1.1 
Coding of AEs 
Adverse events are coded using MedDRA terminology (v19.0 or later). 
 
2.8.1.2 
General rules for AE reporting 
AE summaries will include all treatment-emergent AEs (TEAEs). TEAEs are defined as AEs 
starting on or after the first day of study treatment. All AEs will be listed. AEs starting prior to 
the first day of study treatment (non-TEAEs) will be flagged in the listings. 
All TEAEs will be summarized by study phase as defined in Section 2.1.1. 
TEAEs will be summarized by presenting the number and percentage of patients having at least 
one TEAE, having at least one TEAE in each primary SOC, and for each PT using MedDRA 
coding. A patient with multiple occurrences of a TEAE will be counted only once in the AE 
category. 
Separate summaries will be presented by SOC, PT and severity. A patient with multiple 
severities for an AE will be summarized under the worst severity recorded for the event. 
Any information collected will be listed as appropriate. 
 
2.8.1.3 
AE summaries 
The following summary tables will be provided: 
• AEs, regardless of study treatment relationship, by primary SOC, PT and worst severity 
• Most frequent (≥5%) AEs, regardless of study treatment relationship, by PT 
• AEs, suspected to be related to study treatment, by primary SOC and PT 
• Serious adverse events (SAE), regardless of study treatment relationship, by primary 
SOC and PT 
• SAEs, suspected to be related to study treatment, by primary SOC and PT 
• SAEs occurring with a frequency of ≥0.5%, regardless of study treatment relationship, 
by PT 
• SAEs, regardless of study treatment relationship, by primary SOC, PT and seriousness 
criteria 
• AEs leading to discontinuation, regardless of study treatment relationship, by primary 
SOC and PT 
• AEs requiring dose adjustment or study treatment interruption, regardless of study 
treatment relationship, by primary SOC and PT 
• AEs requiring additional therapy, regardless of study treatment relationship, by primary 
SOC and PT 


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• Death resulting from AEs, regardless of study treatment relationship, by primary SOC 
and PT 
 
2.8.1.4 
In addition, an overview of TEAEs presenting the number of 
percentage of patients having at least one TEAE for each of the above 
categories will be provided.Adverse events of special interest / 
grouping of AEs 
Separate summaries will be provided for AEs related to all angioedema, positively adjudicated 
angioedema, elevated creatinine, hyperkalemia and symptomatic hypotension. The summaries 
will be presented by primary SOC, PT and worst severity. 
Additionally, a sensitivity analysis will be performed on the AEs of special interest for patients 
randomized to sacubitril/valsartan. The number and percentages of AEs of special interest 
occurring prior to the active dose of sacubitril/valsartan will be presented along with the number 
and percentages of AEs of special interest occurring on or after the active dose of 
sacubitril/valsartan during the double-blind phase. The following definition will be used: 
Angioedema: 
AE prior to active study treatment = if event occurred within 1 day of dosing as recorded on 
the Angioedema Assessment Visit 2 (randomization) 
AE after active study treatment = if event occurred after 1 day of dosing as recorded on the 
Angioedema Assessment Visit 2 (randomization) 
Symptomatic hypotension: 
AE prior to active study treatment = First dose date ≤ event < Third dose date of study treatment 
AE after active study treatment = Third dose date of study treatment ≤ event ≤ Last dose date 
of double-blind medication 
Elevated creatinine and hyperkalemia: 
AE prior to active study treatment = First dose date:time of study treatment ≤ event < Third 
dose date:time of study treatment 
AE after active study treatment = Third dose date:time of study treatment ≤ event ≤ Last dose 
date:time of double-blind medication 
 
2.8.2 
Deaths 
Patient deaths will be summarized by total, primary cause of death, type of cardiovascular death 
and type of non-cardiovascular death and will be presented by study phase (see Section 2.1.1 
for study phase definitions). A patient listing of all deaths with recorded principal cause of death 
will be provided. All patients in the FAS will be included for the above analysis. 
 
2.8.3 
Laboratory data 
Laboratory values will be summarized using shift tables (from baseline to most extreme post 
baseline value) by each laboratory parameter at its worst severity by study phase (see  Section 
2.1.1 for study phase definitions). The number and percentage of patients with laboratory values 


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will be presented by low/normal/high (low and high) classifications to compare baseline to 
worst post baseline value. 
In addition, laboratory values and the change from baseline for each parameter by visit will be 
summarized by treatment group and open-label sacubitril/valsartan. In the event that there are 
multiple laboratory values within a visit, the worst value will be summarized. 
A separate summary table will be presented by study phase (see Section 2.1.1 for study phase 
definitions) with the number and percentage of patients having notable lab abnormalities based 
on percent change from baseline (see Section 5.3 for a list of notable laboratory abnormalities). 
A summary of hyperkalemia labs by visit will also be presented by treatment group and open- 
label sacubitril/valsartan. The highest potassium value for the event and any potassium re-test 
results will be descriptively summarized. Similarly, creatinine labs will also be presented by 
visit, treatment group and open-label sacubitril/valsartan. The highest creatinine value for the 
event and any creatinine re-test results will be descriptively summarized. 
Listings of all laboratory values will be provided. Separate listings for hyperkalemia labs, 
creatinine labs and pregnancy tests will also be provided. Any notable laboratory abnormalities 
will also be flagged. 
 
2.8.4 
Other safety data 
 
2.8.4.1 
ECG and cardiac imaging data 
ECG data will be collected at screening and all data, including unscheduled visits, will be listed. 
 
2.8.4.2 
Vital signs 
All vital signs (systolic and diastolic blood pressure [mmHg], pulse rate [sitting/beats per 
minute], weight [kg], height [cm], BMI [kg/m2] and waist/hip circumference) will be 
descriptively summarized at each visit by treatment group and open-label sacubitril/valsartan. 
Change from baseline will also be presented. 
A separate summary table will be presented with the number and percentages of patients having 
notable vital signs based on changes relative to baseline values (see Section 5.4 for a list of 
notable vital signs) by study phase (see Section 2.1.1 for study phase definitions). 
The number and percentages of patients having symptomatic hypotension will also be 
summarized by study phase. The following variables associated with symptomatic hypotension 
will also be presented: symptoms occurring while standing, any treatment or medication change 
as a result of episode, lowest documented systolic blood pressure, systolic blood pressure 
position, lowest documented diastolic blood pressure and diastolic blood pressure position. A 
listing for symptomatic hypotension will also be presented. 
 
2.8.4.3 
Heart Failure Event 
Any new heart failure event information will be collected and listed. The following will be 
presented: 
• Type of event (HF hospitalization [hospital stay ≥24 hours], Heart failure emergency 
department visit, Urgent/unplanned heart failure office visit, Worsening heart    failure 


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during the index hospitalization [qualifying heart failure event], None of the 
aforementioned types occurred with, or apply to, this HF event) 
• Symptoms of worsening HF (Dyspnea – [Dyspnea at rest, Dyspnea on exertion, 
Orthopnea, Paroxysmal nocturnal dyspnea, Tachypnea], Decreased exercise tolerance 
[reduced ability to perform activities that induce physical exertion due to dyspnea or 
fatigue], Fatigue [lack of energy, extreme tiredness, inability to complete usual 
activities], Worsening end-organ perfusion – [Confusion (thought to be from low 
cardiac output), Reduced urine output], Symptoms of volume overload – [Lower 
extremity swelling, Increased abdominal distension)], Other) 
• Physical exam signs of worsening HF (Peripheral edema, Increased abdominal 
distension or ascites [in the absence of hepatic disease], Pulmonary rales/crackles, 
Elevated jugular venous pressure and/or hepatojugular reflux, New or worsening 3rd 
heart sound, Clinically significant weight gain thought to be related to fluid retention 
[>3 - 4 lbs. in 3 to 4 days], Other) 
• Laboratory evidence of worsening HF (Increased NT-proBNP [>2,000 pg/mL], 
Radiographic evidence of pulmonary congestion, Right heart catheterization with 
pulmonary capillary wedge pressure ≥18 mmHg, central venous pressure ≥12 mmHg, 
or a cardiac index of <2.2 L/min/m2, Other) 
• Increased or additional therapy (No, Yes, Unknown) 
o Therapy type (Augmentation of oral diuretic therapy with additional diuretic, 
Initiation of intravenous diuretic, Uptitration of intravenous therapy, if already 
on therapy, Initiation of inotrope, or vasodilator therapy, Initiation of 
percutaneous mechanical circulatory support, Initiation of temporary surgical 
support [ECMO or temporary surgical ventricular assist device (VAD) i.e. 
centrimag], Implantation of durable LVAD, Listed for heart transplantation) 
• Evidence of cardiogenic shock (No, Yes, Unknown) 
• Blood sample collected for BNP or NT-proBNP (No, Yes, Unknown) 
o BNP result (pg/mL) 
o NT-proBNP result (mg/mL) 
• Contributors/precipitants of worsening heart failure (Medication nonadherence, Dietary 
indiscretion, Acute coronary syndrome, Other systemic illness – [Respiratory infection, 
Urinary tract infection, Other]) 
 
2.8.4.4 
HF Signs and Symptoms 
Heart failure signs and symptoms will be collected at screening, randomization and at post 
randomization visits. The number and percentage of the following parameters will be 
summarized at each visit by treatment group and open-label sacubitril/valsartan: 
• Heart failure signs or symptoms within the past 24 hours prior to this visit (No, Yes) 
• Rales (Not present, Basilar only, >1/3 of lung filled, Not done) 


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• Peripheral edema (Absent, Trace, Feet and ankles, Lower legs or thighs, Sacrum, Not 
done) 
• Current NYHA heart failure classification (Class I, Class II, Class III, Class IV, Not 
done) 
• Fatigue (Not present, Seldom, Frequent, Continuous, Not done) 
• Dyspnea (Not present, Seldom, Frequent, Continuous, Not done) 
• Orthopnea (Not present, Seldom, Frequent, Continuous, Not done) 
2.8.4.5 
Hospitalization 
Information related to hospitalization will be listed. The following will be presented: 
• Type of hospitalization (Elective, Planned, Unplanned) 
• Reason for hospitalization (refer to eCRF for list of reasons) 
• Patient discharged (No, Yes, Unknown) 
o Duration of hospitalization in days [date of discharge – date of admission + 1] 
• Patient admitted to ICU or Coronary Care Unit (CCU) (No, Yes, Unknown) 
o Number of days in ICU or CCU 
• Discharge disposition (Home or with family/friends, Rehabilitation facility, Skilled 
nursing facility, Death, Unknown) 
 
2.8.4.6 
Angioedema 
Data collected from the angioedema assessment and questionnaire at screening, randomization 
and follow-up visits will be summarized. Separate summaries will be produced for all 
angioedema and positively adjudicated angioedema. The number and percentage for categorical 
variables and summary statistics for continuous variables of the following will be presented by 
visit, treatment group and open-label sacubitril/valsartan: 
• Outcome  (Not  recovered/Not  resolved,  Recovered/Resolved, Recovering/Resolving, 
Recovered/Resolved with Sequelae, Fatal, Unknown)\ 
o Duration of angioedema in days [end date – start date + 1] 
• Timing of event (After first dose, after multiple doses, dose not given) [not asked at 
screening] 
o Study medication discontinued due to event (No, Yes, Unknown) 
o Event occurred within 1 day of dosing (Within 1 day of dose but less than or 
equal to 1 hour, within 1 day of dose but greater than 1 hour, After 1 day of 
dosing, Unknown) 
• History of prior angioedema or angioedema like event (No, Yes, Unknown) 
o If yes, medications taken at time of previous event: 


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 ACE inhibitor (No, Yes, Unknown) 
 ARB (No, Yes, Unknown) 
 Renin inhibitor (No, Yes, Unknown) 
 Other medications (No, Yes, Unknown) 
• Presence of hereditary angioedema (No, Yes, Unknown) 
• Any family members with history of angioedema-like events (No, Yes, Unknown) 
• Signs and symptoms for current event 
o Shortness of breath/dyspnea (No, Yes, Unknown) 
o Difficulty swallowing/dysphagia (No, Yes, Unknown) 
o Difficulty speaking/dysarthria (No, Yes, Unknown) 
o Pain on swallowing/odynophagia (No, Yes, Unknown) 
o Stridor (No, Yes, Unknown) 
o Abdominal pain (No, Yes, Unknown) 
o Other (No, Yes, Unknown) 
• Edema present (No, Yes) 
o Periorbital edema (No, Yes, Unknown) 
o Head edema (No, Yes, Unknown) 
o Neck edema (No, Yes, Unknown) 
o Lip edema (No, Yes, Unknown) 
o Tongue edema (No, Yes, Unknown) 
o Throat edema (No, Yes, Unknown) 
o Submandibular edema (No, Yes, Unknown) 
o Genitalia edema (No, Yes, Unknown) 
o Extremities edema (No, Yes, Unknown) 
o Other (No, Yes, Unknown) 
• Previous edematous episodes (No, Yes, Unknown) 
o Number of previous edematous episodes 
• ACEi taken in the past (No, Yes, Unknown) 
• ACEi taken during trial participation after screening (No, Yes, Unknown) [not asked at 
screening] 
o Dose changed within 2 days of event (No, Yes, Unknown) 
• ARB taken in the past (No, Yes, Unknown) 


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• ARB taken during trial participation after screening (No, Yes, Unknown) [not asked at 
screening] 
o Dose changed within 2 days of event (No, Yes, Unknown) 
• Patient suffering from influenza, common cold or upper respiratory tract infection (No, 
Yes, Unknown) 
• Medication allergies (No, Yes, Unknown) 
• Food allergies (No, Yes, Unknown) 
• Potential causes of angioedema-like event 
o Food (No, Yes, Unknown) 
o Insect bite (No, Yes, Unknown) 
o Animal exposure (No, Yes, Unknown) 
o Medication (No, Yes, Unknown) 
o Dental work (No, Yes, Unknown) 
o Pollen (No, Yes, Unknown) 
o Dust (No, Yes, Unknown) 
o Concomitant disease (No, Yes, Unknown) 
o Idiopathic (No, Yes, Unknown) 
o Other (No, Yes, Unknown) 
• Medical intervention (No, Yes) 
o Administration of H-1 blocker (No, Yes) 
o Administration of H-2 blocker (No, Yes) 
o Administration of steroids (No, Yes) 
o Administration of epinephrine (No, Yes) 
o Admission to hospital (No, Yes) 
o Admission to ER (No, Yes) 
o Endotracheal intubation (No, Yes) 
o Tracheostomy (No, Yes) 
o Discontinuation of ACE inhibitor (No, Yes) 
o Discontinuation of ARB (No, Yes) 
o Other 
All assessment data will be listed. The adjudicated assessment of the event will be listed 
separately. 


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In addition, key characteristics of positively adjudicated angioedema will be summarized with 
descriptive statistics by study phase as defined in Section 2.1.1. 
 
2.9 
Pharmacokinetic endpoints 
Not applicable. 
 
2.10 
PD and PK/PD analyses 
Not applicable. 
 
 


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2.12 
Biomarkers 
BNP and NT-proBNP will be collected and descriptively summarized by visit, treatment group 
and open-label sacubitril/valsartan. Values and the change from baseline for each parameter 
will be summarized by visit, treatment group and open-label sacubitril/valsartan. Analyses will 
be based on the FAS. BNP and NT-proBNP values will be based on clinical laboratory samples 
processed and assessed by the central laboratory. 
Additional biomarker measurements believed to be relevant to the pathophysiology of the 
disease processes of heart failure and dysfunction will also be collected and summarized by 
visit, treatment group and total. These may include, but no limited to those assessing cardiac 
and renal benefit or biomarkers related to the study treatment mechanism of action such as: 
• Neurohormones BNP and NT-proBNP 
• hs-Troponin T 
• 
 
• 
 
• 
 
• urinary cGMP 
• 
 
 
Additional analysis of biomarkers is discussed in Sections 2.5, 2.7 and 2.13. 
Biomarker samples from patients who withdrew consent will not be analyzed by the central 
laboratory. 
 


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2.14 
Interim analysis 
No interim analysis is planned. 
 
3 
Sample size calculation 
Assuming a significance level of 0.05 and 85% power, a sample size of 882 patients would be 
needed to detect an 18% reduction in the geometric mean of the time-averaged proportional 
change from baseline (average of Weeks 4 and 8) in NT-proBNP for the sacubitril/valsartan 
treatment group assuming a value of 0.95 for the enalapril group, a common standard deviation 
of 0.85 and a 25% rate of missing/non-evaluable samples. The estimates are based on the day 5 
to day 14 data from the RELAX-AHF study. The standard deviation estimate is supported by 
data from PARADIGM. 
The assumption of a 18% reduction in the geometric mean for NT-proBNP for the 
sacubitril/valsartan treatment group vs. the enalapril group is consistent with NT-proBNP 
results seen in PARADIGM (26% and 25% relative reduction of sacubitril/valsartan vs. 
enalapril at Week 4 and Month 8 respectively), PARAMOUNT (23% relative of 
sacubitril/valsartan vs. valsartan at Week 12) and RELAX-AHF (19% relative reduction of 
serelaxin vs. placebo at Day 2). 
Sample size and power for various rate of reduction in sacubitril/valsartan group given alpha = 
0.05 are given in Table 9-1 in the protocol. 
 
4 
Change to protocol specified analyses 
The following changes to protocol specified analyses were made: 
• Specified the following additional biomarkers as secondary endpoints: 
o UcGMP to urinary creatinine ratio 
o BNP 
o NT-proBNP to BNP ratio 


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• Added sensitivity analyses for the following endpoints using the “strict” baseline 
definition (i.e., collection date:time < first dose date:time): 
o Primary endpoint 
 
 
 
 
 
• Clarified that tables summarizing demographics and baseline data will be run only on 
the FAS, and not also on the RS as indicated in the protocol 
• Replaced supportive analysis of the primary endpoint consisting of summary statistics 
and t-test p-values for comparing treatment groups on the proportional change from 
baseline in a logarithmic scale at Weeks 4 and 8 with ANCOVA at Weeks 4 and 8 
 
 
 
 
 
 
• Modified the Safety Set definition to remove the word ‘active’ so that inclusion in the 
Safety Set is not restricted to patients who received at least one dose of active study 
treatment 
 
 
 
 
 
 
 
 
• Added Weeks 4 and 8 to the analysis of change from baseline in biomarkers defined as 
secondary endpoints 
 
 
 
 
 
 
• Modified the PPS definition to clarify that major protocol deviations will exclude 
patients from the PPS regardless of the study phase in which they occur 
 
 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study treatment 
Full dates for study treatment collected on the eCRF are required; therefore, no imputations will 
be made. 
 
5.1.2 
AE date imputation 
The following algorithm should be used to estimate start dates for which only partial 
information is known: 
• 
Missing day and month 
- 
If the year is the same as the year of first study treatment, then the day and 
month of the start date of treatment will be assigned to the missing fields. 
- 
If the year is prior to the year of first study treatment, then December 31 will be 
assigned to the missing fields. 
- 
If the year is after the year of first study treatment, then January 1 will be 
assigned to the missing fields. 
• 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above 
procedure. 
• 
Missing day only 
- 
If the month and year are the same as the year and month of first study 
treatment, then the start date of treatment will be assigned to the missing day. 
- 
If the month and year are before the year and month of first study treatment, 
then the last day of the month will be assigned to the missing day. 
- 
If the month and year are after the year and month of first study treatment, then 
the first day of the month will be assigned to the missing day. 
If the imputed start date result is after the stop date (and the stop date is complete), the 
imputed start date will be reset to the stop date. 
The following algorithm should be used to estimate stop dates for which only partial 
information is known: 
• 
Missing year 
- 
Date left missing. 
• 
Missing month 
- 
Impute ‘December’. 
• 
Missing day 
- 
Impute ‘last date of that month’. 
 
5.1.3 
Concomitant medication date imputation 
The following algorithm should be used to estimate start dates for which only partial 
information is known: 
• 
Missing day and month 
- 
If the year is the same as the year of first study treatment, then the day and 
month of the start date of treatment will be assigned to the missing fields. 


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- 
If the year is prior to the year of first study treatment, then December 31 will be 
assigned to the missing fields. 
- 
If the year is after the year of first study treatment, then January 1 will be 
assigned to the missing fields. 
• 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above 
procedure. 
• 
Missing day only 
- 
If the month and year are the same as the year and month of first study 
treatment, then the start date of treatment will be assigned to the missing day. 
- 
If the month and year are before the year and month of first study treatment, 
then the last day of the month will be assigned to the missing day. 
- 
If the month and year are after the year and month of first study treatment, then 
the first day of the month will be assigned to the missing day. 
If the imputed start date result is after the stop date (and the stop date is complete), the 
imputed start date will be reset to the stop date. 
The following algorithm should be used to estimate stop dates for which only partial 
information is known: 
• 
Missing year 
- 
Date left missing. Consider the medication to have been received at all periods 
after that period determined by the start date. 
• 
Missing month 
- 
Impute ‘December’. 
• 
Missing day 
- 
Impute ‘last date of that month’. 
 
5.1.3.1 
Prior therapies date imputation 
The same imputation as concomitant medication will be used. See Section 5.1.3. 
 
5.1.3.2 
Post therapies date imputation 
The same imputation as concomitant medication will be used. See Section 5.1.3. 
 
5.2 
AEs coding/grading 
The 
 coding team will code the AE terms using MedDRA terminology (v19.0 or later). If 
any terms are not coded, the data management team will issue queries to sites to update the AE 
term appropriately. 
 
5.3 
Laboratory parameters derivations 
5.3.1 
Laboratory grading 
The collected laboratory values will be summarized by severity (low/normal/high) and not 
converted to Common Terminology Criteria for Adverse Events (CTCAE) grades. 


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5.3.2 
Notable laboratory values 
Hematology 
RBC count 
>50% increase, >20% decrease 
Hemoglobin 
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
Blood Chemistry 
ALT (SGPT) 
>150% increase 
AST (SGOT) 
>150% increase 
BUN 
>50% increase 
Creatinine 
>50% increase 
Total bilirubin 
>100% increase 
CPK 
>300% increase 
Alkaline phosphatase >100% increase 
Potassium 
>20% increase, >20% decrease 
Chloride 
>10% increase, >10% decrease 
Calcium 
>10% increase, >10% decrease 
Uric acid 
>50% increase 
 
5.4 
Vital signs 
5.4.1 
Notable vital sign values 
Systolic blood pressure 
<90 mmHg and decrease of >20 mmHg from baseline 
>140 mmHg and increase of >20 mmHg from baseline 
>160 mmHg and increase of >20 mmHg from baseline 
<90 mmHg 
>140 mmHg 
>160 mmHg 
Decrease of >20 mmHg from baseline 
Increase of >20 mmHg from baseline 
Diastolic blood pressure 
<50 mmHg and decrease of >15 mmHg from baseline 
>100 mmHg and increase of >15 mmHg from baseline 


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<50 mmHg 
>100 mmHg 
Decrease of >15 mmHg from baseline 
Increase of >15 mmHg from baseline 
Pulse 
<50 bpm and decrease of >15 bpm from baseline 
>120 bpm and increase of >15 bpm from baseline 
<50 bmp 
>120 bpm 
Decrease of >15 bpm from baseline 
Increase of >15 bpm from baseline 
Weight 
>7% decrease; >7% increase 
 
5.5 
Statistical models 
5.5.1 
Primary analysis 
The null hypothesis for the primary analysis is the ratio of the geometric means of NT-proBNP 
for the sacubitril/valsartan and enalapril group are equal. An ANCOVA model will be used. 
The model will have the time-averaged proportional change from baseline in a logarithmic scale 
be the dependent variable with treatment as a fixed effect factor and the logarithmic baseline 
value as a covariate. The general form for the ANCOVA model is: 
yij  = µ + Ti + B(xij − xi) + Eij 
PROC MIXED in SAS will be used for the analysis. The LSMEANS option will be used with 
options of CL to output the confidence limits. 
 
5.5.2 
Key secondary analysis 
Similar to the primary analysis, the null hypothesis for the secondary analysis is the ratio of the 
geometric means of different biomarkers (BNP to NT-proBNP ratio, hs-Troponin and urinary 
cGMP) for the sacubitril/valsartan and enalapril group are equal. An ANCOVA model will be 
used. The model will have the time-averaged proportional change from baseline in a logarithmic 
scale be the dependent variable with treatment as a fixed effect factor and the logarithmic 
baseline value as a covariate. The general form for the ANCOVA model is: 
yij  = µ + Ti + B(xij − xi) + Eij 
PROC MIXED in SAS will be used for the analysis. The LSMEANS option will be used with 
options of CL to output the confidence limits. 


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5.6 
Rule of exclusion criteria of analysis sets 
Table 1 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
D01 
Patient   met   one   or   more  of  the 
Discontinuation 
of 
Study 
Drug 
criteria but study drug was not 
discontinued 
E02 
Patient is enrolled in another clinical 
trial involving an investigational 
agent or investigational device 
E03 
Patients      has      a       history      of 
hypersensitivity, known or suspected 
contraindications, or intolerance to 
the study drugs, including ACEIs, 
ARBs, or Sacubitril (NEP inhibitor) 
E04 
Patient  has a history of angioedema 
related to previous ACE inhibitor or 
ARB therapy 
E11 
The  patient  had  implantation  of  a 
cardiac resynchronization therapy 
device (CRTD) within the prior 3 
months from Visit 1, the patient 
intends to have implantation of a 
cardiac resynchronization therapy 
device (CRTD) 
E19 
Patient   is   a   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 
hCG laboratory test 
I07 
LVEF was not ≤ 40% within the past 
6 months (including current 
hospitalization) using 
echocardiography, multi gated 
acquisition scan (MUGA), CT 
scanning 
I09 
Patient did not have an elevated NT- 
proBNP ≥ 1600pg/mL or BNP ≥ 400 
pg/mL during current hospitalization 
Exclusion from PPS 
 
 
 
Exclusion from PPS 
 
 
Exclusion from PPS 
 
 
 
 
Exclusion from PPS 
 
 
Exclusion from PPS 
 
 
 
 
 
 
Exclusion from PPS 
 
 
 
 
Exclusion from PPS 
 
 
 
 
Exclusion from PPS 


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Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
M01 
Patient had concomitant intake of a 
Exclusion from PPS 
prohibited medication as outlined in 
the protocol 
O04 
Patient randomized in error and not 
Exclusion from FAS and PPS 
dosed with study drug 
O05 
Missing NT-ProBNP sample at 
Exclusion from PPS 
either baseline, week 4 or week 8 
O06 
Patient took first dose of study drug 
Exclusion from PPS 
before baseline NT-proBNP sample 
was drawn 
O07 
Patient missed 1 or more 
Exclusion from PPS 
consecutive dose(s) of study drug 
immediately or prior to visit 5 or 
visit 7 
 
 
Table 2 
Patient Classification 
Analysis Set 
PD ID that cause subjects to 
be excluded 
 
Non-PD criteria that cause subjects to be 
excluded 
 
RS 
NA 
Not randomized 
FAS 
O04 
Not in RS 
PPS 
D01, E02, E03, E04, E11, E19, 
I07, I09, M01, O04, O05, O06, 
O07 
Not in FAS 
SS 
NA 
No double-blind study treatment received 
 
 
 
 
6 
Reference