Clinical trial NCT02900378
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Keywords: sacubitril/valsartan enalapril physical activity actigraphy sleep heart failure reduced ejection fraction randomized controlled trial accelerometry
Sponsor: Novartis Pharmaceuticals
Start date: 2016-12-20; Completion date: 2018-04-11
Enrollment: 621 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this randomized, actively controlled, double-blind study with prospective data collection was to assess differences between sacubitril/valsartan versus enalapril in increasing exercise capacity and non-sedentary physical activity in HFrEF patients. Physical activity was assessed by the 6 minute walk test, and daily physical activity was continuously measured by means of a wrist-worn accelerometry device from 2 weeks before until 12 weeks after start of study therapy (sacubitril/valsartan or enalapril).

Detailed description:

Arms: arm 1: After randomization, patients in this arm received LCZ696 (Sacubitril/Valsartan) twice daily and matching placebo of Enalapril depending on the patient's previous ACEI/ARB dose (enalapril equivalent dose) for 2 weeks. Patients could start study medication at dose level 1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ) or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 97 mg/103 mg bid LCZ696(sacubitril/valsartan) and matching placebo, provided no safety and tolerability issues arised during uptitration. arm 2: After randomization, patients in this arm received Enalapril twice daily and matching placebo of LCZ696 (Sacubitril/Valsartan) depending on the patient's previous ACEI/ARB for 2 weeks. Patients could start study medication at dose level 1 or 2a or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 10 mg bid enalapril and matching placebo, provided no safety and tolerability issues arised during uptitration
Interventions: intervention 1: LCZ696 (Sacubitril/Valsartan) intervention 2: Placebo of LCZ696 (Sacubitril/Valsartan) intervention 3: Enalapril intervention 4: Placebo of Enalapril
Intervention descriptions: intervention 1: LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets intervention 2: Placebo of LCZ696 (sacubitril/valsartan) was available to match 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets intervention 3: Enalapril was available in 2.5 mg, 5 mg and 10 mg film-coated tablets intervention 4: Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
LCZ696
Clinical Trial Protocol CLCZ696B3301 / NCT02900378
A multi-center, prospective, randomized, double-blind study to 
assess the impact of sacubitril/valsartan vs. enalapril on daily 
physical activity using a wrist worn actigraphy device in adult 
chronic heart failure patients
Document type:
Amended Protocol Version
EUDRACT number:
2016 – 003085 – 32
Version number:
v04 Clean
Clinical trial phase:
IIIB
Release date:
11-Sep-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
3
Investigational plan ...........................................................................................................25
3.1
Study design...........................................................................................................25
3.2
Rationale for study design .....................................................................................28
3.3
Rationale for dose/regimen, route of administration and duration of treatment....28
3.4
Rationale for choice of comparator .......................................................................29
3.5
Purpose and timing of interim analyses/design adaptations..................................29
3.6
Risks and benefits..................................................................................................29
4
Population..........................................................................................................................30
4.1
Inclusion criteria ....................................................................................................30
4.2
Exclusion criteria...................................................................................................31
5
Treatment...........................................................................................................................33
5.1
Study treatment......................................................................................................33
5.1.1
Investigational and control drugs..........................................................33
5.1.2
Additional treatment..............................................................................34
5.2
Treatment arms......................................................................................................34
5.3
Treatment assignment and randomization.............................................................35
5.4
Treatment blinding.................................................................................................35
5.5
Treating the patient................................................................................................36
5.5.1
Patient numbering .................................................................................36
5.5.2
Dispensing the study drug.....................................................................36
5.5.3
Handling of study and additional treatment..........................................36
5.5.4
Instructions for prescribing and taking study treatment........................37
5.5.5
Permitted dose adjustments and interruptions of study treatment ........38
5.5.6
Rescue medication ................................................................................40
5.5.7
Concomitant medication .......................................................................40
5.5.8
Prohibited medication ...........................................................................41


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5.5.9
Emergency breaking of assigned treatment code..................................42
5.6
Study completion and discontinuation...................................................................42
5.6.1
Study completion and post-study treatment..........................................42
5.6.2
Discontinuation of study treatment .......................................................43
5.6.3
Withdrawal of informed consent...........................................................44
5.6.4
Loss to follow-up ..................................................................................44
5.6.5
Early study termination by the sponsor.................................................44
6
Visit schedule and assessments .........................................................................................45
6.1
Information to be collected on screening failures..................................................49
6.2
Patient demographics/other baseline characteristics .............................................49
6.3
Treatment exposure and compliance .....................................................................49
6.4
Efficacy..................................................................................................................49
6.4.1
Actigraphy.............................................................................................50
6.4.2
Six minute walking test.........................................................................50
.51
.51
51
6.4.6
Appropriateness of efficacy assessments..............................................51
6.5
Safety.....................................................................................................................52
6.5.1
Physical examination ............................................................................52
6.5.2
Vital signs..............................................................................................52
6.5.3
Height and weight .................................................................................52
6.5.4
Laboratory and diagnostic evaluations..................................................53
6.5.5
Pregnancy and assessments of fertility .................................................53
6.5.6
Appropriateness of safety measurements..............................................53
53
53
7
Safety monitoring..............................................................................................................54
7.1
Adverse events.......................................................................................................54
7.2
Serious adverse events...........................................................................................56
7.2.1
Definition of SAE .................................................................................56
7.2.2
SAE reporting........................................................................................57
7.3
Liver safety monitoring .........................................................................................57
7.4
Renal safety monitoring.........................................................................................58
7.5
Serum potassium safety monitoring ......................................................................58
7.6
Hypotension monitoring........................................................................................58


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7.7
Angioedema monitoring........................................................................................59
7.8
Reporting of study treatment errors including misuse/abuse ................................59
7.9
Pregnancy reporting...............................................................................................59
7.10
Prospective suicidality assessment ........................................................................60
8
Data review and database management.............................................................................60
8.1
Site monitoring ......................................................................................................60
8.2
Data collection.......................................................................................................60
8.3
Database management and quality control............................................................61
8.4
Data Monitoring Committee..................................................................................61
8.5
Adjudication Committee........................................................................................62
9
Data analysis......................................................................................................................62
9.1
Analysis sets ..........................................................................................................62
9.2
Patient demographics and other baseline characteristics.......................................62
9.3
Treatments .............................................................................................................62
9.4
Analysis of the primary variable(s) .......................................................................63
9.4.1
Variable(s).............................................................................................63
9.4.2
Statistical model, hypothesis, and method of analysis..........................63
9.4.3
Handling of missing values/censoring/discontinuations.......................64
9.4.4
Sensitivity analyses ...............................................................................64
9.5
Analysis of secondary variables ............................................................................64
9.5.1
Efficacy variables..................................................................................64
9.5.2
Safety variables .....................................................................................65
9.5.3
Resource utilization...............................................................................65
9.5.4
Pharmacokinetics ..................................................................................66
9.5.5
DNA......................................................................................................66
9.5.6
Biomarkers............................................................................................66
9.5.7
PK/PD ...................................................................................................66
66
9.7
Interim analyses.....................................................................................................66
9.8
Sample size calculation..........................................................................................66
10 Ethical considerations........................................................................................................68
10.1
Regulatory and ethical compliance........................................................................68
10.2
Informed consent procedures.................................................................................68
10.3
Responsibilities of the investigator and IRB/IEC..................................................68
10.4
Publication of study protocol and results...............................................................69
10.5
Quality Control and Quality Assurance.................................................................69


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11 Protocol adherence ............................................................................................................69
11.1
Protocol amendments.............................................................................................69
12 References .........................................................................................................................70
13 Appendix 1: Clinically notable laboratory values.............................................................74
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................75
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................77
16 Appendix 4: Treatment guidelines for hyperkaliemia (serum potassium greater than 
or equal to 5.5 mmol/L).....................................................................................................77
17 Appendix 5: Guidelines for the management of blood pressure .......................................79
18 Appendix 6: Guidelines for the management of renal dysfunction...................................79
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 3-1
Minimum required pre-study daily doses of commonly prescribed 
ACEIs and ARBs (considered equivalent to 2.5 mg/d enalapril) .........26
Table 5-1
Study drug dose levels ..........................................................................37
Table 5-2
Study drug titration according to previous ACEI/ARB dose................38
Table 5-3
Prohibited medication ...........................................................................42
Table 6-1
Assessment schedule.............................................................................46
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................59
Table 9-1
Power of the study considering both the end-points – Considering 
259 subjects in each arm .......................................................................67
Table 9-2
Power of the study considering both the end-points – Considering 
300 subjects in each arm .......................................................................67
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................75
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...75
Table 15-1
Specific Renal Alert Criteria and Actions.............................................77
List of figures
Figure 3-1
Study design..........................................................................................27


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List of abbreviations
6MWT
6 Minute Walking Test
ACEI
Angiotensin Converting Enzyme Inhibitor
ACR
Albumin-Creatinine Ratio
AE
Adverse Event
ALP
Alkaline Phosphatase Level test
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
ARB
Angiotensin II Receptor Blocker
ARNI
Angiotensin Receptor-Neprilysin Inhibitor
AST
Aspartate Aminotransferase
AUC
Area Under Curve
bid
Bis in die (twice a day)
BMI
Body Mass Index
BNP
Brain Natriuretic Peptide
BP
Blood Pressure
CCB
Calcium Channel Blocker
CFR
US Code of Federal Regulations 
COPD
Chronic Obstructive Pulmonary Disease
CHF
Chronic Heart Failure
CRF
Case Report/Record Form (paper or electronic)
CRT
Cardiac Resynchronization Therapy
CRT-P
Cardiac Resynchronization Therapy Pacemaker
CRT-D
Cardiac Resynchronization Therapy Defibrillator
COX-2
Cyclo-Oxygenase-2
CPO
Country Pharma Organization
CQA
Compliance Quality Assurance
CRO
Contract Research Organization
CT
Computed Tomography
CTC
Common Terminology Criteria
CV
Cardiovascular
DAR
Dose Administration Record
DS&E
Drug Safety & Epidemiology
DSM
Drug Supply Management
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
ESC
European Society of Cardiology
FAS
Full Analysis Set


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GCP
Good Clinical Practice
hCG
human Chorionic Gonadotropin
HDPE
High-Density Polyethylene
HF
Heart Failure
HFmrEF
Heart Failure with mid-range Ejection Fraction
HFpEF
Heart Failure with preserved Ejection Fraction
HFrEF
Heart Failure with reduced Ejection Fraction
IB
Investigator’s Brochure
ICD
Implantable Cardioverter Defibrillator
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IMPs
Investigational Medicinal Products
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
i.v.
Intravenous
IVRS/IWRS
Interactive Web and Voice Response System
KCCQ
Kansas City Cardiomyopathy Questionnaire
LCZ696
Sacubitril/valsartan
LFT
Liver Function Test 
LOCF
Last-observation-carried-forward principle
LVEF
Left Ventricular Ejection Fraction
MCS-12
Mental Health Composite Score
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities 
METs
Metabolic Equivalents
MI
Multiple Imputation
MLHFQ
Minnesota Living with Heart Failure
MRA
Mineralocorticoid Receptor Antagonist
MRI
Magnetic Resonance Imaging
MUGA
Multiple-Gated Acquisition scan
M6min
Maximum six minutes of daily activity (6-minute walk test)
NEP
Neprilysin
NSAID
Non-Steroidal Anti-Inflammatory Drug
NT-proBNP
N-terminal prohormone of Brain Natriuretic Peptide
NYHA
New York Heart Association
PCI
Percutaneous Coronary Intervention
PCR
Protein-Creatinine Ratio
PCS-12
Physical Health Composite Score


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PGA
Patient Global Assessment
 
p.o.
Per os (oral)
PK/PD
Pharmacokinetic/Pharmacodynamic
PP
Per-Protocol
PT/INR
Prothrombin Time/International Normalized Ratio
QM
Quality Management
QoL
Quality of Life
RAAS
Renin Angiotensin Aldosterone System
SAE
Serious Adverse Event
SAF
Safety Data Set
SBP
Systolic Blood Pressure
SD
Standard deviation
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total Bilirubin Level
TD
Study Treatment Discontinuation
ULN
Upper Limit of Normal
UNS
Unscheduled visit
VAD
Ventricular Assistance Device
VAS
Visual analog scale
WHO
World Health Organization 
WoC
Withdrawal of Consent
yGT
Gamma Glutamyl Transferase


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


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Amendment 4
Amendment rationale
This amendment is introduced as a consequence of new and previously unavailable key data 
regarding the use of accelerometry as a clinical endpoint in trials concerning heart failure 
patients and new positioning from the Committee for Medicinal Products for Human Use 
(CHMP) at the European Medicines Agency on the use of 6 min walk test (6MWT) in heart 
failure studies (CHMP, 2017).
When conceptualizing this study, there was a paucity of data validating actigraphy and 
especially actigraphy as measured by the MotionWatch8, in heart failure patients. However, 
access to the first interpretable results of another recently completed study, the AWAKE-HF 
trial (NCT02970669), has raised doubts to whether accelerometry is the best available and 
sensitive enough method to measure potential change in daily physical activity in heart failure 
patients. This is in line with recent literature from use of accelerometry in other related 
disease areas such as in COPD. A recent study (Troosters et al., 2018) demonstrated that a 
specific investigational pharmacotherapy in COPD combined with self-management behavior-
modification program (SMBM) showed statistical and clinical improvement in 6MWT 
compared to a comparator drug and SMBM. However, this observed improvement in 6MWT 
did not translate into increased daily physical activity as measured by an actigraphy device.
The 6MWT is a commonly used method to clinically assess the patient's physical activity in 
cardiopulmonary diseases and is a validated endpoint in heart failure studies as such (Ferreira 
et al., 2016). Combined with the fact that the 6MWT is positioned by the CHMP to be a 
reliable and preferred method for elucidating functional capacity, whereas accelerometry is 
still not validated in heart failure, we have increased the importance of the 6MWT in this 
current study from a secondary endpoint to now a co-primary endpoint. As the 6MWT was 
already accounted for when calculating the initial sample size when planning the study, the 
changes implemented herein do not affect the study sample size nor the remaining of the trial 
conduct .   
Study status
The study is fully recruited and has achieved last patient last visit. The amendment does not 
imply changes in the study sample size.
Changes to the protocol
Section 1.2
Included 6MWT into the purpose of the trial.  
Section 2
Description of the 6MWT conduct and definition of the new 6MWT related endpoints. 
Section 9.1
Revision of the analysis sets due to the impact of introducing a new primary endpoint. 
Section 9.4.1


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Defining the primary study variables by including 6MWT. 
Section 9.4.2
Including the definition of the primary hypothesis by adding the 6MWT variable.  
Section 9.4.3
Specification of the sensitivity analysis.
Section 9.5.1
Increased the specifications of the efficacy variables. 
Section 9.8
Included the testing strategy as well as a table of the power calculation of the two primary 
endpoints.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes herein do 
NOT affect the trial specific model ICF.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.
Amendment 3
Amendment rationale
This amendment was introduced as a consequence to the realization that combining specific 
visit windows could allow a mismatch in number of days between visits and number of 
available study drug. In addition, we have added a precision to the dosing level ranges to 
avoid any ambiguity and lastly, an additional method for imputing missing data has been 
added. 
Implementation of this amendment will secure that the study patients will have sufficient 
study drug throughout the study regardless of how their study visits are constructed within the 
new visit windows given. Additionally, adding a new method for imputing the missing data 
would allow better utilization of data which is not complete but useful. We do not expect, by 
implementing this amendment, that the study objectives or the expected overall interpretation 
of the results will be significantly altered. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes herein do 
NOT affect the trial specific model ICF.


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Amendment 2
Amendment rationale
This amendment was introduced due to a specific requirement from Health Authorities. The 
scope of this amendment is to change specific criteria for when patients are found to be 
eligible for re-screening in this study. 
Implementation of this amendment will increase the precision of patients re-screened and
optimize the recruitment of the patients of interest of this study. We do not expect, by 
implementing this amendment, that the study objectives or the expected overall interpretation 
of the results will be significantly altered. The requirements by the Health Authorities are
found to be well justified and therefore implemented.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes herein do 
NOT affect the trial specific model ICF.
Study status
The study has been submitted to Health Authorities as its first submission. So far, the trial has
not yet started.
Section 6.1
Specific criteria are deleted from the definition of which patients that are eligible for re-
screening in the study.
Amendment 1 
This amendment was introduced as a consequence of feedback and specific requirements from 
Health Authorities. In summary, these requirements are put in place to detail the potential risk 
of interaction between specific antidiabetic medication and both the comparator and 
investigational medicinal product. Furthermore, a precision of specific exclusion criteria are 
given (26 and 32), by which prohibited concomitant medication and the need for ECG is 
further specified. In addition, patients eligible for re-screening in the study are further 
specified as well as further guidance is provided for the eligibility and potential use of the 
unscheduled visits between set visits. The alert criteria to kidney function are refined in 
appendix 3 where the Urine Events are deleted due to redundancy with Serum Events as well 
as appendix 6. A precision is also added in the hypothetical terms where the study might be 
terminated.


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Protocol summary
Protocol number
CLCZ696B3301
Title
A multi-center, prospective, randomized, double-blind study to assess the 
impact of sacubitril/valsartan vs. enalapril on daily physical activity using a 
wrist worn actigraphy device in adult chronic heart failure patients
Brief title
randOmized stUdy using acceleromeTry to compare Sacubitril/valsarTan 
and Enalapril in Patients with Heart Failure (OUTSTEP-HF)
Sponsor and Clinical 
Phase
Novartis, Clinical phase IIIB
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
Limitations of daily physical and social activities are common hallmark of 
the different physical and emotional symptoms patients with chronic heart 
failure (HF) experience and are often the main reason for these patients 
seeking medical care. When asking HF patients how they define quality of 
life (QoL), the ability to perform desired physical and social activities in 
order to meet their and their families' needs is among the most frequent
definitions.
An increase of physical activity in HF patients is positively correlated with 
improved outcome and negatively correlated with the occurrence of fatigue 
(as a limiting factor of physical activity) which is a known independent long-
term prognostic factor. Many of the current evidence based therapies for 
chronic HF, such as angiotensin converting enzyme inhibitors (ACEIs), 
angiotensin II receptor blockers (ARBs) or cardiac resynchronization 
therapy (CRT) lead to improvement in exercise capacity.
Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin 
inhibitor (ARNI). It has been recently approved for the treatment of HF with 
reduced ejection fraction (HFrEF) by demonstrating its superiority over the 
ACEI
enalapril in terms of mortality and morbidity in the pivotal
PARADIGM-HF trial. However, while the positive effects of ACEI, ARB and 
CRT on exercise capacity have been widely studied, it is unknown whether 
sacubitril/valsartan exerts similar effects on physical activity.
The purpose of this randomized, actively controlled, double-blind study with
prospective 
data 
collection 
is 
to 
assess 
differences 
between
sacubitril/valsartan versus enalapril in increasing exercise capacity and 
non-sedentary physical activity in HFrEF patients. Physical activity will be 
assessed by the 6 minute walk test, and daily physical activity will be 
continuously measured by means of a wrist-worn accelerometry device 
from
2 weeks before until
12 weeks after start of study therapy 
(sacubitril/valsartan or enalapril).
Primary Objectives 

To  elucidate the change in physical activity as assessed by the 
distance walked in meters during the 6-minute walk test between 
baseline and 12 weeks of study drug treatment in sacubitril/valsartan 
vs. enalapril patients.

To assess changes in daily non-sedentary daytime activity between 
baseline and after 12 weeks of treatment in sacubitril/valsartan vs. 
enalapril treated patients.


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Secondary Objectives

To compare the proportion of patients with improved performance (≥ 
30m (Shoemaker et al., 2013, Tager et al., 2014) in the 6-minute walk 
test between sacubitril/valsartan vs. enalapril during the treatment 
period (weeks 0 to 12).

To demonstrate that sacubitril/valsartan is superior in improving 
exercise capacity as assessed by the six-minute walk test (6MWT) at 
week 12 in a subset of patients with baseline six-minute walk distance 
equal to or less than 300 meters

To demonstrate that sacubitril/valsartan is superior in improving 
exercise capacity as assessed by the six-minute walk test (6MWT) at 
week 12 in the patients with baseline six-minute walk distance between 
100-450 meters. 

To compare the effects of sacubitril/valsartan vs. enalapril on patients’ 
symptom progression by means of the Patient Global Assessment 
(PGA) questionnaire at week 4, week 8 and week 12.

To assess dynamics of changes from baseline in daily non-sedentary 
daytime physical activity in sacubitril/valsartan vs. enalapril treated 
patients in weekly and two-weekly intervals

To assess changes from baseline in mean daily non-sedentary daytime 
physical activity classified by its intensity for sacubitril/valsartan vs. 
enalapril treated patients after week 4, week 8 and week12.

To assess the difference in non-sedentary daytime physical activity 
between sacubitril/valsartan vs. enalapril treated patients during the 
treatment period (weeks 0 to 12).

To assess changes from baseline on M6min (an actigraphy-based 
measure of the peak six minutes of daytime physical activity) in 
sacubitril/valsartan vs. enalapril treated patients after week 4; week 8 
and week 12.

To assess changes from baseline (week 0) in exercise capacity 
assessed by means of the 6-minute walking test at weeks 4, 8 and 12.
Study design
This is an European, randomized, actively controlled, double-blind, double-
dummy, interventional study with prospective data collection powered to 
assess differences between sacubitril/valsartan versus enalapril in terms of 
increasing daily physical activity in HFrEF patients. The study comprises 6
visits over 14 weeks. 
Actigraphy will be performed during the entire duration of the study by 
means of a wrist-worn accelerometry device. The device will be worn 
continuously for two weeks prior to randomization in order to obtain an 
individual baseline for each patient, and throughout the double-blind 
treatment period of the study (12 weeks).
Population
Adult male and female patients with symptomatic HFrEF managed in an 
ambulatory or outpatient setting (i.e. primary care physicians, office based 
cardiologists, HF outpatient clinics). Patients will be randomized in a 1:1 
allocation to receive sacubitril/valsartan or enalapril during the double-blind 
treatment period. The target projected sample size is 600 patients (300 
patients per treatment arm) included at approximately 140 study sites
across Europe. 
Key Inclusion criteria

Written informed consent obtained before any study assessment is 
performed.

Ambulatory ≥ 18 years of age with a diagnosis of chronic symptomatic 


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HF (NYHA class ≥ II) with reduced ejection fraction, defined as known 
LVEF ≤ 40% (known LVEF ≤ 40% at Visit 1 reflects any local 
measurement, made within the past 12 months using 
echocardiography, MUGA, CT scanning, MRI or ventricular 
angiography, provided no subsequent measurement with LVEF results 
above 40% is available). 
AND one of the following two criteria:
-
Plasma NT-proBNP level of ≥ 300 pg/mL or BNP ≥ 100 pg/mL 
(measurement may be recorded no longer than past 12 months)
OR 
-
Confirmation of a heart failure hospitalization last 12 months.

Patients must be on stable HF medication (ACEI/ARB, beta-blockers 
and MRA) for at least 4 weeks prior to Visit 1, where the minimal daily 
dose of ACEI/ARB dose is equivalent to at least 2.5 mg/d enalapril
(See Table 3-1).

Willingness to wear the accelerometer wristband continuously for the 
duration of the trial.

Patients must be living in a setting, allowing them to move about freely 
and where they are primarily self-responsible for scheduling their 
sleep and daily activities.
Key Exclusion criteria

History of hypersensitivity to any of the study drugs or their excipients 
or to drugs of similar chemical classes

Use of sacubitril/valsartan prior to Visit 1. 

Bedridden patients, or patients with significantly impaired/limited
physical activity and/or fatigue due to medical conditions other than HF, 
such as, but not limited to angina (chest pain at exertion), arthritis, 
gout, peripheral artery occlusive disease, obstructive or restrictive lung 
disease, malignant disease, neurological disorders (e.g. Parkinson’s or 
Alzheimer’s disease, central and peripheral neuroinflammatory and -
degenerative disorders or functional central nervous lesions due to 
hemodynamic or traumatic incidents), injuries (incl. diabetic foot ulcers) 
or missing limbs

Patients with palsy, tremor or rigor affecting the non-dominant arm.

Patients with any skin or other condition of the non-dominant arm that
would limit the ability to wear the actigraphy device continuously 
(24h/day) over 14 weeks. 

Patients fully depending on a mobility support system, e.g. wheelchair, 
scooter or walker. Patients are allowed to use a cane as long as this is 
not used with the non-dominant arm.
Study treatment

Sacubitril/valsartan (target dose 97 mg/103 mg bid)

Placebo to match sacubitril/valsartan at all dose levels

Enalapril (target dose 10 mg bid)

Placebo to match enalapril at all dose levels
Efficacy assessments

Actigraphy-derived parameters

6-minute walking test

Patient Global Assessment questionnaire (PGA)


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Key safety 
assessments

Adverse event monitoring

Physical examinations and blood pressure monitoring

Monitoring of laboratory markers in blood (e.g. potassium, creatinine, 
AST/ALT). 
Other assessments
Not applicable
Data analysis
Descriptive statistical analysis will be provided for all data assessed in this 
study:
Quantitative data (e.g. age) will be described by the statistical parameters 
valid N, missing N, mean, standard deviation (SD), minimum, median, and 
maximum. If indicated by the data, an additional frequency distribution will 
be provided after appropriate grouping of data. Qualitative (e.g. gender) 
and categorical variables (e.g. score values) will be presented by absolute 
and relative frequency distributions. 
The 
primary 
endpoint 
will 
be 
tested 
between 
enalapril 
and 
sacubitril/valsartan using analysis of covariance (ANCOVA), with the 
baseline value as a covariate. Two-sided tests of significance (with α = 
0.05) between the two treatment groups will be performed for all secondary 
endpoints on an exploratory basis, using appropriate testing procedures.
All analyses will be carried out by means of the SAS® software package 
(version 9.2 or higher).
Key words
Physical activity, actigraphy, sleep, sacubitril/valsartan, enalapril, heart 
failure, reduced ejection fraction, randomized controlled trial, accelerometry


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1
Introduction
1.1
Background 
Heart failure (HF) is one of the main causes for hospitalization and pharmacotherapy use in 
the western world; in Europe its prevalence varies between 1-2%, but rises to more than 10% 
for people older than 70 years (Mosterd and Hoes, 2007). HF is defined as an abnormality of 
cardiac structure or function leading to failure of the heart to deliver oxygen at a rate that 
commensurate with the requirements of the metabolizing tissues (Ponikowski et al., 2016). 
The typical symptoms of chronic HF initially bringing patients to medical attention include 
breathlessness, ankle swelling, fatigue and reduced exercise tolerance. Based on left 
ventricular ejection fraction (LVEF), HF can be classified as HF with reduced ejection 
fraction (HFrEF), HF with preserved ejection fraction (HFpEF) or HF with mid-range ejection 
fraction (HFmrEF) (Ponikowski et al., 2016). Thus, LVEF in HF patients is important, both as 
a prognostic marker (lower LVEF is associated with worse prognosis (Curtis et al., 2003) and 
for guiding therapeutic decisions (Ponikowski et al., 2016).
HF patients have a grim prognosis; the five-year survival rate is about 50% (Mozaffarian et al., 
2015) and the mortality in patients suffering from severe heart failure is reported to be around 
50% within one year (Friedrich and Bohm, 2007). In addition, due to the chronic progressive 
nature of HF, increasing symptom burden (e.g. progression of breathlessness, fatigue, edema 
etc.) has a negative impact on multidimensional domains of the patients’ daily health related 
quality of life (QoL), especially related to physical, mental, emotional and social functioning
(Ponikowski et al., 2016). Poor QoL in HF patients is associated to higher hospitalization and 
mortality rates (Alla et al., 2002, Konstam et al., 1996, Moser et al., 2009). In fact, HFrEF 
patients report much stronger deterioration of their QoL as compared to patients with other 
chronic illnesses such as chronic lung disease, arthritis, diabetes, hypertension or angina
(Hobbs et al., 2002, Stewart et al., 1989). There is also evidence that amongst symptomatic 
HF patients, clinically meaningful improvements of QoL are considered to be the most 
important outcome measure (Stanek et al., 2000), thus underlining its increasing relevance as 
a treatment goal in HF management (Moser et al., 2009). 
Limitations of daily physical and social activities are a common hallmark of the different 
physical and emotional symptoms patients with chronic HF experience (Heo et al., 2009, 
Wilson et al., 1999) and thus are often the reason for these patients to seek medical care (Pina 
et al., 2003). This is also reflected by the increasing recognition of both physical and social 
activity as important domains of QoL, e.g. within standardized and validated instruments such 
as the Kansas City Cardiomyopathy Questionnaire (KCCQ) (Green et al., 2000) and 
Minnesota Living with Heart Failure Questionnaire (MLHFQ) (Rector and Cohn, 1992). 
When asking HF patients how they define QoL, the ability to perform desired physical and 
social activities in order to meet their and their families' needs was among the three
definitions rated as most important (Heo et al., 2009). Medical tests utilizing physical exercise
are also becoming standard examinations in HF patients as they allow an objective evaluation 
of exercise capacity and exertional symptoms, such as breathlessness and fatigue (Arena et al., 
2011). 


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An increase of physical activity in HF patients is positively correlated with improved outcome
(Arslan et al., 2007, Passantino et al., 2006, Swank et al., 2012) and is negatively correlated 
with the occurrence of physical fatigue, a limiting factor of physical activity and is a known
independent long-term prognostic factor (Ekman et al., 2005, Walke et al., 2007). Many of the 
current evidence based therapies for chronic HF, such as angiotensin converting enzyme 
inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or cardiac resynchronization 
therapy (CRT) lead to improvement in exercise capacity (Coats, 2002, Garg and Yusuf, 1995, 
Ponikowski et al., 2016).
Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI). It has 
been recently approved by the EMA for the treatment of HFrEF by demonstrating its 
superiority over the ACEI enalapril in terms of mortality and morbidity in the pivotal
PARADIGM-HF trial (McMurray et al., 2014). In the same study, patients receiving 
sacubitril/valsartan after 8 months of treatment reported significantly less deterioration of 
their QoL (assessed by means of the KCCQ), compared to patients receiving enalapril. 
Despite this statistically significant difference, one might argue that PARADIGM-HF had 
intrinsic limitations in terms of design which likely led to underestimation of the true 
differences in KCCQ scores and, thus, did not allow a proper assessment of the effects of the 
two treatments on QoL. The baseline KCCQ score was measured at randomization, which 
took place after a 6-8 week long run-in period during which the patients first received target 
doses of enalapril and then sacubitril/valsartan. Therefore no “true” baseline QoL was 
captured. Due to this, especially the early effects of the respective treatments were likely not 
adequately captured in the PARADIGM-HF trial. 
While the positive effects of ACEI, ARB and CRT on exercise capacity have been widely 
studied (Coats, 2002, Garg and Yusuf, 1995, Ponikowski et al., 2016), it is unknown whether 
sacubitril/valsartan 
exerts 
similar 
effects 
on 
physical 
activity. 
However, 
since 
sacubitril/valsartan did have a significant beneficial effect on the KCCQ (McMurray et al., 
2014) and physical and social activity are major determinants of the KCCQ-assessed QoL, it 
is justified to assume that sacubitril/valsartan might increase physical activity in chronic HF 
patients. As described above, increasing physical activity and exercise capacity in HF patients 
is an important therapy goal due to its relevance for the patients’ QoL and prognosis and it has 
been demonstrated that even a 10-minute increase in physical activity in HF patients has 
beneficial effects on mortality and hospitalization risk (Conraads et al., 2014). Therefore, 
proving a significant difference of sacubitril/valsartan in terms of improving the physical 
activity of chronic HF patients versus enalapril would be of clinical significance. 
Assessing physical activity can be done by a plethora of methods. However, commonly used 
methods like patient reported physical activity questionnaires or diaries/logs are subject to 
personal bias and may not necessarily reflect the full effects of a therapy on a patient’s daily 
physical activity. Intermittent supervised exercise tests (such as the frequently used 6-minute
walking test or various treadmill tests) are often employed, but such supervised tests 
performed in a clinical setting at specific time points may not necessarily give insights into a 
patient’s functional performance over longer periods of time (Howell et al., 2010). Lately, 
much attention has therefore been drawn to wearable devices which measure physical activity
(Strath et al., 2013). These accelerometers provide objective and continuous assessment of 
physical activity during patients’ daily life over long periods of time and therefore may reflect 


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the true effect of a therapy on physical activity more accurately than the aforementioned 
methods (Gorman et al., 2014). Since medical graded activity tracking devices are small, 
light-weight, water resistant and have a comparably long battery life, they can be readily 
adopted by patients. In a 9-month prospective study in older HF patients, Howell and co-
workers demonstrated a strong compliance of patients with continuously wearing the activity 
trackers as the study showed that 90% of the patients wore the accelerometers throughout the 
study (Howell et al., 2010). Importantly, in the same study, accelerometer derived functional 
data reflecting physical capacity showed good correlation with the traditional 6-minute
walking test, as well as significant associations with subsequent events independently of age, 
gender, ejection fraction, NYHA class, biomarkers and baseline-6-minute walking test
(Howell et al., 2010). In a similar study, Maurer and co-workers showed by means of 
continuous accelerometry based tracking of physical activity over 3 months in HF patients
(NYHA classes I to III) that as many as 39% of patients fulfilled the criteria for anergia, a 
criterion-based syndrome reflecting a lack of energy. The same study showed that anergia was 
significantly associated with intercurrent hospitalizations (Maurer et al., 2009).
Furthermore, da Silva and colleagues demonstrated, in a small population of HF patients
wearing accelerometers for six days, that they barely engage in any kind of meaningful 
physical activity and spend the majority of their time in sedentary or engaging only light 
intensity activity such as standing or slow walking (da Silva et al., 2013). This is also 
supported by Dontje and co-workers who found that fifty percent of the HF patients studied 
had a lifestyle that qualifies as sedentary (Dontje et al., 2014).
To our knowledge, no study thus far has used state of the art accelerometry technology in a 
big European population of HFrEF patients to compare the effects of pharmacotherapies on
physical activity.
1.2
Purpose 
The purpose of this randomized, actively controlled, double-blind study with prospective data 
collection is to assess differences between sacubitril/valsartan versus enalapril in distance 
walked in a 6 minute walk test (6MWT) and increasing non-sedentary daytime physical 
activity in HFrEF patients. To this end, the 6MWT will be performed before the patients are 
randomized to any of the treatments and at 12 weeks of randomized treatment whereas 
physical activity will be continuously measured by means of a wrist-worn accelerometry 
device from 2 weeks before until 12 weeks after start of study therapy (sacubitril/valsartan or 
enalapril).
2
Study objectives and endpoints
The main aim of the study is to elucidate any potential change in the 6MWT as assessed in the 
distance walked before treatment randomization compared to the end of study in both 
sacubitril/valsartan and enalapril treated patients and to assess differences between 
sacubitril/valsartan versus enalapril in improving non-sedentary daytime physical activity in 
HFrEF patients. The study objectives and the related endpoints are presented in Table 2-1. 
Patients will be  performing the 6MWT at visit 2, 4, 5 and 6 and will be wearing wrist-worn 
accelerometry devices over the time period between two weeks prior to (baseline) and 12 


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weeks after randomization to receive either sacubitril/valsartan or enalapril. For each patient,
an individual baseline activity level will be recorded over the two weeks prior to 
randomization.
Table 2-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To assess changes from baseline (week 0) 
in exercise capacity assessed by means of 
the 6-minute walking test at week 12
Title: Change from baseline in 6-
minute walking test
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals. 
Time frame: baseline (week 0, at 
randomization) and week 12
Section 9.4
To assess changes in daily non-sedentary 
daytime activity between baseline and after 
12 weeks of treatment in 
sacubitril/valsartan vs. enalapril treated 
patients.
Title: Change in mean daily non-
sedentary daytime activity between 
baseline1 and end of study.
Description: non-sedentary physical 
activity is defined as ≥178.50 activity 
counts per minute; the average 
number of minutes per day spent in 
non-sedentary physical activity will be 
calculated over 14 days before 
randomization (baseline1) and the last 
14 days of treatment (i.e. week 10 to 
week 12). 
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions
including 95% confidence intervals.
Time frame: baseline1 epoch (i.e. 
week -2 to week 0), end of study2
epoch (i.e. week 10 to week 12)
Section 9.4
Secondary
To assess changes from baseline (week 0) 
in exercise capacity assessed by means of 
the 6-minute walking test at week 12
Title: Proportion of patients with 
improved performance (≥ 30m) (Tager 
et al., 2014, Shoemaker et al., 2013) in 
the 6-minute walking test. 
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals. 
Time frame: baseline (week 0, at 
randomization) and week 12
Section 9.5
To demonstrate that sacubitril/valsartan is 
superior in improving exercise capacity as 
assessed by the six-minute walk test 
(6MWT) at week 12 in a subset of patients 
with baseline six-minute walk distance 
Title: Proportion of patients with 
improved performance (≥ 30m)
(Shoemaker et al., 2013, Tager et al., 
2014) in the 6-minute walking test and 
which walked equal to or less than 300 
Section 9.5


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equal to or less than 300 meters
meters at baseline
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals. 
Time frame: baseline (week 0, at 
randomization) and week 12
To demonstrate that sacubitril/valsartan is 
superior in improving exercise capacity as 
assessed by the six-minute walk test 
(6MWT) at week 12 in the patients with 
baseline six-minute walk distance between 
100-450 meters.
Title: Proportion of patients with 
improved performance (≥ 30m)
(Shoemaker et al., 2013, Tager et al., 
2014) in the 6-minute walking test and 
which walked 100-450 meters at 
baseline
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals. 
Time frame: baseline (week 0, at 
randomization) and week 12
Section 9.5
To assess changes from baseline (week 0) 
in exercise capacity assessed by means of 
the 6-minute walking test at weeks 4, 8 and 
12
Title: Change from baseline in 6-
minute walking test
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals. 
Time frame: baseline (week 0, at 
randomization), under treatment (week 
4, week 8, week 12)
Section 9.5
To assess changes in daily non-sedentary 
daytime activity between baseline and after 
12 weeks of treatment in 
sacubitril/valsartan vs. enalapril treated 
patients.
Title: Proportion of patients who show 
increased levels (≥ 10% increase) of 
non-sedentary daytime physical 
activity at week 12 compared to 
baseline 
Description: non-sedentary physical 
activity is defined as ≥178.50 activity 
counts per minute; the average 
number of minutes per day spent in 
non-sedentary physical activity will be 
calculated over 14 days before 
randomization (baseline1) and the last 
14 days of treatment (i.e. week 10 to 
week 12). 
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals. 
Time frame: baseline1 epoch (i.e. 
week -2 to week 0), end of study2
epoch (i.e. week 10 to week 12)
Section 9.5


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Objective
Endpoint
Analysis
To compare the effects of 
sacubitril/valsartan vs. enalapril on patients’ 
symptom progression by means of the 
Patient Global Assessment (PGA) 
questionnaire at week 4, week 8 and week 
12.
Title: PGA score at week 4, week 8 
and week 12.
Title: Proportion of patients with 
improved symptoms of HF as 
assessed by PGA.
Description: PGA score of symptoms 
of HF will be assessed as previously 
described.
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions
including 95% confidence intervals.
Time frame: week 4, week 8, week 12
Section 9.5
To assess dynamics of changes from 
baseline1 in daily non-sedentary daytime 
physical activity in sacubitril/valsartan vs. 
enalapril treated patients in weekly and 
two-weekly intervals.
Title: Change from baseline1 in mean 
daily non-sedentary daytime activity in 
weekly and two-weekly intervals
Title: Proportion of patients at weekly
and two-weekly intervals who show 
increased levels (≥ 10% increase) of
mean daily non-sedentary daytime 
physical activity compared to baseline 
Description: mean daily non-
sedentary daytime physical activity 
(definition see above) will be 
calculated over weekly and two-weekly
epochs and compared to baseline (1 for 
two-weekly intervals). For comparison 
of weekly intervals, the last 7 days of 
baseline recording prior to 
randomization will serve as baseline. 
While two-weekly intervals allow for 
more stable baseline and post-titration 
values, weekly intervals will be used to 
visualize and analyze the dynamics of 
change post randomization. 
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions
including 95% confidence intervals.
Time frame: baseline1 epoch (i.e. 
week -2 to week 0 for two-weekly 
intervals or last 7 days prior to 
randomization for comparison of 
weekly intervals), weekly or two-
weekly from week 0 to week 12.
Section 9.5
To assess changes from baseline 1 in 
mean daily non-sedentary daytime physical 
activity classified by its intensity for 
sacubitril/valsartan vs. enalapril treated 
patients after week 4, week 8 and week12.
Title: Change from baseline1 in mean 
daily light and moderate-to-vigorous 
non-sedentary daytime physical 
activity between baseline1 and different 
time points under treatment.
Description: non-sedentary physical 
Section 9.5


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Objective
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activity is defined as ≥178.5 activity 
counts per minute; light physical 
activity is defined as 178.5 – 565.5 
counts per minute; moderate-to-
vigorous activity is defined as > 565.5 
counts per minute. The average 
number of minutes per day spent in the 
different non-sedentary physical 
activity categories (light and moderate-
to-vigorous) will be calculated over 14 
day epochs. 
Units of measure: descriptive 
statistics for quantitative data.
Time frame: baseline1 epoch (i.e. 
week -2 to week 0), week 2 to week 4, 
week 6 to week 8, week 10 to week12.
To assess the difference in non-sedentary 
daytime physical activity between
sacubitril/valsartan vs. enalapril treated 
patients during the treatment period (weeks 
0 to 12).
Title: Total weekly time spent in non-
sedentary daytime physical activity.
Title: Total weekly time spent in light
non-sedentary daytime physical 
activity.
Title: Total weekly time spent in 
moderate-to-vigorous non-sedentary 
daytime physical activity
Description: Non-sedentary physical 
activity is defined as ≥178.5 activity 
counts per minute; light physical 
activity is defined as 178.5 – 565.5 
counts per minute; moderate-to-
vigorous activity is defined as > 565.5 
counts per minute. The total time spent 
in non-sedentary physical activity and 
the time spent in light and moderate-
to-vigorous physical activity will be 
calculated for each patient in weekly 
intervals and the temporal course for 
each patient will be assessed.
Units of measure: descriptive 
statistics for quantitative data.
Time frame: week 0 to week 12 in 
weekly epochs
Section 9.5
To assess changes from baseline1 on 
M6min (an actigraphy-based measure of 
the peak six minutes of daytime physical 
activity) in sacubitril/valsartan vs. enalapril 
treated patients after week 4; week 8 and 
week 12.
Title: Change from baseline1 in 
M6min.
Title: Proportion of patients with 
increased M6min compared to 
baseline1 at week 4, week 8 and week 
12. 
Description: M6min is a parameter 
derived by validated algorithms of the 
software that will be used to pre-
process actigraphy data. The 
Section 9.5


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parameter reflects the peak 6 minutes 
of physical activity. The mean daily
M6min will be calculated over 14 day
epochs.
Units of measure: descriptive 
statistics for quantitative data, absolute 
and relative frequency distributions 
including 95% confidence intervals.
Time frame: baseline1 epoch (i.e. 
week -2 to week 0), week 2 to week 4, 
week 6 to week 8, week 10 to week12


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1 For all objectives/endpoints assessed by means of actigraphy, the baseline value is obtained over a 
period of two weeks prior to randomization, i.e. weeks -2 to week 0.
3
Investigational plan
3.1
Study design
This is an international (European), randomized, actively controlled, double-blind, double-
dummy, interventional study with prospective data collection. The study comprises 6 visits 
over 14 weeks. Adult patients with symptomatic HFrEF (NYHA classes II or III/IV at a 1:1 
ratio, see Section 5.3) managed in an ambulatory setting (i.e. by primary care physicians, 
office based cardiologists, HF outpatient clinics) will be randomized in a 1:1 allocation to 
receive sacubitril/valsartan or enalapril during the double-blind period. Actigraphy will be 
performed during the entire duration of the study by means of a wrist-worn accelerometry 
device; the device will be worn continuously for two weeks prior to randomization in order to 
obtain an individual baseline for each patient, and throughout the treatment period of the 
study (12 weeks). Figure 3-1 depicts the study design along with the treatment and visit 
schedule. 


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Visit 1
Eligible patients, after signing informed consent, will receive the actigraphy device at Visit 1
(week -2). Eligible patients are those who satisfy all inclusion and exclusion criteria (Section 
4), i.e. among other criteria, they have been on stable dose of at least enalapril 2.5 mg/d, or 
equivalent ACEI or ARB for at least 4 weeks prior to Visit 1 (see Table 3-1). The patients at 
this time should continue stable intake of their current ACEI/ARB, as well as concomitant
medication, until the Visit 2 (week 0). 
Table 3-1
Minimum required pre-study daily doses of commonly prescribed 
ACEIs and ARBs (considered equivalent to 2.5 mg/d enalapril)
ACEIs
Minimum daily dose
ARBs
Minimum daily dose
Enalapril
2.5 mg
Candesartan
4 mg
Benazepril
5 mg
Eprosartan
100 mg
Captopril
25 mg
Irbesartan
37.5 mg
Cilazapril
0.625 mg
Losartan
12.5 mg
Fosinopril 
5 mg
Olmesartan
2.5 mg
Lisinopril
5 mg
Telmisartan
10 mg
Moexpril
3.75 mg
Valsartan
40 mg
Perindopril
2 mg
Quinapril
5 mg
Ramipril
1.25 mg
Trandolapril
1 mg
Zofenopril
7.5 mg
Visit 2
At Visit 2 (week 0), patients will be randomized to receive either sacubitril/valsartan or 
enalapril; patients should continue to take their background medication for HF during the 
study, with the exception of ACEI or ARBs – these are replaced by the study treatment and 
must be discontinued 36 hours before first application of the study drug. The first application 
of the study drug is planned for the day after Visit 2 (randomization) – therefore the last 
intake of the patient’s ACEI or ARB before commencing study drug intake should be on the 
evening before Visit 2 (e.g. if Visit 2 is scheduled for Wednesday the last ACEI or ARB 
medication should be taken by the patient on Tuesday evening. The patient will then start to 
take the first dose of study medication (sacubitril/valsartan or enalapril) on Thursday 
morning).
Treatment will be initiated depending on the patient’s previous ACEI/ARB. Refer to Table 
5-2). After 2 weeks (i.e. at Visit 3) the doses are up-titrated and after another 2 weeks (i.e. at 
Visit 4) all patients should have achieved the target dose of either 10 mg bid enalapril or 97 
mg/103 mg bid sacubitril/valsartan, provided no safety and tolerability issues arise during up-
titration. The titration steps for the three dose levels are described in detail in Section 5.5.4.


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Note: according to the sacubitril/valsartan SmPC and the investigator’s medical judgement, 
patients suffering from moderate hepatic impairment, moderate renal impairment or patients 
with SBP ≥100 to 110 mmHg should be initiated at dose level 1.
At this visit the baseline actigraphy data will be downloaded from the wrist-worn device.
Visit 3 to Visit 6
The visit schedule continues in two-weekly intervals until Visit 4 (week 4), where up-titration 
is expected to be finished for the majority of patients (see Section 5.5.4). Thereafter two more 
visits are planned in 4-weekly intervals (i.e. Visit 5 at week 8 and Visit 6 at week 12). At all 
visits, physical examination and current NYHA status is documented, as well as safety 
monitoring and adverse events. At Visit 4 and Visit 6, the data from the actigraphy device are 
downloaded; at Visit 4 the battery of the actigraphy device should be replaced according to 
the manual provided in the site folder. At Visit 4, Visit 5 and Visit 6 the 
 PGA, 
, 
and the 6-minute walking test are performed and documented. Further 
information on the visit schedule and data collection scheme is found in Table 6-1.
Figure 3-1
Study design 
1-2 sacubitril/valsartan or enalapril (double-blind study drugs) will be given at dose levels (up-titration) 
depending on pre-study ACEI/ARB doses. See Table 5-1 regarding doses levels and Table 5-2 for 
titration scheme.
3Pre-study ACEI and/or ARB are replaced by study medication after Visit 2. Therefore washout period 
(WO) of 36 hours is required; it should start 12 hours before Visit 2 (randomization); the first study 


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treatment intake should be 24 hours after Visit 2. 
All other HF background and CV medications (e.g. beta blockers, MRAs etc.) and symptomatic 
treatment (e.g. diuretics) the patient has been taking should remain unchanged throughout the study, if 
possible and medically justified in the judgement of the investigator.
“Background HF medication per local practice”: patients must be on stable HF treatment regimen for at 
least 4 weeks prior Visit 1. After Visit 1, patients shall retain their pre-study HF treatment for another 2 
weeks (week -2 to week 0) for baseline actigraphy recording.
3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.
The aim of the present study is to assess differences between sacubitril/valsartan versus 
enalapril in improving exercise capacity and daily non-sedentary daytime physical activity of 
patients with HFrEF. For such comparative objectives, randomized, actively controlled, 
interventional trials with balanced (selected) study populations are the state of the art and 
allow for controlling the patients’ treatment and thus reducing bias. The study is double-blind 
in order to avoid subjective bias in the 6MWT, PGA, 
 
 ratings; in addition, while actigraphy per se allows for obtaining objective measures of 
physical activity, blinding of the patients to their treatments is crucial in order to avoid a bias 
due to treatment expectations. Circadian activity profiles will be performed by means of 
wearable (wrist-worn) actigraphy devices in order to obtain objective activity readouts. As 
daytime activity as well as sleep profiles are highly individual, it is important to obtain a 
stable baseline as well as to monitor activity profiles continuously. These crucial features are 
incorporated into the present study design, as the patients receive and are asked to 
permanently wear (24 hours a day) the actigraphy device for the entire study duration of 14 
weeks - including 2 weeks where they still receive their pre-study HF medication. The 
actigraphy device will record activity data every 30 seconds over the 14 weeks study duration, 
thus allowing for an great level of data completeness; these data will be integrated in two-
weekly bins (weekly for certain endpoints, see Table 2-1), in order to obtain stable data for 
each patient and to minimize the effects of individual extremes (e.g. days with very high or 
very low activity). Finally, the study will be performed at centers in different European 
countries, thus allowing for analysis of country- and healthcare system effects. Taken together, 
the present randomized, actively-controlled, double-blind, double-dummy approach is the 
most suitable design for achieving the study objective of demonstrating a difference between
sacubitril/valsartan versus enalapril in improving the daily physical activity in patients with 
HFrEF. 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Strong clinical rationale for the target dose (97 mg/103 mg bid) as well as titration steps of 
sacubitril/valsartan is derived from the pivotal clinical trial PARADIGM-HF (McMurray et al., 
2014) and this dosing schedule has been shown to be efficacious, safe (Senni et al., 2016) and 
is approved by the European Medicines Agency (EMA) for the treatment of symptomatic 
patients with chronic HF and reduced LVEF. The sacubitril/valsartan target dose of 97 
mg/103 mg bid delivers an equivalent daily dose of valsartan as Diovan® 160 mg bid, the dose 
commonly recommended by current HF management guidelines (Ponikowski et al., 2016). 


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The twice-daily dosing regimen of sacubitril/valsartan also ensures a sustained neprilysin 
(NEP) inhibition over 24 hours. 
3.4
Rationale for choice of comparator
Enalapril, the comparator chosen for this study, is an ACEI - the drug class considered a gold 
standard by current therapy guidelines for the treatment of HFrEF patients (Ponikowski et al., 
2016). ACE inhibitors and enalapril in particular, are the pharmacological standard of care for 
HFrEF management in Europe and – according to the current label – sacubitril/valsartan can 
be used to replace ACEI or ARBs in the management of HF. Furthermore, in the pivotal 
clinical trial PARADIGM-HF (McMurray et al., 2014), enalapril was the active comparator 
for sacubitril/valsartan. Thus, enalapril was chosen as the active comparator for the present 
study. Enalapril will be used in this study according to its label and recommended dosing of 
10 mg bid, which is the most commonly recommended target dose for HFrEF patients and has 
been shown to reduce the risk of death and hospitalizations in HF patients (SOLVD, 1992).
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits 
Both treatments, sacubitril/valsartan and enalapril, are approved for the treatment of the 
studied indication. Please refer to the Summary of Product Characteristics (SmPC) of the 
corresponding products as well as the Investigator’s Brochure (IB) of sacubitril/valsartan for 
information on known adverse drug reactions or special precautions with both investigational 
medicinal products (IMPs). 
Patients will be instructed not to take any renin angiotensin aldosterone system (RAAS) 
blocking agents (ACEIs or ARBs) within 36 hours prior to start of study treatment in order to 
avoid excessive RAAS inhibition. The risks associated with the temporary discontinuation of 
RAAS blockade (36h washout period) is minimal as it represents a common safety measure 
also performed in clinical routine outside of clinical trials; in addition, RAAS blockade 
represents only one pillar of pharmacotherapy for HFrEF and the patients other HF 
medication (so called background HF medication), such as beta-blocking agents or 
mineralocorticoid receptor antagonists (MRAs) will not be altered due to study participation. 
The risk of excess RAAS inactivation will be mitigated by the 36h washout period, as well as 
the staggered titration of study medication (see Table 5-2). 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures and close clinical monitoring. 
In women of child-bearing potential, a possible risk of developmental toxicity cannot be 
excluded. Thus, women of child-bearing potential should use a highly effective method of 
contraception during dosing and for 7 days off study medication as described under Section 
4.2. 
Participating patients will benefit from careful monitoring and follow-up during the entire 
study. 


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The current study aims to elucidate the short term effects of sacubitril/valsartan compared to 
enalapril on physical activity of HFrEF patients considering the period between treatment 
initiation, achievement and first maintenance of a stable tolerated dose, as such data currently 
are not available. However, due to the proven long-term superiority of sacubitril/valsartan 
over enalapril in terms of reduced mortality and morbidity shown in PARADIGM-HF
(McMurray et al., 2014), the duration of the double-blind, randomized treatment phase of the 
present study was limited to a total of 12 weeks, which allow for an up-titration and 
maintenance of a stable tolerated dose, but is short enough to mitigate the risk for the patients 
due to treatment blinding. Furthermore, the treatment regimens stipulated within the present 
protocol are compliant with the recommendations on pharmacological treatment of HFrEF 
patients, as defined in the current ESC Guidelines for the treatment in ambulatory HFrEF 
patients (Ponikowski et al., 2016).
4
Population
The study population will consist of adult (≥ 18 years old) male and female patients with 
symptomatic HFrEF who are ambulatory managed by a primary care physician, office-based
cardiologist or in HF outpatient clinics for their HF. The goal is to randomize a total of 600 
patients at ~132 sites across Europe. Eligible patients should be on a stable HF treatment for 
at least 4 weeks prior to screening; the required minimal doses of pre-study ACEI or ARB are 
listed in Table 3-1. 
The investigator must ensure that all patients who satisfy all inclusion and exclusion criteria 
are offered enrollment in the study. No additional parameter can be applied by the investigator.
4.1
Inclusion criteria
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent obtained before any study assessment is performed.
2. Ambulatory ≥ 18 years of age with a diagnosis of chronic symptomatic HF (NYHA class 
≥ II) with reduced ejection fraction, defined as known LVEF ≤ 40% (known LVEF ≤ 40% 
at Visit 1 reflects any local measurement, made within the past 12 months using 
echocardiography, MUGA, CT scanning, MRI or ventricular angiography, provided no 
subsequent measurement with LVEF results above 40% is available). 
AND one of the following two criteria:
-
Plasma NT-proBNP level of ≥ 300 pg/mL or BNP ≥ 100 pg/mL (measurement 
may be recorded no longer than past 12 months)
OR 
-
Confirmation of a heart failure hospitalization last 12 months
3. Patients must be on stable HF medication (i.e. ACEI/ARB, beta-blockers and MRA) for at 
least 4 weeks prior to Visit 1, where the minimal daily dose of ACEI/ARB dose is 
equivalent to at least 2.5 mg/d enalapril (see Table 3-1).
4. Willingness to wear the accelerometer wristband continuously for the duration of the trial.


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5. Patients must be living in a setting, allowing them to move about freely and where they 
are primarily self-responsible for scheduling their sleep and daily activities.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients/subjects.
1.
Use of other investigational drugs within 5 half-lives, or within 30 days of enrollment, 
whichever is longer.
2.
History of hypersensitivity to any of the study drugs or their excipients or to drugs of 
similar chemical classes
3.
Use of sacubitril/valsartan prior to Visit 1. 
4.
Known history of angioedema (any kind of angioedema i.e. hereditary, idiopathic, 
angioedema related to previous drug use such as ACEI).
5.
Bedridden patients, or patients with significantly impaired/limited physical activity 
and/or fatigue due to medical conditions other than HF, such as, but not limited to angina 
(chest pain at exertion), arthritis, gout, peripheral artery occlusive disease, obstructive or 
restrictive lung disease, malignant disease, neurological disorders (e.g. Parkinson’s or 
Alzheimer’s disease, central and peripheral neuroinflammatory and -degenerative 
disorders or functional central nervous lesions due to hemodynamic or traumatic 
incidents), injuries (incl. diabetic foot ulcers) or missing limbs.
6.
Patients with significant chronic obstructive pulmonary disease (COPD) contributing to 
dyspnea or patients whose COPD medication has been altered within 4 weeks prior to 
Visit 1. 
7.
Patients with palsy, tremor or rigor affecting the non-dominant arm.
8.
Patients with any skin or other condition of the non-dominant arm that would limit the 
ability to wear the actigraphy device continuously (24h/day) over 14 weeks.
9.
Patients fully depending on a mobility support system, e.g. wheelchair, scooter or walker. 
Patients are allowed to use a cane as long as this is not used with the non-dominant arm.
10. Patients requiring a dual RAAS blockade (i.e. treatment with both ACEIs and ARBs or 
concomitant treatment with aliskiren)
11. Patients with acute decompensated HF within 4 weeks of Visit 1, i.e. exacerbation of 
chronic HF manifested by signs and symptoms that may require intravenous therapy.
12. Symptomatic hypotension and/or a systolic blood pressure (SBP) < 100 mmHg at Visit 1 
(screening) or at Visit 2 (randomization).
13. Estimated GFR (eGFR) < 30 mL/min/1.73 m² as calculated by simplified MDRD 
formula at Visit 1 or Visit 2
14. Serum potassium > 5.4 mmol/L at Visit 1 or at Visit 2
15. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other 
major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty 
within 3 months prior Visit 1.
16. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 14 week study duration.


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17. Implantation of cardiac resynchronization therapy pacemaker (CRT-P) or -defibrillator 
(CRT-D) or upgrading of an existing conventional pacemaker or implantable 
cardioverter defibrillator (ICD) to a CRT device within 3 months prior to Visit 1 or 
intended/planned such procedure within the 14 weeks study duration; patients with a 
implantation of conventional pacemaker or an ICD or with a revision of a pacemaker or 
other device electrodes within 1 month prior to Visit 1 are also excluded.
18. Patients with existing or planned/intended heart transplant or ventricular assistance 
device (VAD). 
19. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within 12 months
prior to Visit 1.
20. Documented untreated ventricular arrhythmia with syncopal episodes within 3 months 
prior to Visit 1. 
21. Symptomatic bradycardia or second or third degree of cardiac electrical conduction 
without a pacemaker. 
22. Hemodynamically significant mitral and/or aortic valve disease, except mitral 
regurgitation due to ventricular dilatation.
23. Other hemodynamically significant obstructive lesions of left ventricular outflow, 
including aortic and sub-aortic stenosis. 
24. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism or excretion of study drugs, including but not limited to:

History of active inflammatory bowel disease during 12 months before Visit 1. 

Current duodenal or gastric ulcers during the 3 months prior to Visit 1.
25. Evidence of hepatic disease as determined by any one of the following: AST or ALT 
values exceeding 2 x upper limit of normal (ULN) at visit 1, severe hepatic insufficiency 
(classification Child-Pugh C), biliary cirrhosis, cholestasis (current or anamnestic 
evidence), history of hepatic encephalopathy, history of esophageal varices, history of 
portocaval shunt. 
26. Current or planned active treatment with bile sequestering agents such as cholestyramine,
colestipol resins, colesevelam, or similar medication.
27. Patients with bilateral renal artery stenosis.
28. Patients with thyroidal dysfunction who have not been on a stable dose L-thyroxin within 
the last 3 months prior Visit 1. 
29. Patients with Graves’ disease.
30. Patients with severe adipositas (adipositas per magna – BMI ≥ 40).
31. Patients with ongoing alcohol or drug abuse or dependence.
32. Documented long QT syndrome or QTc > 450 msec for males and 470 msec for females
within 3 months prior to Visit 1.
33. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases.
34. 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 ( > 5 mIU/mL)


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35. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for further 7 days. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. In 
case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.

Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
All eligible patients will be randomized in a 1:1 allocation to receive either 
sacubitril/valsartan or enalapril in addition to their individualized cardiovascular (CV) 
medication (i.e. background HF medication) as considered appropriate by the investigator but 
with exception of ACEI or ARBs which will be replaced by the investigational treatment. 
Thus the use of an ACEI or an ARB is allowed only during the baseline recording period 
(week -2 to week 0, where patients remain on their already existing HF treatment regimen), 
but is strictly prohibited beyond the day prior to randomization when a 36 hour washout 
period for ACEIs and ARBs commences. During the dosing of study medication, i.e. beyond 
randomization until the end of the study, the intake of ACEIs or ARBs remains prohibited.
The following study drugs will be provided:

sacubitril/valsartan 24 mg/26 mg film-coated tablets (LCZ696 50 mg dose level 1)


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
placebo to match sacubitril/valsartan 24 mg/26 mg film-coated tablets (placebo matching 
LCZ696 50 mg dose level 1)

sacubitril/valsartan 49 mg/51 mg film-coated tablets (LCZ696 100 mg dose level 2, dose 
level 2a)

placebo to match sacubitril/valsartan 49 mg/51 mg film-coated tablets (placebo matching 
LCZ696 100 mg dose level 2, dose level 2a)

sacubitril/valsartan 97 mg/103 mg film-coated tablets (LCZ696 200 mg dose level 3)

placebo to match sacubitril/valsartan 97 mg/103 mg film-coated tablets (placebo 
matching LCZ696 200 mg dose level 3)

enalapril 2.5 mg film-coated tablets (enalapril dose level 1)

placebo to match enalapril 2.5 mg film-coated tablets (placebo matching enalapril dose 
level 1)

enalapril 5 mg film-coated tablets (enalapril dose level 2)

placebo to match enalapril 5 mg film-coated tablets (placebo matching enalapril dose level 
2)

enalapril 10 mg film-coated tablets (enalapril dose level 3, dose level 2a)

placebo to match enalapril 10 mg film-coated tablets (placebo matching enalapril dose 
level 3, dose level 2a)
Target doses: sacubitril/valsartan 97 mg/103 mg bid (total daily dose 194 mg/206 mg) and 
enalapril 10 mg bid (total daily dose 20 mg). 
All tablets provided have different shapes and colors. Thus, the study will employ a double-
blind, double-dummy design to ensure blinding during its entire course. To this end, patients 
will receive their assigned active study treatment as well as placebo matching the opposite 
treatment. The patients are required to take study medication twice daily (bid: meaning in the 
morning and in the evening) along with their concomitant medication (as prescribed by their 
treating physician). 
All doses of sacubitril/valsartan and its matching placebo will be provided in HDPE bottles. 
Enalapril 2.5 mg and its matching placebo will be provided in HDPE bottles, while the other 
doses of enalapril and its matching placebo will be provided in blister packs.
5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
Patients who are eligible for randomization at Visit 2 will be assigned to one of the following 
two treatment arms in a 1:1 ratio:

sacubitril/valsartan and placebo matching enalapril bid

enalapril and placebo matching sacubitril/valsartan bid


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5.3
Treatment assignment and randomization 
At Visit 2 all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study drug to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management (DSM) using a validated system that 
automates the random assignment of medication numbers to packs containing the 
investigational drug(s). 
A proportionate stratified random sampling will be performed using the NYHA class at Visit 
1 as stratification parameter (i.e. patients with NYHA class II or III/IV). This approach will 
ensure balanced allocation of patients to treatment groups within the NYHA class strata. 
Additionally, the proportionate sampling aims to allow the study population to achieve a
similar proportion of patients with NYHA II and patients with NYHA III or IV as expected in 
the general population of adult HFrEF patients. Based on the literature (Jonsson et al., 2010, 
Salvador et al., 2004, Sartipy et al., 2014, Tebbe et al., 2014) this ratio is assumed to be close 
to 1:1 and proportionate sampling will be performed accordingly.
5.4
Treatment blinding
Patients/subjects, 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 following exceptions: 

Specific vendors whose role in the trial conduct requires unblinding (e.g. IRT)

Drug supply management (DSM). 
2. The identity of the treatments will be concealed by the use of study drug that are all 
identical in packaging, labeling, schedule of administration, appearance, taste and odor.
3. A double-dummy design is used because the identity of the study drug cannot be disguised, 
as the drug products are visibly different.
Unblinding will only occur in the case of patient emergencies (see Section 5.6) and at the 
conclusion of the study. 


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5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. 
Upon signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site, the first patient is assigned patient number 1, and subsequent 
patients/subjects are assigned consecutive numbers (e.g. the second patient is assigned patient 
number 2, the third patient is assigned patient number 3). The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the patient to register 
them into the IRT. Once assigned to a patient, the patient number will not be reused. If the 
patient fails to be randomized for any reason, the IRT must be notified within 2 days that the 
patient was not randomized. The reason for not being randomized will be entered on the 
Screening Log, and the Demography eCRF should also be completed.
5.5.2
Dispensing the study drug 
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the two treatment arms and a specific dose level. 
Investigator staff will identify the study drug package(s) to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing 
the package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
subject number. 
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number. The investigator must maintain an 
accurate record of the shipment and dispensing of study treatment in a drug accountability log. 
Monitoring of drug accountability will be performed by monitors during site visits or 
remotely and at the completion of the trial. Patients will be asked to return all unused study 


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treatment and packaging at the end of the study or at the time of discontinuation of study 
treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment 
Novartis will supply the investigators with all study medication sufficient for the course of the 
study. Patients will be provided with medication packs containing the study drug 
corresponding to their assigned treatment arm and dose level, sufficient to last until their next 
scheduled visit. Site personnel must ensure to plan the study visits within 35 days to ensure 
that the patient by all times have sufficient study drug. In order to maintain blinding, patients 
will be required to take two tablets (one sacubitril/valsartan or its matching placebo and one 
enalapril or its matching placebo) twice a day for the duration of the study. The dose levels of 
study medication that will be used for titration purposes are shown in Table 5-1.
Table 5-1
Study drug dose levels
Dose level
Sacubitril/valsartan
Enalapril
3*
97 mg/103 mg or matching placebo bid
10 mg or matching placebo bid
2a#
49 mg/51 mg or patching placebo bid
10 mg or matching placebo bid
2
49 mg/51 mg or matching placebo bid
5 mg or matching placebo bid
1
24 mg/26 mg or matching placebo bid
2.5 mg or matching placebo bid
*This dose level must be maintained for as long a duration as possible. If a down-titration is necessary 
due to side effects, the patient should be re-challenged as soon as possible, per the investigator’s 
judgement. In case down-titration is necessary due to tolerability issues, down-titration is possible to 
dose level 2 or 0.
# Level 2a is only a starting dose level for patients who received a pre-study Enalapril total daily dose 
above 10 mg/d (or equivalent dose of other ACEI/ARB).
Patients will begin study treatment at a dose level according to their pre-study ACEI or ARB 
dose (enalapril equivalent dose, also see Table 3-1. Patients who had a pre-study enalapril 
total daily dose of <5 mg/d (or equivalent dose of other ACEI/ARB) will start study 
medication at dose level 1 (see Table 5-1). Patients with a pre-study enalapril total daily dose 
of ≥5 mg/d to 10 mg/d (or equivalent dose of other ACEI/ARB) will start study medication at 
dose level 2. Patients with a pre-study enalapril total daily dose of >10 mg bid (or equivalent 
dose of other ACEI/ARB) will start study medication at dose level 2a. 
Note: according to the sacubitril/valsartan SmPC and the investigator’s medical judgement, 
patients suffering from moderate hepatic impairment, moderate renal impairment or patients 
with SBP ≥100 to 110 mmHg should be initiated at dose level 1.


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Two weeks (Visit 3) after randomization, up-titration is performed to the next higher level, 
provided good tolerability of the starting dose level; this means that patients, who started on 
dose level 2 or 2a will receive the target dose of study medication (level 3) at this point. 
Patients, who started study medication at dose level 1, will have a final up-titration after 
additional 2 weeks, i.e. at Visit 4. Therefore, after Visit 4 all patients will be receiving the 
target dose (level 3), unless safety issues prevent up-titration, or down-titration becomes 
necessary (see Section 5.5.4). See the following Table 5-2 for an overview of up-titration 
scheme of study medication according to pre-study ACEI/ARB total daily dose.
Table 5-2
Study drug titration according to previous ACEI/ARB dose
Enalapril total daily 
dose before Visit 1 
(week -2)
(or equivalent dose of 
other ACEI/ARB, see 
Table 3-1)
Study drug dose level 
after randomization at 
Visit 2 (week 0)
Up-titration at Visit 3 
(week 2)
Up-titration at Visit 4 
(week 4)
< 5.0 mg/day
Dose level 1
Dose level 2
Dose level 3
5.0 mg to ≤10 mg/day
Dose level 2
Dose level 3
>10 mg/day 
Dose level 2a
Dose level 3
Note: according to the sacubitril/valsartan SmPC and the investigator’s medical judgement, patients 
suffering from moderate hepatic impairment, moderate renal impairment or patients with SBP ≥100 to 
110 mmHg should be initiated at dose level 1.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
Patients will be instructed to take the study medication twice daily – once in the morning and 
once in the evening. The morning study drug dose should occur around 08.00 (8 am), the 
evening dose at approximately 19.00 (7 pm). The study medication should be taken with a 
glass of water with or without food. If the patient misses taking any study 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 be instructed to skip the missed dose and return to his/her regular 
study drug intake schedule. 
The investigator must promote adherence by instructing the patient to take the study drug
exactly as prescribed and by stating that adherence is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Once patients achieve the target study drug dose, every attempt should be made to maintain 
the target study drug dose level for as long as possible throughout the trial. 
If, however, in the opinion of the investigator, the patient does not tolerate the target dose of 
the study drug, the investigator should consider whether non-disease modifying medication 
(e.g. calcium channel blockers, diuretics, nitrates or alpha-blockers) can be reduced to rectify 
the situation, before considering to reduce the dose of study drug to the next lower dose level. 
In addition, the investigator may adjust the doses of disease-modifying medications, if he/she 
believes that they are more likely causes of adverse events. If such adjustments of 


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concomitant medications are not medically indicated, the investigator may down-titrate the 
dose of study drug to the next lower dose level up to a complete withdrawal of the 
investigational treatment, if necessary. In such cases, the patient should be re-challenged with 
the higher dose level when the investigator feels that doing so is appropriate; the re-challenge 
should be performed according to the guidance provided in this section (see below) of the 
protocol.
If necessary, study drug may be stopped completely, but the patients should continue to attend 
study visits and be followed until completion of the study. 
Study drug dose level adjustments should be based on overall safety and tolerability with a 
special focus on 

Hyperkaliemia (see Appendix 1 and Appendix 4 for guidelines for managing 
hyperkaliemia)

Symptomatic hypotension (see Appendix 5 for guidelines on BP management) 

Clinically significant decrease in eGFR or clinically significant increase in serum 
creatinine (see Appendix 1 and Appendix 6 for guidelines on managing renal 
dysfunction) 

Worsening hepatic function (see Appendix 2)
For patients/subjects who are unable to tolerate the protocol-specified dosing scheme, dose 
adjustments and interruptions of investigational drug are permitted in order to keep the patient 
on study drug. 
The following guidelines must be followed: 
Adjustment of study drug dose level
During the double-blind treatment period down-titration of the study drug is allowed at any 
time based on the safety and tolerability criteria defined in Appendix 1, Appendix 14, 
Appendix 3 and Appendix 4. If down-titration is necessary, the next lower dose level should 
be prescribed (see Table 5-1; Please note, that dose level 2a is only allowed as a starting dose). 
The patient may continue receiving the lower dose level for a recommended period of one to 
two weeks before re-challenging the patient with the next higher dose level. For example: a 
patient who encounters tolerability issues at the target dose level (level 3) should receive the 
study drug at dose level 2 for one to two weeks, before he/she is re-challenged with an up-
titration back to dose level 3. 
If the first initial dose reduction does not lead to alleviation of the tolerability issues, the 
investigator may lower the study drug dose further to the next lower level for another one to 
two weeks. If necessary, the study drug may be temporarily withdrawn. Once stable, the 
patient should be re-challenged with the next higher dose level every one to two weeks in an 
attempt to gradually up-titrate he patient to receive the target dose (level 3) (Table 5-1).
In some cases, according to the safety and tolerability criteria described above and the 
investigator’s judgement, the study drug dose level 2 could be maintained if the patient’s 
condition does not allow up-titration (or re-challenge) to the target dose (dose level 3). In 
these cases, it is acceptable to maintain the patient on dose level 2. Similarly, if dose level 2 is 
not tolerated by the patient, a down-titration to dose level 1 is allowed and, if necessary and 


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justified within the judgement of the investigator, the patient may be maintained on dose level 
1, if up-titration or re-challenge is not tolerated by the patient. 
Study drug re-start after temporary treatment interruption
Study drug should be re-introduced in patients for whom a temporary interruption becomes 
necessary; if possible and medically justified in the judgement of the investigator the duration 
of the interruption should be one to two weeks.
Once the investigator considers the patient’s condition appropriate for re-introducing the 
study drug, the investigator should re-start the study drug at the most appropriate dose level 
(Table 5-1, Note, that dose level 2a, is only for initial dose and will not be available for up-
titration after re-start) according to his/her judgement. If the safety and tolerability criteria 
(see above and Appendix1, Appendix 2, Appendix 3 and Appendix 4) are not violated, the 
patient’s study drug dose should be up-titrated after re-starting every one to two weeks to the 
next higher level, until the target dose level is reached. If the patient does not tolerate the up-
titration after temporary treatment interruption, the dose can be down-titrated again (if 
appropriate) or study drug should be discontinued. 
Patients who are re-started after temporary interruption of the study drug will retain their 
initial randomization and study identification numbers. 
Note for all dose adjustments: These changes will be tracked in the IRT system.
5.5.6
Rescue medication
Guidance on handling hyperkaliemia, hypotension and renal dysfunction are provided in 
Appendix1, Appendix 4, Appendix 5 and Appendix 6. If necessary, patients may receive 
open-label ACEI and/or ARBs ONLY if study medication is interrupted temporarily or 
discontinued permanently. NOTE that a washout phase of 36 hours is required for the study 
drug, but also for any ACEI or ARB before (re-)introducing study drug.
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies Record in the CRF.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
The patients’ pre-study ACEIs or ARBs will be replaced by the study drug. As per inclusion 
criteria, the patients need to be on stable HF therapy regimen for at least 4 weeks prior to Visit 
1 and should remain on a stable regimen, if medically justified, throughout the entire study 
duration.


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Diuretics may be used and may be adjusted at any time throughout the duration of the study at 
the discretion of the investigator. 
Potassium-sparing diuretics (e.g. amiloride), potassium supplements, mineralocorticoid 
receptor antagonists (e.g. spironolactone) and any other medications known to raise potassium 
levels should be used with caution while the patients receive study medication, due to 
increased possibility of hyperkaliemia. The investigators are encouraged to assess patients’ 
potassium levels regularly, especially during the up-titration and in those receiving such 
medications.
Phoshodiesterase-5 inhibitors should be used with caution while patients receive study 
medication due to increased possibility of occurrence of hypotension. 
Caution should be exercised upon co-administration of statins such as atorvastatin, pravastatin 
or pitavastatin and study medication, due to potential interactions between statins and 
sacubitril/valsartan. Similarly, potential interactions between sacubitril/valsartan and lithium 
or non-steroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase-2 
(COX-2) inhibitors should be considered.
Due to potential drug interactions between ACE-inhibitors and specific anti-diabetic 
medication (such as insulins, specific oral hypoglycemic agents) as well as potential 
interaction between metformin and sacubitril/valsartan, patients on antidiabetic treatment are 
encouraged to be followed up to ensure adequate management of their diabetes according to 
investigators discretion.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-3 is NOT allowed after the start of the washout 
period, i.e. the evening before Visit 2. Note, during the baseline recording period, i.e. over 
two weeks after Visit 1 (i.e. week -2 until 12 hours before Visit 2) the patients will receive 
their usual pre-study medication to obtain a baseline. 
ACEIs and/or ARBs are replaced by study medication and therefore need to be discontinued 
12 hours before Visit 2 (i.e. the evening before Visit 2). At Visit 2, patients will be 
randomized to receive either sacubitril/valsartan or enalapril; the patients will receive the first 
dose of study medication 24h after the randomization visit, resulting in a washout period from 
ACEIs or ARBs of 36 hours. In order to avoid excessive RAAS inhibition, it is crucial to 
respect the washout period and instruct the patient to not take any ACEI or ARB while taking 
double-blind study medication.
Direct renin inhibitors (i.e. aliskiren) are also prohibited for safety reasons, as concomitant 
intake of renin inhibitors and study medication could increase the likelihood of occurrence of 
hyperkaliemia.
Bile acid sequestering agents are prohibited due to potential interference with the absorption 
of study drugs.


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Table 5-3
Prohibited medication
Medication
Action taken
Any ACEI, Any ARB, Renin 
inhibitors
Discontinue these drugs starting at 12h before Visit 2, prohibited 
until at least 36 hours after study drug 
discontinuation/interruption/end of study.
In case these drugs are taken / need to be taken during the 
double-blind treatment period of the study, discontinue study 
drug.
Bile acid sequestering agents
(e.g. cholestyramine, colestipol)
Discontinue before randomization, prohibited throughout the 
study. No action required with study medication.
5.5.9
Emergency breaking of assigned treatment code
Emergency treatment code breaks must only be undertaken when it is required in order to 
treat the patient safely. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a patient, he/she must 
provide the requested patient identifying information and confirm the necessity to break the 
treatment code for the patient. The investigator will then receive details of the investigational 
drug treatment for the specified patient and a fax or email confirming this information. The 
system will automatically inform the Novartis monitor for the site and the Study Team that 
the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
After an emergency treatment code break, the patient must discontinue study treatment. 
In case of accidental unblinding, Novartis personnel and the investigator will decide on the 
patient’s continuation of the trial.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
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. This care may 


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include initiating another treatment outside of the study as deemed appropriate by the 
investigator
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish 

Pregnancy (see Section 6.5.5 and Section 7.9)

Use of prohibited treatment as per recommendations in Table 5-3

Any situation in which study participation might result in a safety risk to the patient.

Suspected occurrence of angioedema. A patient with any signs of symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator. Clinically 
significant angioedema constitutes a reason for temporary interruption or permanent 
discontinuation of study drug. 
Study medication may be discontinued at the investigator’s discretion if any of the following 
occur:

Any severe suspected drug-related adverse event (AE)

If safety and tolerability criteria are met, as defined in Appendix 1, Appendix 2, Appendix 
3 and Appendix 4. 

Any other protocol deviation that results in a significant risk to a patient’s safety. 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of the study drug, for a study treatment discontinuation visit. Treatment 
discontinuation visit assessments detailed in the "unscheduled visit" (UNS) in Table 6-1
should be completed and recorded in the eCRF. The investigator must determine the primary 
reason for the patient’s premature discontinuation of study treatment and record this 
information in the source data and the Study Discontinuation page. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits: 

new / concomitant treatments

adverse events/Serious Adverse Events
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.


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Please note that the End of Study Visit (EOS) should be performed for all patients who either 
complete the study or discontinue the treatment, but start the abbreviated visits and for 
patients who prematurely discontinued the study.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table below.
5.6.4
Loss to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons,
alternations in accepted clinical practice that make the continuation of the trial unfeasible, or 
for regulatory or reasons or insufficient patient recruitment. Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 


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will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the assessments are 
performed.
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible
with an allowed “visit window” defined in Table 6-1. Missed or rescheduled visits should not 
lead to automatic discontinuation. Patients/subjects who prematurely discontinue the study for 
any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments will be performed (EOS visit). At this final visit, all dispensed investigational 
product should be reconciled and the adverse event and concomitant medications reconciled 
on the CRF. Please note that patients who discontinue the study treatment and come to the 
unscheduled visit (UNS), study drug, tablet and motionwatch should be returned.
Patients will be contacted for safety evaluations until the 30 days following the last 
administration of study treatment. Evaluations can be made by phone and should be 
documented in the source data.


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Table 6-1
Assessment schedule
Epoch 
Screening
Double-blind Treatment
Notes
Visit
1
2
3
4
5
6 
(EoS)
FU Call
uns
Day (Week)
-14 (-2)
1 (0)
14 
(2)
28 (4) 56 (8)
84 
(12)
Up to 30 
days after 
last drug 
dose
Visit Window
-3/+1
-3/+3 -3/+3
-5/+5
-1/+5
the interval between the visits must not exceed 35 days as study 
comes in pre-filled packages for 35 days of treatment
Obtain informed consent
X
Inclusion/Exclusion criteria
X
X
Some exclusion criteria apply for both Visit 1 and Visit 2
Demography
X
Medical History / Current medical 
conditions
X
Previous and concomitant 
drug/non-drug treatments
X
X
X
X
X
X
X1
Previous treatments will only be recorded for prior discontinued HF 
drug and non-drug therapy
Physical Exam
S
S
S
S
S
S
S1
At Visit 1, a full physical exam is performed; at all other visits a 
short exam is to be performed (see Section 6.5.1)
Height
X
Weight
X
X
Vital signs
X
X
X
X
X
X
X1
     Determine NYHA class
X
X
X
X
X
X
X1
     6-minute walking test
X
X
X
X
PGA
X
X
X
Patient’s Global Assessment
Contact IVRS/IWRS
X
X
X
X
X
X
At randomization, at study drug dispensation and at any time in 
case of study treatment discontinuation or emergency unblinding


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Epoch 
Screening
Double-blind Treatment
Notes
Visit
1
2
3
4
5
6 
(EoS)
FU Call
uns
Day (Week)
-14 (-2)
1 (0)
14 
(2)
28 (4) 56 (8)
84 
(12)
Up to 30 
days after 
last drug 
dose
Visit Window
-3/+1
-3/+3 -3/+3
-5/+5
-1/+5
the interval between the visits must not exceed 35 days as study 
comes in pre-filled packages for 35 days of treatment
Dispense Study Medication
X3
X
X
X
X
See Table 5-1 and Table 5-2 for dosing levels and titration. For 
patients who discontinue the treatment study drug should be 
returned.
Training patient on use of 
actigraphy device
X
Download actigraphy data from 
patient’s device
X
X
X
X1
Change Actigraphy Device
X
Adverse event monitoring
X
X
X
X
X
X
X
X1
Urine pregnancy test
S
S
S1
Additional testing should be done as per local laws and regulations
Diagnostic and Laboratory evaluations
     Potassium 
X
X
X
X
X
X
X1
also as per discretion of investigator (local lab)
     AST and ALT
X
X
X
X
X
X
X1
also as per discretion of investigator (local lab)
    Creatinine / eGFR
X
X
X
X
X
X
X
also as per discretion of investigator (local lab)
    ECG
X4
    NT-proBNP
X#
X#
X#
X#
X#
X#
X#
Only if available – not required by the protocol during visit
    Hemoglobin
X#
X#
X#
X#
X#
X#
X#
Only if available – not required by the protocol during visit
    LVEF
X#
X#
X#
X#
X#
X#
X#
Only if available – not required by the protocol during visit
X = assessment to be recorded on clinical data base; S = assessment to be recorded on source documents only
1These assessments are to be conducted for patients who early discontinue the treatment and for all other reasons an unscheduled visit is needed (see details below). If 
a patient prematurely discontinues the study, an EOS should be performed. The UNS visit should also be done for patients who discontinue the treatment and continue 
the abbreviated visits until EOS.


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Epoch 
Screening
Double-blind Treatment
Notes
Visit
1
2
3
4
5
6 
(EoS)
FU Call
uns
Day (Week)
-14 (-2)
1 (0)
14 
(2)
28 (4) 56 (8)
84 
(12)
Up to 30 
days after 
last drug 
dose
Visit Window
-3/+1
-3/+3 -3/+3
-5/+5
-1/+5
the interval between the visits must not exceed 35 days as study 
comes in pre-filled packages for 35 days of treatment
3 Study Medication will be dispensed but not be taken until the next day
4 Only if no ECG has been performed within the last 3 months
# assessments not required by the protocol, however if available within the diagnostic routine, they should be entered in the study data base
uns – unscheduled visit; when deemed necessary, unscheduled visits may be performed to ensure adequate medical management. This is exemplified by, but not 
limited to, patients achieving target dose at visit 4 and are perceived as fragile and thus need an extra monitoring visit, NYHA IV, renal impairment, patients prone to 
hypotension and or hepatic impairment. Investigator’s clinical judgement and discretion is advised.


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6.1
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next epoch
(i.e. who were not randomized) will have the study completion page for the screening epoch, 
demographics, inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse 
events that are not SAEs will be followed by the investigator and collected only in the source 
data. Collected actigraphy data will be downloaded by the investigator and recorded in the 
study data base. 
Re-screening
If a patient is not eligible to enter the double-blind treatment epoch (i.e. screening failures), 
the investigator may consider re-screening the patient at a later time, if he/she believes that the 
patient’s condition has changed and the patient may be potentially eligible. However, re-
screening will only be possible for inclusion criterion 3 and exclusion criteria 1, 6, 11, 15, 17, 
20, as well as 28. In this case, a completely new patient number will be allocated to the patient 
and all Visit 1 assessments will be performed again.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
year of birth, age, sex, race, ethnicity, source of patient referral (if applicable), the patients’ 
living conditions, smoking status, relevant medical history/current medical condition present 
before signing informed consent (where possible, diagnoses and not symptoms will be 
recorded) previous drug/non-drug therapy of HF (prior Visit 1), concomitant medication and 
non-drug therapy. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.3
Treatment exposure and compliance 
Adherence will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source document at each visit. The patients’ compliance should at least be 80 % (i.e. the 
patient took at least 80 % of the tablets that were to be taken in the respective time period) 
during the double-blind treatment epoch. If compliance is below this threshold the 
investigator or study personnel will counsel the patient. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log. 
6.4
Efficacy
Efficacy will be assessed by means of 

Actigraphy-derived parameters

6-minute walking test (6MWT)

Patient Global Assessment questionnaire (PGA)


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6.4.1
Actigraphy
Actigraphy is a non-invasive method of monitoring human physical activity patterns. 
Actigraphy will be performed in this study by means of a wrist-worn device that collects data 
on activity (by means of tri-axial accelerometry). The device (MotionWatch8®, CamNtech, 
Cambridge, UK) collects the data on movement continuously in 30-second bins. The device is 
lightweight and waterproof and worn on the wrist of the non-dominant arm continuously (24 
hours/day) for the entire study duration. Based on accelerometry for each 30-second bin, 
activity counts for each minute of each day are generated. Higher counts reflect a higher level 
of activity. For an elderly population, cut-off values for activity counts per minute defining 
the intensity of physical activity have previously been defined (Landry et al., 2015) . These 
cut-off values will be used to define sedentary, light and moderate to vigorous activity counts 
for each minute the device is worn. Sedentary activity is defined as < 178.5 activity counts per 
minute; light activity as 178.5 – 565.5 activity counts/minute and > 565.5 activity 
counts/minute define moderate to vigorous physical activity (see also Figure 3-1). The time 
patients spend in a given activity intensity category will be recorded and represents the basis 
for all endpoints that are derived from actigraphy. Where appropriate, activity data will be 
integrated over 2-week intervals (i.e. baseline non-sedentary physical daytime activity is the 
mean time per day the patient spent in non-sedentary activity during the daytime during the 14 
days of baseline recording (week -2 to week 0). 
6.4.2
Six minute walking test
The distance covered by the patient walking during 6 minutes will be determined and 
recorded at Visit 2, Visit 4, Visit 5 and Visit 6. 
The assessment is performed according to the current standards (Tager et al., 2014) and will 
be provided as a separate manual to all sites. In brief – patients are instructed to walk down a 
long corridor at their own pace, attempting to cover as much distance as possible within 6 
minutes. At the end of the 6 minute duration, the walked distance is calculated and recorded 
along with the symptoms experienced by the patient. It is crucial that patients are allowed to 


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rest, before the test is performed – therefore the 6-minute walking test should be done as the 
last assessment at the respective visits. 
6.4.3
Patient Global Assessment (PGA)
The Patient Global Assessment(PGA) is a self-reported tool to assess the patients’ subjective 
rating of their disease activity widely used in HF research and other indications. It has been 
shown that the PGA responses of CHF patients correlate the patients’ functional capacity 
assessed by means of the 6-minute walk test (Cooper et al., 2016). 
The patients are asked to report functioning or response to an intervention by rating their 
current condition compared to their pre-intervention condition on a numerical scale: 
1) much improved 2) moderately improved 3) a little improved 4) unchanged 5) a little worse 
6) moderately worse or 7) much worse. 
This self-assessment will be completed by the patients in a quiet environment, before any 
study assessment or drug dispensing at Visit 4, Visit 5 and Visit 6. 
6.4.6
Appropriateness of efficacy assessments 
Actigraphy represents a state of the art, objective measure of human physical activity. 
Provided the accelerometry device is worn continuously (or only with minor interruptions) the 
data collected provide the most objective and accurate measure of patients’ activity and sleep 
profiles. The raw accelerometry data are subject to integration by means of dedicated software
which ensures data integrity and quality. The software employs algorithms to derive objective 
actigraphy measures (e.g. activity counts per minute) from the raw accelerometry data which 
in turn are used to derive the actigraphy-based study endpoints. Actigraphy-based endpoints 
reflect the patients’ physical activity and behavior in their familiar environment. In addition, 
the 6-minute walking test is a frequently used functional test that allows for the evaluation of 
the patients’ submaximal exercise capacity and thus provides information on the patients’ 


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physical activity tolerance.
 
 
 
6.5
Safety 
The sponsor may request additional information on specific AEs or laboratory events of 
interest and may make requests to perform additional diagnostic tests to further assess the 
safety profile of sacubitril/valsartan. Such information may include diagnostic procedure 
reports, discharge summaries, autopsy reports and other relevant information that may help in
assessing the reported adverse event. All such additional information must be de-identified 
prior collection by Novartis or its representatives. 
6.5.1
Physical examination
A complete physical examination will be performed at Visit 1. A complete physical 
examination will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed.
A short physical exam will include the examination of general appearance and vital signs 
(blood pressure (BP) and pulse). A short physical exam will be performed at all visits starting 
from visit 2 except where a complete physical examination is required (Visit 1, see above). 
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be included in the Medical History part of the CRF. Significant findings made after signing 
the informed consent form which meet the definition of an AE must be recorded on the 
Adverse Event section of the CRF.
6.5.2
Vital signs 
Vital signs will be assessed at every visit and include BP and pulse measurements. After the 
patient has been sitting for five minutes, with back supported and both feet placed on the floor, 
systolic and diastolic blood pressure will be measured three times using a standard 
sphygmomanometer with an appropriately sized cuff. The repeat sitting measurements will be 
made at 1 - 2 minute intervals and the mean of the three measurements will be used. 
Guidelines for BP-management are provided in Appendix 5.
6.5.3
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured at visit 1; weight will be measured again at the 
final visit.


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6.5.4
Laboratory and diagnostic evaluations
For patient safety the following laboratory parameters should be monitored at the screening 
visit (Visit 1) and before randomization (Visit 2), as well as throughout the up-titration of 
study drug and as per discretion of the investigator. 

Potassium

Creatinine and eGFR

AST and ALT
These laboratory evaluations are standard safety parameters in the context of prescribing 
ACEI, ARBs or sacubitril/valsartan. They will be performed by the local lab and should be 
entered into the patient’s source data and into the clinical study database. 
Clinically notable laboratory findings are defined in Appendix1, Appendix 2, Appendix 3 and 
Appendix 4.
A standard 12-lead ECG will be performed at screening (Visit 1, unless an ECG performed 
within the last 3 months is available) to assess the eligibility of patients regarding inclusion 
and exclusion criteria. Interpretation of the tracing must be made by a qualified physician. 
Each ECG tracing should be labeled with the study number, patient number, and date and kept 
in the source documents at the study site. Clinically significant abnormalities according to the 
judgment of the investigator should also be recorded on the relevant medical history/current 
medical conditions or AE eCRF page.
In addition, if available within the investigator’s routine management of HF, any assessment 
of LVEF, NT-proBNP and hemoglobin during the study can be entered into the study 
database, but is not stipulated by the protocol. 
6.5.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have urine pregnancy testing at 
Visit 2 prior to randomization and at the end of study visit. In case, urine pregnancy test is 
positive, results are to be confirmed by local serum pregnancy tests. Additional pregnancy 
testing might be performed if and as requested by local requirements.
6.5.6
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication and patient population.


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7
Safety monitoring
7.1
Adverse events
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign, 
including abnormal laboratory findings, symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study 
until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must 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 findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 


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patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment 

“No Relationship to study treatment or other investigational treatment” or

“Relationship to study treatment” or

“Relationship to other investigational treatment” or 

“Relationship to both study treatment and other investigational treatment or 
indistinguishable“

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE) 
and which seriousness criteria have been met.

action taken regarding investigational treatment; All AEs must be treated appropriately. 
Treatment may include one or more of the following: 

no action taken (e.g. further observation only) 

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition 
of SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient.


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The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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7.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day 
period should only be reported to Novartis if the investigator suspects a causal relationship to 
study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, complete the SAE Report Form in English, and submit the 
completed form within 24 hours to Novartis. Detailed instructions regarding the submission 
process and requirements for signature are to be found in the investigator folder provided to 
each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
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
Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 of Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 of Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
Repeat laboratory tests must be entered on the appropriate unscheduled local laboratory CRF 
page.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring
To ensure patient safety, a standardized process for identification, monitoring and evaluation 
of renal dysfunction is summarized in Appendix 3.
7.5
Serum potassium safety monitoring
To ensure patient safety, a standardized process for identification, monitoring and evaluation 
of hyperkaliemia is summarized in Appendix 4.
7.6
Hypotension monitoring
To ensure patient safety, a standardized process for identification, monitoring and evaluation 
of hypotension is summarized in Appendix 5.


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7.7
Angioedema monitoring
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. 
Bradykinin has been implicated as the putative mediator. Thus, medications that raise levels 
of endogenous bradykinin (such as ACEI and NEP inhibitors) may result in this potentially 
dangerous effect. It is important that the investigator pays special attention to any swelling or 
edema that may resemble angioedema angioedema-like events that may be reported by the 
patient.
If angioedema occurs, study drug should be immediately discontinued and appropriate therapy 
and monitoring should be provided by the investigator until complete and sustained resolution 
of signs and symptoms have occurred. After discontinuation of study drug due to an 
angioedema, study drug must not be re-administered.
7.8
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
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
7.9
Pregnancy reporting
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.


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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.
7.10
Prospective suicidality assessment
Not applicable.
8
Data review and database management 
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and 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 Novartis CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21Part 11 


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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 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control
Novartis staff, or a CRO working on behalf of Novartis, review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Actigraphy data will be downloaded by the investigator and transferred to a CRO working on 
behalf of Novartis by means described in the investigator’s folder. Raw Data will be 
processed by the CRO working on behalf of Novartis, by means of appropriate and dedicated 
computer programs. The processed data will be sent electronically to the clinical data base for 
analysis.  
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee
Not required.


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8.5
Adjudication Committee
Not required.
9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
Summary statistics for continuous variables will include valid N, missing N, mean, standard 
deviation, minimum, median, maximum. Summary statistics for discrete variables will be 
presented in contingency tables and will include absolute and relative frequencies.
Details of the planned statistical analysis will be described in a separate statistical analysis 
plan (SAP), which will be finalized prior to data base closure. All analyses will be carried out 
by means of the SAS® package (version 9.2 or higher).
9.1
Analysis sets
Three analysis data sets will be defined. The safety data set (SAF) consists of all patients who 
have received the study medication at least once. The full analysis set (FAS) comprises all 
patients of the safety data set who provide the baseline value and any post-baseline value of at 
least one primary endpoint (6-minute walking test or daily non-sedentary daytime activity).
The per-protocol (PP) data set includes all patients of the FAS who do not have any major 
deviations from the protocol. Such deviations will be defined in the Data Validation Plan or 
similar document and in the protocol of the blind data review without knowledge of the 
treatment group assignment.
9.2
Patient demographics and other baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristics, 
including age, age groups (<65 years vs. ≥ 65 years ), sex, race, ethnicity, source of patients’ 
referral, the patients’ living conditions, smoking status, relevant medical history/current 
medical condition, previous drug/non-drug therapy of HF, concomitant medication and non-
drug therapy. Furthermore, weight, height, body mass index (BMI) and NYHA class will be 
provided. BMI will be calculated as weight (kg) / height² (m²) from the collected height and 
weight at the screening Visit 1. 
Variables will be summarized according to the analyses for continuous and categorical data 
described in Section 9 above. The analysis will be performed for all patients in the FAS and 
additionally stratified by treatment group.
9.3
Treatments
The duration of exposure to study drug will be summarized for all patients treated in the SAF, 
separately by treatment group. Additionally, the number and percentage of patients will be 
summarized by treatment group for duration category. Compliance will be calculated in 


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percent as the number of tablets administered divided by the number of tablets scheduled 
according to the protocol.
Prior and concomitant medications and non-drug therapies will be summarized by therapeutic 
class, preferred term, and treatment group for the SAF. Prior medications are defined as 
treatments taken and stopped prior to first dose of study drug. Any medication given at least 
once between the day of first dose of study drug and the last day of study will be a 
concomitant medication, including those which were started pre-Baseline and continued into 
the treatment period.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
There are two primary variables. The physical activity primary variable is the change in 
walking distance in meters from baseline to visit 6 as assessed by the 6 minute walk test. The 
actigraphy primary variable is the change from baseline to ‘end of study’ in mean daily non-
sedentary daytime activity (defined as ≥178.50 counts per minute) as calculated by the 
MotionWatch 8 accelerometer device. Baseline is defined as the average min per day in non-
sedentary daytime activity over 2 weeks (week -2 to week 0) prior to randomization and ‘end 
of study’ is defined as the average minutes per day in non-sedentary daytime activity between 
week 10 to week 12.
The aim of the primary analysis of this study is to assess differences between 
sacubitril/valsartan and enalapril patients with respect to the primary endpoint in the FAS.
9.4.2
Statistical model, hypothesis, and method of analysis
6-minute walk test: The primary hypothesis to be rejected is that the change in 6-minute walk 
test between baseline and ‘end of study’ under sacubitril/valsartan is equal to the change 
under enalapril. 
Non-sedentary daytime activity: The primary hypothesis to be rejected is that the change in 
weighted mean non-sedentary daytime activity between baseline and ‘end of study’ under 
sacubitril/valsartan is equal to the change under enalapril. Both analyses will be performed in 
the same way, let µj denote the expected change in 6-minute walk test or mean daily non-
sedentary daytime activity in group j, j=0,1 where
•
0 corresponds to treatment with sacubitril/valsartan and 
•
1 corresponds to treatment with enalapril.
The following hypothesis will be tested:
H0: µ0 = µ1 vs. H1: µ0 ≠ µ1
The primary efficacy variable will be analyzed using analysis of covariance (ANCOVA), with 
factors treatment and baseline NYHA class (NYHA II vs. III/IV) and the baseline value as 
covariates. The two-sided 95%-confidence interval and the corresponding p-value for the 
between-group difference of the adjusted means (least square means) of both treatment groups 
will be provided from the ANCOVA model.


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Confirmatory testing, i.e. the primary analysis of the primary variable, will be carried out for 
the FAS. The level of significance will be set to α = 0.05 (two-sided).
9.4.3
Handling of missing values/censoring/discontinuations
For patients who do not have the baseline values or patients who drop out prematurely and/or 
do not have a valid measurement in mean daily non-sedentary daytime activity between
weeks 10-12, a Multiple Imputation (MI) method will be used for the primary analysis. 
In case of qualitative (e.g., increased level of non-sedentary daytime physical activity) or 
semi-quantitative (e.g., PGA) efficacy variables, missing Week 12 values of patients 
previously dropped out due to hospitalization or death will be substituted by the worst value 
possible for the respective variable (e.g., increased level of non-sedentary daytime physical 
activity=”No”, PGA=”much worse”).
9.4.4
Sensitivity analyses
In addition to the primary analysis in non-sedentary daytime activity, the variable will also be 
analyzed using the same analysis model in the PP population with MI and without multiple 
imputation as supportive. Furthermore, the analysis of the primary variable will be repeated in 
the FAS population with MI of missing values described in Section 9.4.3.
Besides, the last-observation-carried-forward principle (LOCF) imputation method for non-
sedentary daytime activity will be performed as a sensitivity analysis. For patients who drop 
out prematurely and/or do not have a valid measurement in mean daily non-sedentary daytime
activity between weeks 10-12, the last available value of non- sedentary daytime activity over 
two weeks under treatment will be used for the primary analysis.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
For the secondary variable is the proportion of patients with increased level of non-sedentary 
daytime physical activity at ‘end of study’ compared to baseline. It will be analyzed by 
applying a logistic regression model with factors treatment and baseline NYHA class (NYHA 
II vs. III/IV) and the baseline value as further covariate. The Odds Ratio for the factor 
treatment and its 95%-confidence interval will be given. The analysis of this secondary 
variable will be performed in the FAS (with and without imputation of missing values 
described in Section 9.4.3.) and additionally in the PP population with and without imputation 
of missing values. 
All other secondary efficacy variables will be analyzed descriptively using the statistics for 
continuous and categorical data described in Section 9 above. Additionally, two-sided tests of 
significance (with α = 0.05) between the two treatment groups will be performed for all 
secondary endpoints, using appropriate testing procedures. Details to those statistical testing 
procedures will be defined in the SAP. 


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All statistical tests of secondary efficacy variables will be on an exploratory basis. Therefore, 
no multiple testing strategy will apply for these tests
9.5.2
Safety variables 
All safety evaluations will be performed in the Safety set.
9.5.2.1
Adverse events
Treatment emergent adverse events (events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term) will be summarized. Only primary paths within MedDRA will be considered 
for AE reporting. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects 

having any AE, 

having an AE in each primary system organ class and 

having each individual AE (preferred term). 
Summaries will also be presented for AEs by severity and for study treatment related AEs. If 
a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one adverse 
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable. 
Separate summaries will be provided for death, serious adverse event, adverse events leading 
to discontinuation and adverse events leading to dose adjustment (including study treatment 
discontinuation).
9.5.2.2
Laboratory data
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data 
and change from baseline values (mean, medians, standard deviations, ranges) and by the 
flagging of notable values in data listings.
9.5.2.3
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. All information collected will be listed by subject 
and abnormal values be flagged. 
9.5.3
Resource utilization
Not applicable.


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9.5.4
Pharmacokinetics Not applicable.
9.5.5
DNA
Not applicable.
9.5.6
Biomarkers
Not applicable.
9.5.7
PK/PD Not applicable.
9.7
Interim analyses
Not applicable.
9.8
Sample size calculation
There are no published data on a possible effect of a drug intervention on physical activity in 
HFrEF patients. However, Alosco and colleagues observed patients with HF over a period of 
12 weeks and reported activity levels at baseline and after 12 months using a similar 
accelerometry device (Alosco et al., 2015). The mean activity time in light intensity was 188 
min/day (SD = 56) at baseline and 183 min/day (SD = 58) after 12 weeks. The corresponding 
values for activity in moderate to vigorous intensity were 46 min/day (SD = 35) at baseline 
and 41 min/day (SD = 30) after 12 weeks. From these data an average of 234 min/day at 
baseline and 224 min/day after 12 weeks can be concluded for the non-sedentary daily activity 
time. The observed standard deviations for sedentary daily activity time were 76 min/day 
(baseline) and 63 min/day (month 12), respectively. From these values the standard deviation 
for non-sedentary activity time (which is approximately the same as for sedentary activity 
time) is estimated as SD = 70 min/day for both time points.


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For the present study we assume a mean baseline value of 200 to 230 min/day for both 
treatment groups. If treatment with sacubitril/valsartan leads to an improvement which is at 
least 20 min/day higher than the changes under enalapril, this is considered as clinically 
relevant.
The standard deviation for the changes from baseline is expected not to be larger than the 
standard deviations at the two respective visits (corresponding to a correlation coefficient of 
0.5 between the values at baseline and at week 12 to 14). Accordingly, the standard deviation 
for the primary endpoint is estimated as SD = 70 min/day for both treatment groups.
Planning a two-sided test (using the t-test model with α = 5% and 90% power at Δ = 20 
min/day) results in 259 patients per treatment group (nQuery Advisor® 7.0). In order to 
account for non-eligible patients, it is planned to recruit 300 patients per treatment arm, i.e. 
600 patients in total.
With respect to the primary endpoint "change in 6-minute walk test between baseline and 
weeks 4, 8 and 12", the following sample size considerations apply: From Täger et al. and 
Shoemaker et al., we deduce a minimal important difference of 35 meters at week 12 and a 
standard deviation of 114 meters (Tager et al., 2014). Planning a two-sided test with α = 0.05 
and 90% power for a group difference of 35 meters leads to a sample size of 224 patients per 
group, which is covered by the planned patient numbers.
After defining the primary hypotheses H1 and H2, to control the familywise error rate at level 
5%, the Hochberg procedure will be used to test the primary hypotheses. It will reject both H1 
and H2, if both of them are significant at level 5% simultaneously. Otherwise, it will reject H1 
if it is significant at level α/2, or reject H2 if it is significant at level α/2.
Table 9-1
Power of the study considering both the end-points – Considering 259 
subjects in each arm
Correlation 
between the two 
end-points
Power to reject 
H1
Power to reject 
H2
Power to reject 
any of H1 and H2
Power to reject 
both of H1 and 
H2
0
89.7%
93%
98.5%
84.4%
0.2
89.5%
93%
97.6%
85%
0.4
89.4%
93%
96.5%
85.7%
0.5
89.3%
93%
96%
86%
For power calculations, H1 is based on accelerometry data end-point while H2 is based on the 6 
minutes walking test end-point.
Table 9-2
Power of the study considering both the end-points – Considering 300 
subjects in each arm
Correlation 
between the two 
end-points
Power to reject 
H1
Power to reject 
H2
Power to reject 
any of H1 and H2
Power to reject 
both of H1 and 
H2
0
93.6%
96.2%
99.4%
90.4%
0.2
93.5%
96%
99%
90.6%


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0.4
93.4%
96%
98.2%
91%
0.5
93.3%
95.8%
97.8%
91.3%
For power calculations, H1 is based on accelerometry data end-point while H2 is based on the 6 
minutes walking test end-point.
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 


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patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 


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hazard to patients/subjects may be implemented immediately provided the health authorities
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
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STEWART, A. L., GREENFIELD, S., HAYS, R. D., WELLS, K., ROGERS, W. H., BERRY, 
S. D., MCGLYNN, E. A. & WARE, J. E., JR. 1989. Functional status and well-being 
of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA,
262, 907-13.
STRATH, S. J., KAMINSKY, L. A., AINSWORTH, B. E., EKELUND, U., FREEDSON, P. 
S. & GARY, R. A. 2013. Guide to the assessment of physical activity: Clinical and 
research applications: a scientific statement from the American Heart Association. 
Circulation, 128, 2259-79.
SWANK, A. M., HORTON, J., FLEG, J. L., FONAROW, G. C., KETEYIAN, S., 
GOLDBERG, L., WOLFEL, G., HANDBERG, E. M., BENSIMHON, D., ILLIOU, M. 
C., VEST, M., EWALD, G., BLACKBURN, G., LEIFER, E., COOPER, L., KRAUS, 
W. E. & INVESTIGATORS, H.-A. 2012. Modest increase in peak VO2 is related to 
better clinical outcomes in chronic heart failure patients: results from heart failure and 
a controlled trial to investigate outcomes of exercise training. Circ Heart Fail, 5, 579-
85.
TAGER, T., HANHOLZ, W., CEBOLA, R., FROHLICH, H., FRANKE, J., DOESCH, A., 
KATUS, H. A., WIANS, F. H., JR. & FRANKENSTEIN, L. 2014. Minimal important 
difference for 6-minute walk test distances among patients with chronic heart failure. 
Int J Cardiol, 176, 94-8.


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Protocol No. CLCZ696B3301
TEBBE, U., TSCHÖPE, C., WIRTZ, J. H., LOKIES, J., TURGONYI, E., BRAMLAGE, P., 
STRUNZ, A. M., LINS, K. & BÖHM, M. 2014. Registry in Germany focusing on 
level-specific and evidence-based decision finding in the treatment of heart failure: 
REFLECT-HF. Clin Res Cardiol, 103, 665-73.
TROOSTERS, T., MALTAIS, F., LEIDY, N., LAVOIE, K. L., SEDENO, M., JANSSENS, 
W., GARCIA-AYMERICH, J., ERZEN, D., DE SOUSA, D., KORDUCKI, L., 
HAMILTON, A. & BOURBEAU, J. 2018. Effect of Bronchodilation and Exercise 
Training with Behavior Modification on Exercise Tolerance and Downstream Effects 
on Symptoms and Physical Activity in COPD. Am J Respir Crit Care Med.
WALKE, L. M., BYERS, A. L., TINETTI, M. E., DUBIN, J. A., MCCORKLE, R. & FRIED, 
T. R. 2007. Range and severity of symptoms over time among older adults with 
chronic obstructive pulmonary disease and heart failure. Arch Intern Med, 167, 2503-8.
WILSON, J. R., HANAMANTHU, S., CHOMSKY, D. B. & DAVIS, S. F. 1999. 
Relationship between exertional symptoms and functional capacity in patients with 
heart failure. J Am Coll Cardiol, 33, 1943-7.
To be provided upon request
13
Appendix 1: Clinically notable laboratory values 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline.
Hemoglobin
> 50 % increase, > 20 % decrease
ALT
> 150 % increase
AST
> 150 % increase
Creatinine
> 50 % increase
Potassium
> 20 % increase, > 20 % decrease


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


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


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider patient hospitalization /specialized treatment
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at a 
new level with ±50% variability over last 6 months.
Please also refer to Appendix 6.
16
Appendix 4: Treatment guidelines for hyperkaliemia (serum 
potassium greater than or equal to 5.5 mmol/L)
General principles
Evaluation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken. 
Any patient with a serum potassium ≥ 5.5 mmol/L after enrollment into the study 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 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L). 
Patients with elevated potassium value will be managed according to the corrective actions 
outlined below. Hyperkalemia should be followed until resolution.
Corrective action for management of hyperkalemia
Serum potassium greater than 5.5 and lower than 6.0 mmol/L

Confirm potassium concentration in a non-hemolyzed sample 

Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes etc.) 

Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents: 

Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 


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
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 
trimethoprim/sulfamethoxazole fixed combinations 

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 mmol/L, regularly monitor serum potassium 
levels to ensure stability (suggested once monthly).

Consider down-titration of study medication, according to investigator’s medical 
judgment. 

Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment. 

Repeat serum potassium measurement after 2-3 days 

If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days 
Serum potassium greater than or equal to 6.0 mmol/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 ≥ 5.5 and < 6.0 mmol/L 
No resumption of study drug without individualized case discussion with and permission from 
Novartis medical monitor or his/her designee.


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17
Appendix 5: 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 
c. If hypotension persists, the study drug should be down-titrated or even temporarily 
withdrawn. The dose re-challenge and medications adjust guidelines described in 
Section 5.5.5 should be adhered to as much as possible. 
18
Appendix 6: Guidelines for the management of renal 
dysfunction
General principles: 
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study medication. Moreover, 
renal dysfunction may develop or may deteriorate in some patients after study drug 
administration. These recommendations have been developed to guide the investigators in 
managing patients with renal dysfunction after randomization. 
Two types of response to serum creatinine increase are described: 
Surveillance situation 
If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (Visit 2) (or if 
serum creatinine concentration increase to 2.5 mg/dL [221 μmol/L]), 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 serum creatinine levels

Volume decrease, including that resulting from excessive dosing of diuretics 

Urinary infection 

Urinary tract obstruction 

Study medication 


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Action situation 
If a patient eGFR decreases by ≥ 40% from baseline (Visit 2) (or if serum creatinine 
concentration rises above 3 mg/dL (265 μmol/L)), the investigator will check for potentially 
reversible causes of renal dysfunction (see above). 
If the investigator judges that study medication has to be stopped, he/she will have to contact 
the Novartis medical monitor or his/her designee. Thereafter, serum creatinine assessments 
will have to be repeated at least each week until levels return to acceptable values. If study 
medication was stopped, every effort will be done to restart it again, according to clinical 
conditions.

SAP_001.pdf: 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN
A multi-center, prospective, randomized, double-blind study to assess 
the impact of sacubitril/valsartan vs. enalapril on daily physical activity 
using a wrist worn actigraphy device in adult chronic heart failure 
patients 
Sponsor Study Code: CLCZ696B3301 / NCT02900378
 
 
Sponsor 
Novartis 
Product/Compound
Sacubitril/valsartan (LCZ696) 
Phase of the study 
IIIB 
Author 
, BSc, 
 
Company 
 
Address 
 
 
Telephone number 
Version 
Final 4 
Date 
12 DEC 2018 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
2 (37) 
SIGNATURES 
 
Sponsor Study code:  
 
CLCZ696B3301 
 
 
Author
 
 
 
 
Name, academic level, 
title: 
, BSc, 
  
 
Company 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
Add time to all dates if on the same 
day as unblinding. 
 
 
 
 
 
 
Reviewing Statistician
 
 
 
Name, academic level, 
title: 
, BSc, 
 
 
Company 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Approval
 
 
 
 
Name, academic level, 
title: 
Dr. 
 
  
 
Company 
Novartis 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
Name, academic level, 
title: 
  
 
Company 
Novartis 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
Name, academic level, 
title: 
 
 
 
Company 
Novartis 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
Date/time (xxxx-xxx-xx): 
 
 
 
 
 
 
SIGN
SIGN


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
3 (37) 
 
TABLE OF CONTENT 
 
1 
INTRODUCTION .................................................................................................. 6 
2 
STUDY OBJECTIVES ......................................................................................... 6 
3 
EFFICACY AND SAFETY ENDPOINTS .............................................................. 7 
3.1 
Primary Efficacy Endpoint ................................................................................. 7 
3.2 
Secondary Efficacy Endpoints .......................................................................... 8 
 
 8 
3.4 
Safety Endpoints ................................................................................................ 9 
4 
OVERALL STUDY DESIGN ................................................................................ 9 
4.1 
Overview of Study Design ................................................................................. 9 
4.2 
Determination of Sample Size ......................................................................... 10 
5 
DATA SETS TO BE ANALYSED....................................................................... 12 
6 
STATISTICAL AND ANALYTICAL PLANS ....................................................... 12 
6.1 
Changes in the Planned Analyses .................................................................. 12 
6.2 
Blind Review ..................................................................................................... 14 
6.3 
Hypotheses and Statistical Methods .............................................................. 14 
6.3.1 
Definitions ................................................................................... 14 
6.3.2 
Summary Statistics ...................................................................... 16 
6.3.3 
Patient/Subject Data Listings ....................................................... 17 
6.3.4 
Demographic and other Baseline Characteristics ........................ 17 
6.3.5 
Primary Efficacy analysis ............................................................. 17 
6.3.6 
Secondary Efficacy Analyses ...................................................... 19 
6.3.7 
Sensitivity analyses ..................................................................... 22 
6.3.8 
Exposure to Treatment ................................................................ 23 
6.3.9 
Concomitant Medication .............................................................. 23 
6.3.10 
Adverse Events ........................................................................... 23 
6.3.11 
Liver Events................................................................................. 24 
6.3.12 
Renal Events ............................................................................... 24 
6.3.13 
Other Safety Assessments .......................................................... 24 
6.4 
Level of Significance, Multiple Comparisons and Multiplicity ...................... 25 
6.5 
Adjustment for Covariates ............................................................................... 25 
6.6 
Handling of Dropouts and Missing Data ......................................................... 25 
6.7 
Multicentre Studies .......................................................................................... 26 
6.8 
Examination of Subgroups .............................................................................. 26 
6.9 
Interim Analysis ............................................................................................... 26 
6.10 
Data Monitoring ................................................................................................ 26 
7 
REFERENCES................................................................................................... 27 
8 
APPENDIX 1 ...................................................................................................... 27 
8.1 
Tables to be Produced for the Clinical Study Report (Section 14 
according to ICH E3) ...................................................................................... 27 
8.2 
Graphs (Section 14.2-14.3 in ICH E3) .............................................................. 35 
8.3 
Listings of Individual Subject Data and other Information to be Produced 
for the Clinical Study Report (Sections 16.1 and 16.2 according to ICH 
E3) ................................................................................................................... 36 
8.4 
US Archival Listings (Appendix 16.4 according to ICH E3) ........................... 37 
8.5 
Multiple Imputation: To select the most appropriate MI method .................. 37 
 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
4 (37) 
ABBREVIATIONS 
AE 
 
Adverse Event 
CI 
 
Confidence Interval 
CRF 
 
Case Report Form 
CSR 
 
Clinical study report 
ECG 
 
Electrocardiogram 
EMA 
 
European Medicines Agency 
FAS 
 
Full Analysis Set 
H0 
 
Null hyphotesis 
H1 
 
Alternative hyphotesis 
HF 
 
Heart failure 
HFrEF  
Heart failure with reduced ejection fraction 
HFpEF  
HF with preserved ejection fraction 
HFmrEF 
HF with mid-range ejection fraction 
ITT 
 
Intention to Treat 
IS 
 
Interdaily Stability  
IV 
 
Interdaily Variability  
LOCF  
Last observation carried forward 
LPLV  
Last patient last visit 
M6min  
Actigraphy-based measure of the peak six minutes of daytime physical activity 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
 
Multiple Imputation 
MSE 
 
Mean square error 
NYHA  
New York Heart Association  
NCPRA 
Non Parametric Circadian Rhythm Analysis  
PP 
 
Per Protocol 
PSW  
Premature Study Withdrawal 
Q1 
 
Percentile of 25% 
Q3 
 
Percentile of 75% 
QoL 
 
Quality of Life  
RS 
 
Randomized Set 
SAP 
 
Statistical Analysis Plan 
SAE 
 
Serious adverse events 
SD 
 
Standard deviation 
SE 
 
Standard error 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
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SMQs  
Standard MedDRA Queries 
SOC   
System Organ Class 
TEAE  
Treatment-emergent adverse events 
WHO   
World Health Organization 
6MWT  
6-Minutes walking test 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on Clinical Study Protocol (CLCZ696B3301) 
Version 04, dated September 11, 2018. 
This document describes the planned statistical methods for all safety and efficacy analyses 
which will be used in the phase IIIb clinical trial CLCZ696B3301. 
The purpose of this randomized, actively controlled, double-blind study with prospective data 
collection is to assess differences between sacubitril/valsartan versus enalapril in distance 
walked in a 6 minute walk test (6MWT) and increasing non-sedentary daytime physical 
activity in HFrEF patients. To this end, the 6MWT will be performed before the patients are 
randomized to any of the treatments and at 12 weeks of randomized treatment whereas 
physical activity will be continuously measured by means of a wrist-worn accelerometry 
device from 2 weeks before until 12 weeks after start of study therapy (sacubitril/valsartan or 
enalapril). 
The statistical analyses to be performed in this study were originally specified in the clinical 
study protocol. Further details of the planned statistical analysis are provided in this statistical 
analysis plan (SAP) that will be finalised prior to closing the data base. A summary of the 
contents will also be presented in the clinical study report (CSR). 
Please refer to the following document: 
Clinical Trial Protocol CLCZ696B3301 Version 04, dated September 11, 2018 
 
2 
STUDY OBJECTIVES 
Primary objectives 
• 
To elucidate the change in physical activity as assessed by the distance walked in meters 
during the 6-minute walking test between baseline and 12 weeks of study drug treatment 
in sacubitril/valsartan vs. enalapril patients. 
• 
To assess changes in daily non-sedentary daytime activity between baseline and after 12 
weeks of treatment in sacubitril/valsartan vs. enalapril treated patients. 
 
  
Secondary objectives 
• 
To compare the proportion of patients with improved performance (≥30m) in the 6-minute 
walking test at week 12 between sacubitril/valsartan vs. enalapril treated patients. 
• 
To demonstrate that sacubitril/valsartan is superior in improving exercise capacity as 
assessed by the six-minute walk test (6MWT) at week 12 in a subset of patients with 
baseline six-minute walk distance equal to or less than 300 meters 
• 
To demonstrate that sacubitril/valsartan is superior in improving exercise capacity as 
assessed by the six-minute walk test (6MWT) at week 12 in the patients with baseline 
six-minute walk distance between 100-450 meters. 
• 
To assess changes from baseline (week 0) in exercise capacity assessed by means of 
the 6-minute walking test at weeks 4, 8 and 12 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
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• 
To compare the effects of sacubitril/valsartan vs. enalapril on patients’ symptom 
progression by means of the Patient Global Assessment (PGA) questionnaire at week 4, 
week 8 and week 12. 
• 
To assess dynamics of changes from baseline in daily non-sedentary daytime physical 
activity in sacubitril/valsartan vs. enalapril treated patients in weekly and two-weekly 
intervals. 
• 
To assess changes from baseline in mean daily non-sedentary daytime physical activity 
classified by its intensity for sacubitril/valsartan vs. enalapril treated patients after week 4, 
week 8 and week12. 
• 
To assess the difference in non-sedentary daytime physical activity between 
sacubitril/valsartan vs. enalapril treated patients during the treatment period (weeks 0 to 
12). 
• 
To assess changes from baseline on M6min (an actigraphy-based measure of the peak 
six minutes of daytime physical activity) in sacubitril/valsartan vs. enalapril treated 
patients after week 4; week 8 and week 12. 
 
 
 
 
 
3 
EFFICACY AND SAFETY ENDPOINTS 
3.1 
Primary Efficacy Endpoint 
Change in distance walked in meters during the 6-minute walking test between baseline and 
‘end of study’. 
Change in mean daily non-sedentary daytime activity between baseline and ‘end of study’. 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
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3.2 
Secondary Efficacy Endpoints 
The secondary efficacy variables are the following:  
 
• 
6-minute walking test, proportion of patients with improved performance (≥ 30 m) from 
baseline (week 0) at week 12 
• 
6-minute walking test, proportion of patients with improved performance (≥ 30 m) from 
baseline (week 0) at week 12 in a subset of patients with baseline six-minute walk 
distance equal to or less than 300 meters 
• 
6-minute walking test, proportion of patients with improved performance (≥ 30 m) from 
baseline (week 0) at week 12 in a subset of patients with baseline six-minute walk 
distance between 100-450 meters. 
• 
6-minute walking test, changes from baseline (week 0) at weeks 4, 8 and 12 
• 
Proportion of patients who show increased levels (≥ 10% increase) of non-sedentary 
daytime physical activity at week 12 compared to baseline  
• 
PGA score at week 4, week 8 and week 12. 
• 
Proportion of patients with improved symptoms of HF as assessed by PGA 
• 
Change from baseline in mean daily non-sedentary daytime activity in weekly and 
two-weekly intervals  
• 
Proportion of patients at weekly and two-weekly intervals who show increased levels 
(≥ 10% increase) of mean daily non-sedentary daytime physical activity compared to 
baseline  
• 
Change from baseline in mean daily light and moderate-to-vigorous non-sedentary 
daytime physical activity between baseline and different time points under treatment. 
• 
Total weekly time spent in non-sedentary daytime physical activity. 
• 
Total weekly time spent in light non-sedentary daytime physical activity. 
• 
Total weekly time spent in moderate-to-vigorous non-sedentary daytime physical 
activity  
• 
Change from baseline in M6min (actigraphy-based measure of the peak six minutes 
of daytime physical activity). 
• 
Proportion of patients with increased M6min compared to baseline at week 4, week 8 
and week 12. 
 


 
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3.4 
Safety Endpoints 
The following safety variables will be measured: 
• 
All AEs, including treatment-emergent adverse events (TEAEs) 
• 
Laboratory data 
• 
Vital Signs 
• 
Treatment exposure and treatment compliance 
• 
Prior and concomittant drug/non-drug therapies 
• 
Physical examination 
• 
Diagnostic evaluations 
• 
Pregnancy and assessment fertility 
4 
OVERALL STUDY DESIGN 
4.1 
Overview of Study Design 
This is an international (European), randomized, actively controlled, double-blind, double-
dummy, interventional study with prospective data collection. The study comprises 6 visits 
over 14 weeks. Adult patients with symptomatic HFrEF (NYHA classes II or III/IV at a 1:1 
ratio) managed in an ambulatory setting (i.e. by primary care physicians, office based 
cardiologists, HF outpatient clinics) will be randomized in a 1:1 allocation to receive 
sacubitril/valsartan or enalapril during the double-blind period. Actigraphy will be performed 
during the entire duration of the study by means of a wrist-worn accelerometry device; the 
device will be worn continuously for two weeks prior to randomization in order to obtain an 
individual baseline for each patient, and throughout the treatment period of the study (12 
weeks). Figure 4-1 depicts the study design along with the treatment and visit schedule. 
 


 
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Figure 4-1 Study design  
AVERAGE DAY TIME/NIGHT TIME ACTIVITY
ACTIVITY COUNTS PER MINUTE
Screening
-2 w
0 w
2 w
4 w
6 w
8 w
10 w
12 w
ACEI/ARB³
enalapril²
sacubitril/valsartan1
Level 1 (<178.5 counts/minute)
Sedentary activities: sitting, reclining positions
Level 2 (178.5 - 565.5 counts/minute) 
Light activities: standing, slow walking
Level 3 (> 562.5 activity counts / minute)
•
Vigorous activities: hiking, jogging, soccer, basketball
•
Moderate activities: brisk walking, cleaning, mowing
Randomization
w
o
Background HF medication as per local practice






Mean daily activity and sleep profiles, calculated
over 14 day periods (for certain endpoints 7 days)
Actigraphy via wrist-worn accelometer
Visits
Ø
Baseline
 
1-2 sacubitril/valsartan or enalapril (double-blind study drugs) will be given at dose levels (up-titration) depending on pre-study 
ACEI/ARB doses.  
3Pre-study ACEI and/or ARB are replaced by study medication after Visit 2. Therefore washout period (WO) of 36 hours is 
required; it should start 12 hours before Visit 2 (randomization); the first study treatment intake should be 24 hours after Visit 2.  
All other HF background and CV medications (e.g. beta blockers, MRAs etc.) and symptomatic treatment (e.g. diuretics) the 
patient has been taking should remain unchanged throughout the study, if possible and medically justified in the judgement of 
the investigator. 
“Background HF medication per local practice”: patients must be on stable HF treatment regimen for at least 4 weeks prior Visit 
1. After Visit 1, patients shall retain their pre-study HF treatment for another 2 weeks (week -2 to week 0) for baseline actigraphy 
recording. 
4.2 
Determination of Sample Size 
There are no published data on a possible effect of a drug intervention on physical activity as 
measured by accelerometer in HFrEF patients. However, Alosco and colleagues observed 
patients with HF over a period of 12 weeks and reported activity levels at baseline and after 
12 months using a similar accelerometry device (Alosco, Spitznagel et al. 2015). The mean 
activity time in light intensity was 188 min/day (SD = 56) at baseline and 183 min/day (SD = 
58) after 12 weeks. The corresponding values for activity in moderate to vigorous intensity 
were 46 min/day (SD = 35) at baseline and 41 min/day (SD = 30) after 12 weeks. From these 
data an average of 234 min/day at baseline and 224 min/day after 12 weeks can be 
concluded for the non-sedentary daily activity time. The observed standard deviations for 
sedentary daily activity time were 76 min/day (baseline) and 63 min/day (month 12), 
respectively. From these values the standard deviation for non-sedentary activity time (which 
is approximately the same as for sedentary activity time) is estimated as SD = 70 min/day for 
both time points. 


 
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For the present study we assume a mean baseline value of 200 to 230 min/day for both 
treatment groups. If treatment with sacubitril/valsartan leads to an improvement which is at 
least 20 min/day higher than the changes under enalapril, this is considered as clinically 
relevant. 
The standard deviation for the changes from baseline is expected not to be larger than the 
standard deviations at the two respective visits (corresponding to a correlation coefficient of 
0.5 between the values at baseline and at week 12 to 14). Accordingly, the standard 
deviation for the primary endpoint is estimated as SD = 70 min/day for both treatment 
groups. 
Planning a two-sided test (using the t-test model with α = 5% and 90% power at ∆ = 20 
min/day) results in 259 patients per treatment group (nQuery Advisor® 7.0). In order to 
account for non-eligible patients, it is planned to recruit 300 patients per treatment arm, i.e. 
600 patients in total. 
With respect to other primary endpoint "change in 6-minute walk test between baseline and 
weeks 4, 8 and 12week 12", the following sample size considerations apply: From Täger et 
al. we deduce a minimal important difference of 35 meters at week 12 and a standard 
deviation of 114 meters (Tager, Hanholz et al. 2014). Planning a two-sided test with α = 0.05 
and 90% power for a group difference of 35 meters leads to a sample size of 224 patients 
per group, which is covered by the planned patient numbers. 
After defining the primary hypotheses H1 and H2, to control the familywise error rate at level 
5%, the Hochberg procedure will be used to test the primary hypotheses. It will reject both 
H1 and H2, if both of them are significant at level 5% simultaneously. Otherwise, it will reject 
H1 if it is significant at level α/2, or reject H2 if it is significant at level α/2. 
 
Table 9-1 
Power of the study considering both the end-points – Considering 259 
subjects in each arm 
 
Correlation 
between the two 
end-points 
Power to reject 
H1 
Power to reject 
H2 
Power to reject 
any of H1 and H2 
Power to reject 
both of H1 and 
H2 
0 
89.7% 
93% 
98.5% 
84.4% 
0.2 
89.5% 
93% 
97.6% 
85% 
0.4 
89.4% 
93% 
96.5% 
85.7% 
0.5 
89.3% 
93% 
96% 
86% 
For power calculations, H1 is based on accelerometry data end-point while H2 is based on the 6 
minutes walking test end-point. 
 
Table Error! No text of specified style in document.-2 
Power of the study considering 
both the end-points – Considering 300 subjects in each arm 
 
Correlation 
between the two 
end-points 
Power to reject 
H1 
Power to reject 
H2 
Power to reject 
any of H1 and H2 
Power to reject 
both of H1 and 
H2 
0 
93.6% 
96.2% 
99.4% 
90.4% 
0.2 
93.5% 
96% 
99% 
90.6% 
 


 
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5 
DATA SETS TO BE ANALYSED 
The following analysis sets will be used for the statistical analysis and presentation of data:  
 
The screen set (SCR) comprises all patients who have signed the informed consent. 
 
The Randomized Set (RS) consist of all patients who had been randomized in the study. 
 
The safety data set (SAF) consists of all patients who have received the study medication at 
least once. Safety analyses will be performed based on the SAF set, and according to the 
treatment received. 
 
The full analysis set (FAS) comprises all patients of the safety data set who provide the 
baseline value and any post-baseline value of at least one primary endpoint (6-minute 
walking test or daily non-sedentary daytime activity). 
 
The per-protocol (PP) data set includes all patients of the FAS who do not have any major 
deviations from the protocol. Such deviations will be defined in the Data Validation Plan or 
similar document and in the protocol of the blind data review without knowledge of the 
treatment group assignment. Patients with more than 12 days between last dose 
administration date and 6MWT date at visit 6 will be excluded from the per-protocol (PP). 
 
Efficacy analyses will be conducted based on FAS and PP, and according to the treatment 
patients were randomized to. 
 
6 
STATISTICAL AND ANALYTICAL PLANS 
The planned tables and listings are presented in Appendix 1. 
6.1 
Changes in the Planned Analyses 
Following sleep parameters are not possible to be collected as defined in protocol 
• 
Mean daily sleep efficiency 
• 
Mean daily time in bed 
• 
Actual sleep time 
• 
Actual wake time 
• 
Sleep latency. 
• 
Mean daily sleep fragmentation, defined as the sum percent mobile time and percent 
immobile bouts of ≤ 1 min duration 
 
In order to give more information about the actigraphy data and the evolution of the patients 
during the study, new variables (Non Parametric Circadian Rhythm Analysis (NPCRA)) will 
be add to the analysis. 


 
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Non Parametric Circadian Rhythm Analysis (NPCRA): Long-term recordings of activity levels 
show a rhythmic pattern with alternating high levels of activity during the day and low levels 
of activity during the night. Such alternating patterns are known as circadian rhythms, from 
the Latin words ‘circa’ (approximately) and ‘dies’ (day). These rhythms are not only present in 
activity levels but also in hormone levels, body temperature and virtually all measurable 
biological events, including molecular, physiological, behavioral and cognitive phenomena. 
The specific characteristics of circadian rhythms may be of interest to researchers and 
clinicians, and thus need to be quantified. Many circadian rhythms resemble a cosine wave, 
and indeed there is a long tradition in circadian rhythm research to fit a cosine curve to the 
data, and to use the mesor (mean), amplitude and phase of the fitted curve as variables of 
interest. One may for example be interested whether a patient group differs from a control 
group on their average mesor, amplitude or phase. The method is known as Cosinor-
analysis. 
Activity data, however, seldom resemble a cosine wave, and it is consequently not 
appropriate to apply Cosinor-analysis in order to obtain valid parameters describing the 
rhythms. Therefore, a number of alternative quantification methods have been developed. 
These methods do not suppose the rhythm to have a cosine-like shape. Details on the 
mathematics and usefulness of the measures can be found in e.g. (Van Someren et al., 
1996; Van Someren et al., 1997a; Van Someren et al., 1997b; Van Someren et al., 1998; 
Van Someren et al., 1999). 
NPCRA Variables – Interdaily Stability (IS) 
A first nonparametric variable is the Interdaily Stability (IS). This variable quantifies the 
degree of resemblance between the activity patterns on individual days. If, for example, a 
subject has a very rigid schedule of getting up in the morning every day at the same time, 
and shows activity and rest periods every day at the same time, this will result in a high 
Interdaily Stability. The measure theoretically ranges from 0 to 1, and may typically be about 
0.6. A higher value indicates a more stable rhythm. The variable has shown to be sensitive to 
rhythm changes in Alzheimer’s dementia: whereas normal human aging is associated with 
rather regular or even rigid daily activity schedules, demented elderly may show very 
different profiles from day to day. 
NPCRA Variables – Intradaily Variability (IV) 
Another nonparametric variable is the Intradaily Variability (IV). This variable quantifies the 
fragmentation of periods of rest (or sleep) and activity (or wakefulness). Healthy subjects 
usually show one prolonged activity period and one prolonged rest period in every 24-hour 
cycle. Under certain conditions, as high age and Alzheimer’s dementia, the periods of rest 
and activity may become shorter, or fragmented, for example due to naps during the day and 
periods of nocturnal restlessness. The measure theoretically ranges from 0 to 2, with higher 
values indicating a more fragmented rhythm, and typically is below 1. 
NPCRA Variables – L5 and M10 
As mentioned before, it is not appropriate to fit a cosine wave to activity data. However, one 
may still want to have an indication of the trough level, peak level, amplitude, and phase of 
the rhythm. Useful nonparametric variables have been developed in order to quantify these 
rhythm phenomena. They are all based on an average 24-hour curve, calculated by 
overlaying all available 24-hour periods. In this 24-hour average curve, the sequence of the 
five least active hours is denoted ‘L5’. The average activity during these five hours gives an 
indication of the trough or nadir of the rhythm, i.e. how restful and regular the rest (sleep) 
periods are. The time of onset of the sequence marks the phase of the onset of the most 
restful five hours. 


 
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In a similar way, the sequence of the ten most active hours is denoted ‘M10’. The average 
activity during these ten hours gives an indication the peak of the rhythm, i.e. of how active 
and regular the activity (wake) periods are. The time of onset of the sequence marks the 
phase of the onset of the most active ten hours. 
NPCRA Variables – Amplitude 
The difference between the average activity level during M10 and the average activity level 
during L5 gives an indication of the amplitude of the rhythm, and is denoted as ‘AMP’. This 
measure is sensitive to the overall level of activity, which is not always wanted. For example, 
if one measures activity on the trunk instead of the wrist, the activity level will drop both 
during the day and during the night, resulting in a ‘smaller’ amplitude. 
As a correction for the offset in sensitivity to movements, one may prefer to use the relative 
amplitude (RA), which is calculated by dividing AMP by the sum of L5 and M10. The 
measure theoretically ranges from 0 to 1, with higher values indicating a rhythm of higher 
amplitude. 
 
6.2 
Blind Review 
The blind review meeting will be held before database closure and before breaking the blind 
to make final assessments of which patients should be included in the analysis sets and 
other decisions regarding the statistical analysis. 
Protocol deviations observed and documented during the study (Protocol deviation log from 
the study site and observed during the data validation) will be listed in Section 16 of the CSR. 
Patients with major protocol deviations will be excluded from the PP population.  
All relevant listings and tables prepared for the data review meeting will be verified for 
consistency and correctness by the study data manager and the statistician 
 and the 
Sponsor before the database is locked. 
Apart from the data review meeting after LPLV, other data review meetings during the study 
may be done if appropriate to review protocol deviations and identify trends or recurrent 
queries within or across sites/countries. 
 
6.3 
Hypotheses and Statistical Methods 
6.3.1 
Definitions 
 
Study baseline  
 
For all objectives/endpoints assessed by means of actigraphy, the baseline value is obtained 
over a period of two weeks prior to randomization, i.e. week -2 to week 0. 
 
Parameters collected in both Visit 1 and Visit 2: for assessments (Vital signs, NYHA class, 
 and laboratory evaluations) the last non-missing assessment prior to the first dose will 
be considered as the baseline value in order to calculate the changes between baseline visit 
and following visits.  
 


 
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Actigraphy 
Actigraphy is a non-invasive method of monitoring human physical activity patterns. 
Actigraphy will be performed in this study by means of a wrist-worn device that collects data 
on activity (by means of tri-axial accelerometry). The device (MotionWatch8®, CamNtech, 
Cambridge, UK) collects the data on movement continuously in 30-second bins. The device 
is lightweight and waterproof and worn on the wrist of the non-dominant arm continuously (24 
hours/day) for the entire study duration. Based on accelerometry for each 30-second bin, 
activity counts for each minute of each day are generated. Higher counts reflect a higher 
level of activity. For an elderly population, cut-off values for activity counts per minute 
defining the intensity of physical activity have previously been defined (Landry, Falck et al. 
2015) . These cut-off values will be used to define sedentary, light and moderate to vigorous 
activity counts for each minute the device is worn. Sedentary activity is defined as < 178.5 
activity counts per minute; light activity as 178.5 – 565.5 activity counts/minute and > 565.5 
activity counts/minute define moderate to vigorous physical activity (see also Figure 3-1). 
The time patients spend in a given activity intensity category will be recorded and represents 
the basis for all endpoints that are derived from actigraphy. Where appropriate, activity data 
will be integrated over 2-week intervals (i.e. baseline non-sedentary physical daytime activity 
is the mean time per day the patient spent in non-sedentary activity during the daytime 
during the 14 days of baseline recording (week -2 to week 0).  
 
M6min 
M6min is a parameter derived by validated algorithms of the software that will be used to pre-
process actigraphy data. The parameter reflects the peak 6 minutes of physical activity. The 
mean daily M6min will be calculated over 14 day epochs. 
 
Actigraphy measurements 
All variables needed for actigraphy objectives will be calculated using CamNtech Motionware 
1.2.18 software or latest version.  
• 
Mean daily non-sedentary daytime activity  
• 
Mean daily light and moderate-to-vigorous non-sedentary daytime physical activity 
• 
Total weekly time spent in non-sedentary daytime physical activity. 
• 
Total weekly time spent in light non-sedentary daytime physical activity. 
• 
Total weekly time spent in moderate-to-vigorous non-sedentary daytime physical 
activity 
• 
M6min 
• 
Interdaily Stability (IS) 
• 
Intradaily Variability (IV) 
• 
L5 average 
• 
M10 average 
• 
Relative Amplitude 
 
Six minute walking test  
The distance covered by the patient walking during 6 minutes will be determined and 
recorded at Visit 2, Visit 4, Visit 5 and Visit 6.  
The assessment is performed according to the current standards (Tager, Hanholz et al. 
2014) and will be provided as a separate manual to all sites. In brief – patients are instructed 


 
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to walk down a long corridor at their own pace, attempting to cover as much distance as 
possible within 6 minutes. At the end of the 6 minute duration, the walked distance is 
calculated and recorded along with the symptoms experienced by the patient. It is crucial that 
patients are allowed to rest, before the test is performed – therefore the 6-minute walking test 
should be done as the last assessment at the respective visits.  
 
Patient Global Assessment (PGA)  
The Patient Global Assessment (PGA) is a self-reported tool to assess the patients’ 
subjective rating of their disease activity widely used in HF research and other indications. It 
has been shown that the PGA responses of CHF patients correlate the patients’ functional 
capacity assessed by means of the 6-minute walk test (Cooper, Anker et al. 2016).  
The patients are asked to report functioning or response to an intervention by rating their 
current condition compared to their pre-intervention condition on a numerical scale:  
1) much improved 2) moderately improved 3) a little improved 4) unchanged 5) a little worse 
6) moderately worse or 7) much worse.  
This self-assessment will be completed by the patients in a quiet environment, before any 
study assessment or drug dispensing at Visit 4, Visit 5 and Visit 6.  
 
 
6.3.2 
Summary Statistics 
In general, categorical data will be summarized with number of missing values, frequencies 
and percentages, while continuous data will be reported using number of patients, number of 
missing values, mean, standard deviation (SD), median, Q1, Q3, minimum and maximum.  
Minimum and maximum values will be provided with the same level of accuracy as raw data; 
means and medians will be provided with an additional decimal place and SD with 2 
additional decimal places. 
For secundary objectives and continuous variables, the 95% CI will be added to the 
statistics. 
Comparing continuous variables between groups, if the variable has a normally distributed 
data a two sample (independent group) t-test will be used, but if the variable has a non-
Normally distributed data then the non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank 
sum) test will be applied. 


 
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Comparing proportions of a categorical outcome between groups of treatment: ussually chi-
square test will be used, but when more than 20% of cells have expected frequencies < 5 the 
Fisher's exact test will be applied. 
 
6.3.3 
Patient/Subject Data Listings 
Data collected in the CRF will generally be listed in Appendix 16.2 (see section 8.3). CRF 
check questions [e.g. lab samples taken (Yes/No)] and reminders will not be listed. 
In CRF modules where a date is recorded, the date and also the relative day may be printed 
in the corresponding listing. In modules where both a start date and stop date is recorded, 
also a duration may be included in the listing. 
 
6.3.4 
Demographic and other Baseline Characteristics 
Subject disposition i.e. number and percentage of patients randomized, screening failures 
i.e. patients who discontinued at screening, patients who discontinued the study and 
discontinued the treatment and the reasons for premature discontinuation will be presented 
for all consented patients. Number of patients enrolled by country and number of patients 
with at least one major protocol deviation will be listed. 
Patients included in the analysis populations and reasons for exclusion and inclusion/ 
exclusion criteria will also be tabulated for all consented patients. 
All background data such as patient demographics (sex, age, age groups (<65 years vs ≥ 65 
years), race, ethnicity, source of patients’ referral, living conditions, smoking status, relevant 
medical history/conditions at baseline by body system, previous drug/non-drug therapy of HF 
and pregnancy test) will be described by presenting absolute and relative frequency and/or 
summary statistics for continuous data.  
Besides, weight, height, body mass index (BMI), NYHA class and actigraphy variables (Mean 
daily non-sedentary daytime activity, Mean daily light and moderate-to-vigorous non-
sedentary daytime physical activity, Total weekly time spent in non-sedentary daytime 
physical activity, Total weekly time spent in light non-sedentary daytime physical activity, 
Total weekly time spent in moderate-to-vigorous non-sedentary daytime physical activity, 
M6min, Interdaily Stability (IS), Intradaily Variability (IV), L5 average, M10 average, Relative 
Amplitude will be summarized. BMI will be calculated as weight (kg) / height² (m²) from the 
collected height and weight at the screening Visit. 
 
6.3.5 
Primary Efficacy analysis 
One of the primary end-points is the change from baseline to ‘end of study’ in the 6-minute 
walking test.  
The aim of the primary analysis of this study is to assess differences between 
sacubitril/valsartan and enalapril patients with respect to the primary endpoint in the FAS 
population excluding the patients who have an AE/SAE (non-HF related) during/around the 
6-minute walking test which directly is causally linked to the 6-minute walking test 
performance. 
 
Change from baseline values will be summarized. The comparison of treatment groups will 
be carried out using an ANCOVA model adjusting for treatment and baseline NYHA class 
(NYHA II vs. III/IV) and the baseline value as covariates.  


 
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The following hypothesis will be tested: 
H0: µ0 = µ1 vs. H1: µ0 ≠ µ1 
 
Where  0 corresponds to treatment with sacubitril/valsartan and 1 corresponds to treatment 
with enalapril. 
 
6MWT0 = 6-minute walking test at baseline (week 0). 
6MWT1 = 6-minute walking test EOS (week 12). 
6MWTch = change in 6-minute walking test from baseline (6MWT1  - 6MWT0). 
GROUPk =   treatment group. 
NYHA0i = baseline NYHA class 
 
ANCOVA model: 
 
6MWTchi = µ+ GROUPk+ 6MWT0i + NYHA0i + eik 
 
where: 
6MWTchi: change in 6-minute walking test for each subject i. 
µ: global mean 
GROUPk: treatment group 
6MWT0i = 6-minute walking test baseline (week 0) value for each subject i. 
NYHA0i = NYHA class baseline value for each subject i. 
eik: associated unobserved error term. 
 
Other primary endpoint is the change from baseline to ‘end of study’ in mean daily non- 
sedentary daytime activity (defined as ≥178.50 activity counts per minute) as calculated by 
the MotionWatch 8 accelerometer device. Baseline is defined as the average minutes per 
day in non-sedentary daytime activity over 2 weeks (week -2 to week 0) prior to 
randomization and ‘end of study’ is defined as the average minutes per day in non-sedentary 
daytime activity between week 10 to week 12. 
The aim of the primary analysis of this study is to assess differences between 
sacubitril/valsartan and enalapril patients with respect to the primary endpoint in the FAS with 
MI . 
 
Change from baseline values will be summarized. The comparison of treatment groups will 
be carried out using an ANCOVA model adjusting for treatment and baseline NYHA class 
(NYHA II vs. III/IV) and the baseline value as covariates.  
 
The following hypothesis will be tested: 


 
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H0: µ0 = µ1 vs. H1: µ0 ≠ µ1 
 
Where  0 corresponds to treatment with sacubitril/valsartan and 1 corresponds to treatment 
with enalapril. 
 
DNSDA0 = daily non- sedentary daytime activity baseline (week -2 to week 0). 
DNSDA1 = daily non- sedentary daytime activity EOS (week 10 to week 12). 
DNSDAch = change in daily non-sedentary daytime activity from baseline (DNSDA1  - 
DNSDA0). 
GROUPk =   treatment group. 
NYHA0i = baseline NYHA class 
 
ANCOVA model: 
 
DNSDAchi = µ+ GROUPk+ DNSDA0i + NYHA0i + eik 
 
where: 
DNSDAchi: change in daily non- sedentary daytime activity for each subject i. 
µ: global mean 
GROUPk: treatment group 
DNSDA0i = daily non- sedentary daytime activity baseline (week -2 to week 0) value for each 
subject i. 
NYHA0i = NYHA class baseline value for each subject i. 
eik: associated unobserved error term. 
 
6.3.6 
Secondary Efficacy Analyses 
 
Proportion of patients with improved performance (≥ 30 m) in 6-minute walking test at week 
12 compared to baseline. The comparison of patient groups will be carried out using logistic 
regression model with factors treatment and baseline NYHA class (NYHA II vs. III/IV) and the 
baseline value as further covariate. The Odds Ratio for the factor treatment and its 95%-
confidence interval will be given. 
 
Proportion of patients with improved performance (≥ 30 m) in 6-minute walking test at week 
12 compared to baseline in a subset of patients with baseline 6-minute walk distance equal 
to or less than 300 meters. The comparison of patient groups will be carried out using logistic 
regression model with factors treatment and baseline NYHA class (NYHA II vs. III/IV) and the 
baseline value as further covariate. The Odds Ratio for the factor treatment and its 95%-
confidence interval will be given. 
 


 
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Proportion of patients with improved performance (≥ 30 m) in 6-minute walking test at week 
12 compared to baseline in a subset of patients with baseline 6-minute walk distance 
between 100-450 meters. The comparison of patient groups will be carried out using logistic 
regression model with factors treatment and baseline NYHA class (NYHA II vs. III/IV) and the 
baseline value as further covariate. The Odds Ratio for the factor treatment and its 95%-
confidence interval will be given. 
 
Score of 6-minute walking test will be summarised at baseline, week 4, week 8 and week 12. 
Change from baseline values will be presented. The comparison of patient groups at week 
12 compared to baseline will be analyzed using a two sample (independent group) t-test or a 
non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test, where applicable. 
 
Proportion of patients who show increased levels (≥ 10% increase) of non-sedentary daytime 
physical activity at week 12 compared to baseline. The comparison of patient groups will be 
carried out using logistic regression model with factors treatment and baseline NYHA class 
(NYHA II vs. III/IV) and the baseline value as further covariate. The Odds Ratio for the factor 
treatment and its 95%-confidence interval will be given. 
 
PGA scores will be tabulated at week 4, week 8 and week 12. The comparison of patient 
groups at week 4, week 8 and week 12 will be analyzed using a chi-square test or Fisher’s 
exact test, where applicable. 
 
Proportion of patients with improved symptoms of HF as assessed by PGA, number and 
proportion will be tabulated at week 4, week 8 and week 12. The comparison of patient 
groups will be presented and analyzed using a chi-square test or Fisher’s exact test, where 
applicable. 
 
Change from baseline in mean daily non-sedentary daytime activity in weekly and two-
weekly intervals will be summarised. The comparison of patient groups will be analyzed 
using a two sample (independent group) t-test or a non-parametric Mann–Whitney–Wilcoxon 
(Wilcoxon rank sum) test, where applicable. 
 
Proportion of patients at weekly and two-weekly intervals who show increased levels (≥ 10% 
increase) of mean daily non-sedentary daytime physical activity compared to baseline will be 
tabulated. The comparison of patient groups will be presented and analyzed using a chi-
square test or Fisher’s exact test, where applicable. 
  
Change from baseline in mean daily light and moderate-to-vigorous non-sedentary daytime 
physical activity between baseline and different time points under treatment (weekly or two-
weekly from week 0 to week 12) will be summarised. The comparison of patient groups will 
be analyzed using a two sample (independent group) t-test or a non-parametric Mann–
Whitney–Wilcoxon (Wilcoxon rank sum) test, where applicable. 
 
Total weekly time spent in non-sedentary daytime physical activity will be summarised by 
week, from week 0 to week 12. The comparison of patient groups will be analyzed using a 
two sample (independent group) t-test or a non-parametric Mann–Whitney–Wilcoxon 
(Wilcoxon rank sum) test, where applicable. 
 
Total weekly time spent in light non-sedentary daytime physical activity will be summarised 
by week, from week 0 to week 12. The comparison of patient groups will be analyzed using a 


 
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two sample (independent group) t-test or a non-parametric Mann–Whitney–Wilcoxon 
(Wilcoxon rank sum) test, where applicable. 
 
Total weekly time spent in moderate-to-vigorous non-sedentary daytime physical activity will 
be summarised by week, from week 0 to week 12. The comparison of patient groups will be 
analyzed using a two sample (independent group) t-test or a non-parametric Mann–Whitney–
Wilcoxon (Wilcoxon rank sum) test, where applicable. 
 
M6min (an actigraphy-based measure of the peak six minutes of daytime physical activity) 
will be summarised at baseline, week 2, week 4, week 6, week 8, week 10 and week 12. 
Change from baseline values will be presented. The comparison of patient groups at week 
12 compared to baseline will be analyzed using a two sample (independent group) t-test or a 
non-parametric Mann–Whitney–Wilcoxon (Wilcoxon rank sum) test, where applicable. 
 
Proportion of patients with increased M6min (an actigraphy-based measure of the peak six 
minutes of daytime physical activity) compared to baseline at week 4, week 8 and week 12 
will be tabulated. The comparison of patient groups will be presented and analyzed using a 
chi-square test or Fisher’s exact test, where applicable. 
 
 
 


 
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6.3.7 
Sensitivity analyses 
6-minute walking test: 
For the main analysis the patients who have an AE/SAE (non-HF related) during/around the 
6-minute walking test which directly is causally linked to the 6-minute walking test 
performance will be remove. A sensitivity analysis will be performed including all patients for 
each population. 
Main analysis for 6-minute walking test primary variable: 
FAS population subset patients without AE/SAE (non-HF related) during/around the test 
Sensitivity analyses for 6-minute walking test primary variable: 
FAS population 
PP population  
PP population subset patients without AE/SAE (non-HF related) during/around the test 
 
Mean daily non-sedentary daytime activity: 
In addition to the primary analysis, the primary efficacy variables will also be analyzed using 
the same analysis model in the PP population as supportive. Furthermore, the analysis of the 


 
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primary variable (mean daily non-sedentary daytime activity) will be repeated in the FAS 
population without MI of missing values. 
Besides, the last-observation-carried-forward principle (LOCF) imputation method will be 
performed as a sensitivity analysis (Section 6.6). 
 
Main analysis for mean daily non-sedentary daytime activity primary variable: 
FAS population with MI  
Sensitivity analyses for mean daily non-sedentary daytime activity primary variable: 
PP population with MI  
PP population with LOCF 
PP population without MI 
FAS population without MI/LOCF 
FAS population with LOCF 
 
6.3.8 
Exposure to Treatment 
The duration of exposure (in weeks) to the study treatment i.e. number of weeks study drug 
was taken as per protocol will be summarized by treatment for the safety population (SAF).  
The number and percentage of patients will be tabulated by treatment group for duration 
(categorized by weeks), defined as  
(Last dose date – First dose date* + 1) / 7 
*First dose date is not collected in the eCRF, we wil use the visit 2 date as a first dose date because it is the 
administration date. 
 
Study drug compliance will be summarized for all patients in the SAF by visit, separately by 
treatment group. The study drug compliance is assessed at each  visit by the investigator.  
Additionally, the number and percentage of patients will be tabulated by visit and treatment 
group for compliance category (categorized in <80% and 80-100%). 
 
6.3.9 
Concomitant Medication 
Concomitant medications will be summarized by the preferred term as coded by the World 
Health Organization Drug (WHODRUG) dictionary for the SAF population. 
 
6.3.10 
Adverse Events  
Treatment emergent adverse events TEAEs (events started on or after the first dose date of 
study treatment or events present prior to the first dose of study treatment but increased in 
severity based on preferred term) will be summarized. Only primary paths within MedDRA 
will be considered for TEAEs reporting.  
TEAEs will be summarized by presenting, for each treatment group, the number and 
percentage of subjects  
• 
having any TEAEs,  
• 
having a TEAEs in each primary system organ class and 


 
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• 
having each individual TEAEs (preferred term).  
Summaries will also be presented for TEAEs by severity and for study treatment related 
TEAEs. If a subject reported more than one adverse event with the same preferred term, the 
adverse event with the greatest severity will be presented. If a subject reported more than 
one adverse event within the same primary system organ class, the subject will be counted 
only once with the greatest severity at the system organ class level, where applicable.  
Separate summaries will be provided for death, serious adverse event, adverse events 
leading to discontinuation and adverse events leading to dose adjustment (including study 
treatment discontinuation). 
A listing of all AEs will be presented, whether treatment emergent or not. 
 
6.3.11 
Liver Events  
 
Number and percentage of patients with liver events and information related with the events 
will be tabulated  
A listing of all liver events will be presented. 
6.3.12 
Renal Events  
 
Number and percentage of patients with renal events and information related with them will 
be tabulated  
A listing of all renal events will be presented. 
 
6.3.13 
Other Safety Assessments 
Vital Signs 
Analysis of the vital sign (blood pressure and pulse) measurements using summary statistics 
for the change from baseline for each post-baseline visit will be performed. These descriptive 
summaries will be presented by vital sign and treatment group. Change from baseline will 
only be summarized for subjects with both baseline and post-baseline values. All information 
collected will be listed by subject and abnormal values be flagged. 
Clinical Laboratory Measurements 
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data 
and change from baseline values (mean, medians, standard deviations, ranges) and by the 
flagging of notable values in data listings. 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline. 
Hemoglobin 
 
> 50 % increase, > 20 % decrease 
ALT 
 
 
> 150 % increase 
AST 
 
 
> 150 % increase 
Creatinine 
 
> 50 % increase 


 
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Potassium 
 
> 20 % increase, > 20 % decrease 
 
6.4 
Level of Significance, Multiple Comparisons and Multiplicity 
All statistical hypotheses will be two-sided and will be performed using a 5% significance 
level. 
No adjustment for multiple comparisons or corrections for multiplicity are planned. 
6.5 
Adjustment for Covariates 
Statistical analyses for efficacy endpoints including ANCOVA model with covariates are 
detailed in Sections 6.3.4 and 6.3.5 of this document. 
6.6 
Handling of Dropouts and Missing Data 
For patients who do not have the baseline values or patients who drop out prematurely 
and/or do not have a valid measurement in mean daily non-sedentary daytime activity 
between weeks 10-12, a Multiple Imputation (MI) method will be used for the primary 
analysis. For the key secondary variable the same imputation strategy will be used. 
Multiple imputation (MI) 
The MI procedure in the SAS Software is a multiple imputation procedure that creates 
multiply imputed data sets for incomplete p-dimensional multivariate data. It uses methods 
that incorporate appropriate variability across the m imputations. Once the m complete data 
sets are analyzed by using standard procedures, the MIANALYZE procedure can be used to 
generate valid statistical inferences about these parameters by combining results from the m 
complete data sets: 
• 
The missing data are filled in m times to generate m complete data sets. 
• 
The m complete data sets are analyzed by using standard procedures. 
• 
The results from the m complete data sets are combined for the inference. 
 
The MI process through SAS software: 
1. 
To explore missing data patterns 
PROC MI DATA=example NIMPUTE=0; 
VAR [list of variables];  
RUN; 
2. 
To select the most appropiate MI method (see appendix 8.5) 
3. 
Process of imputation with PROC MI. Imputation step 
4. 
SAS statistical procedure to analyze each MI repetition (MIXED,MEANS, GENMOD). 
Analysis step 
5. 
Finally, the MIANALYZE procedure combines the results and provides valid statistical 
inferences. Pooled step. 
Sensitivity analysis LOCF. For patients who drop out prematurely and/or do not have a valid 
measurement in mean daily non-sedentary daytime activity between weeks 10-12, the last 


 
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available value of non- sedentary daytime activity over two weeks under treatment will be 
used for the primary analysis (last-observation-carried-forward principle, LOCF). Patients 
with major protocol violations, but with a valid assessment of the primary variable will be 
included in the primary analysis with their observed value. For the key secondary variable the 
same imputation strategy will be used. 
For the analyses of further secondary and of the exploratory endpoints referring to data at 
‘end of study’ the same algorithm will be applied to create an extra LOCF visit next to the 
usual Week 12 visit. This additional ‘end of study’ measure constitutes a conservative 
approach in handling of missing data and ensures much as possible unbiased and 
comparable efficacy results. 
In case of qualitative (e.g., increased level of non-sedentary daytime physical activity) or 
semi-quantitative (e.g., PGA) efficacy variables, missing Week 12 values of patients 
previously dropped out due to hospitalization or death will be substituted by the worst value 
possible for the respective variable (e.g., increased level of non-sedentary daytime physical 
activity=”No”, PGA=”much worse”). 
 
In the event that any date for Adverse Events is incomplete after Data Management 
processing and this date needs to be used for a calculation, the following will be assigned for 
the missing date: 
- if no field is available: no imputation will be performed 
- if only the year is available:  
• 
Onset date: day “01” and month of “January” or first dose administration date, 
whatever occurs after will be imputed 
• 
End date: day “31” and month of “December” or EOS date, whatever occurs 
before will be imputed 
 
- if the month and year are available:   
• 
Onset date: day “01”  will be imputed 
• 
End date: "last day of the month” will be imputed 
6.7 
Multicentre Studies 
No analysis stratified by center will be performed in this study 
6.8 
Examination of Subgroups 
Post-hoc analysis on specific subgroups e.g. by NYHA, country, etc. may be considered 
once the study data has been published. 
6.9 
Interim Analysis  
No interim analysis are planned for the study.  
6.10 
Data Monitoring 
There will be no independent data monitoning committee reviewing the data 


 
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7 
REFERENCES 
 
Alosco, M. L., M. B. Spitznagel, R. Cohen, L. H. Sweet, S. M. Hayes, R. Josephson, J. 
Hughes and J. Gunstad (2015). "Decreases in daily physical activity predict acute decline in 
attention and executive function in heart failure." J Card Fail 21(4): 339-346. 
Buysse, D. J., C. F. Reynolds, 3rd, T. H. Monk, S. R. Berman and D. J. Kupfer (1989). "The 
Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research." 
Psychiatry Res 28(2): 193-213. 
Cooper, T. J., S. D. Anker, J. Comin-Colet, G. Filippatos, M. Lainscak, T. F. Lüscher, C. Mori, 
P. Johnson, P. Ponikowski and K. Dickstein (2016). "Relation of Longitudinal Changes in 
Quality of Life Assessments to Changes in Functional Capacity in Patients With Heart Failure 
With and Without Anemia." Am J Cardiol 117: 1482-1487. 
Tager, T., W. Hanholz, R. Cebola, H. Frohlich, J. Franke, A. Doesch, H. A. Katus, F. H. 
Wians, Jr. and L. Frankenstein (2014). "Minimal important difference for 6-minute walk test 
distances among patients with chronic heart failure." Int J Cardiol 176(1): 94-98. 
Van Someren EJW, Hagebeuk EEO, Lijzenga C, Scheltens P, De Rooij SEJA, Jonker C, Pot 
A-M, Mirmiran M and Swaab DF (1996) Circadian rest-activity rhythm disturbances in 
Alzheimer's disease. Biol Psychiatry 40:259-270. 
Van Someren EJW, Kessler A, Mirmiran M and Swaab DF (1997a) Indirect bright light 
improves circadian rest-activity rhythm disturbances in demented patients. Biol Psychiatry 
41:955-963. 
Van Someren EJW, Lijzenga C, Mirmiran M and Swaab DF (1997b) Long-term fitness 
training improves the circadian rest-activity rhythm in healthy elderly males. J Biol Rhythms 
12:146-156. 
Van Someren EJW, Scherder EJA and Swaab DF (1998) Transcutaneous electrical nerve 
stimulation (TENS) improves circadian rhythm disturbances in Alzheimer's disease. 
Alzheimer Dis Assoc Disord 12:114-118. 
Van Someren EJW, Swaab DF, Colenda CC, Cohen W, McCall WV and Rosenquist PB 
(1999) Bright light therapy: improved sensitivity to its effects on rest-activity rhythms in 
Alzheimer patients by application of nonparametric methods. Chronobiol Int 16:505-518. 
 
8 
 APPENDIX 1 
Data from subjects screened but not included in the study will not be presented in any listings 
or tables.  
8.1 
Tables to be Produced for the Clinical Study Report (Section 14 according to 
ICH E3) 
 
14.1 DEMOGRAPHIC DATA  
 
Subject disposition 
Table 14.1-1. 
Subject disposition in analysis sets and reason for exclusions  
SCR population 


 
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Table 14.1-2. 
Study populations  
SCR population 
Table 14.1-3. 
Inclusion and exclusion criteria 
FAS population 
 
Demographic and baseline characteristics 
Table 14.1-4. 
Demographic data 
SAF population / FAS population  
Table 14.1-5. 
Cardiovascular medical history at baseline 
SAF population / FAS population  
Table 14.1-6. 
Relevant medical history/concurrent medical conditions at baseline 
SAF population / FAS population  
Table 14.1-7. 
Previous drug/non-drug therapy of HF 
SAF population / FAS population  
Table 14.1-8. 
Height, weight, body mass index (BMI) and NYHA class  
SAF population / FAS population  
Table 14.1-9. 
Actigraphy variables (Mean daily non-sedentary daytime activity, Mean 
daily light and moderate-to-vigorous non-sedentary daytime physical 
activity) at baseline 
SAF population   
Table 14.1-10. 
Actigraphy variables (Total weekly time spent in non-sedentary daytime 
physical activity, Total weekly time spent in light non-sedentary daytime 
physical activity, Total weekly time spent in moderate-to-vigorous non-
sedentary daytime physical activity) at baseline 
SAF population   
Table 14.1-11. 
Actigraphy variables (M6min, Interdaily Stability (IS), Intradaily Variability 
(IV), L5 average, M10 average, Relative Amplitude) at baseline 
SAF population   
Table 14.1-12. 
Hospitalizations and medical visits 12 months previous to baseline 
SAF population / FAS population  
Table 14.1-13. 
Etiology of heart failure  
SAF population / FAS population 
Table 14.1-14. 
12 Lead ECG Evaluation at baseline 
SAF population / FAS population  
 
 
14.2 EFFICACY DATA  
 
Primary efficacy analysis 


 
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Table 14.2-1  
6-minute walking test: absolute and change between baseline and end of 
study by treatment group. 
FAS population/PP population/FAS population subset patients without 
AE/SAE/PP population subset patients without AE/SAE 
Descriptive statistics 
Table 14.2-2  
6-minute walking test: ANCOVA comparison of change between baseline 
and end of study. 
FAS population/PP population/FAS population subset patients without 
AE/SAE/PP population subset patients without AE/SAE 
Statistical (mixed model) by treatment group 
Table 14.2-3  
Mean daily non-sedentary daytime activity: absolute and change between 
baseline and end of study by treatment group. 
FAS population with MI/FAS population with LOCF/FAS population without 
MI/LOCF/PP population with MI/ PP population with LOCF/PP population 
without MI 
Descriptive statistics 
Table 14.2-4  
Mean daily non-sedentary daytime activity: ANCOVA comparison of 
change between baseline and end of study. 
FAS population with MI/FAS population with LOCF/FAS population without 
MI/LOCF/PP population with MI/ PP population with LOCF/PP population 
without MI 
Statistical (mixed model) by treatment group 
 
Secondary efficacy analysis 
 
Table 14.2-5  
Improved performance (≥ 30 m) in 6MWT: proportion of patients at the end 
of study by treatment group. 
FAS population/FAS population subset patients without AE/SAE 
Descriptive statistics 
Table 14.2-6  
Improved performance (≥ 30 m) in 6MWT: logistic regression model. 
FAS population/FAS population subset patients without AE/SAE 
Statistical (logistic model) by treatment group 
Table 14.2-7  
Improved performance (≥ 30 m) in 6MWT for patients with baseline 6MWT 
equal to or less than 300 meters: proportion of patients at the end of study 
by treatment group. 
FAS population/FAS population subset patients without AE/SAE 
Descriptive statistics 
Table 14.2-8  
Improved performance (≥ 30 m) in 6MWT for patients with baseline 6MWT 
equal to or less than 300 meters: logistic regression model. 
FAS population/FAS population subset patients without AE/SAE 
Statistical (logistic model) by treatment group 


 
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Table 14.2-9  
Improved performance (≥ 30 m) in 6MWT for patients with baseline 6MWT 
between 100-450 meters: proportion of patients at the end of study by 
treatment group. 
FAS population/FAS population subset patients without AE/SAE 
Descriptive statistics 
Table 14.2-10  
Improved performance (≥ 30 m) in 6MWT for patients with baseline 6MWT 
between 100-450 meters: logistic regression model. 
FAS population/FAS population subset patients without AE/SAE 
Statistical (logistic model) by treatment group 
Table 14.2-11  
6-minute walking test: absolute and change between baseline at week 4, 
week 8 and week 12 by treatment group. 
FAS population/FAS population subset patients without AE/SAE 
Descriptive statistics and statistical analysis by treatment group
Table 14.2-12  
Increased levels (≥ 10% increase) of non-sedentary daytime physical 
activity: proportion of patients at the end of study by treatment group. 
FAS population  
Descriptive statistics
Table 14.2-13  
Increased levels (≥ 10% increase) of non-sedentary daytime physical 
activity: logistic regression model. 
FAS population  
Statistical (logistic model) by treatment group
Table 14.2-14  
PGA score at week 4, week 8 and week 12 by treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-15  
Patients who improved symptoms of HF as assessed by PGA: proportion 
of patients at week 4, week 8 and week 12 by treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-16  
Mean daily non-sedentary daytime activity: absolute and change in weekly 
and two-weekly intervals by treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-17  
Mean daily non-sedentary daytime activity: Proportion of patients at weekly 
and two-weekly intervals who show increased levels (≥ 10% increase) by 
treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-18  
Mean daily light and moderate-to-vigorous non-sedentary daytime physical 
activity: absolute and change by week and treatment group. 
FAS population 


 
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Descriptive statistics and statistical analysis by treatment group
Table 14.2-19  
Total weekly time spent in non-sedentary daytime physical activity: 
absolute and change by week and treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-20  
Total weekly time spent in light non-sedentary daytime physical activity: 
absolute and change by week and treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-21  
Total weekly time spent in moderate-to-vigorous non-sedentary daytime 
physical activity: absolute and change by week and treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-22  
M6min: absolute and change between baseline at week 4, week 8 and 
week 12 by treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
Table 14.2-23  
Increase in M6min: proportion of patients at week 4, week 8 and week 12 
by treatment group. 
FAS population 
Descriptive statistics and statistical analysis by treatment group 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
Table 14.2-27  
Interdaily Stability (IS): absolute and change between baseline at two-week 
intervals by treatment group. 
FAS population 
Descriptive statistics 
Table 14.2-28  
Intradaily Variability (IV): absolute and change between baseline at two-
week intervals by treatment group. 
FAS population 
Descriptive statistics 


 
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Table 14.2-29  
L5 average: absolute and change between baseline at two-week intervals 
by treatment group. 
FAS population 
Descriptive statistics 
Table 14.2-30  
M10 average: absolute and change between baseline at two-week intervals 
by treatment group. 
FAS population 
Descriptive statistics 
Table 14.2-31  
Relative amplitude: absolute and change between baseline at two-week 
intervals by treatment group. 
FAS population 
Descriptive statistics 
  
 
 
 
 
Table 14.2-33  
Mean daily sedentary daytime physical activity: Parameters (∆, c, k, t0) and 
standard error from non-linear least square regression by treatment group. 
Logistic function 
FAS population  
Descriptive statistics and statistical analysis (∆) 
Table 14.2-34  
Mean daily light and moderate-to-vigorous non-sedentary daytime physical 
activity: Parameters (∆, c, k, t0) and standard error from non-linear least 
square regression by treatment group. Logistic function 
FAS population  
Descriptive statistics and statistical analysis (∆) 
Table 14.2-35  
M6min: Parameters (∆, c, k, t0) and standard error from non-linear least 
square regression by treatment group. Logistic function 
FAS population  
Descriptive statistics and statistical analysis (∆) 
 
14.3 SAFETY DATA  
 
Adverse events 
 
Table 14.3.1-1  
Summary of patients with TEAEs by treatment group 
SAF population 
Table 14.3.1-2  
Number of TEAEs by SOC and PT by treatment group 
SAF population 
Table 14.3.1-3  
Number of TEAEs by SOC, PT and maximum severity by treatment group 
SAF population 
Table 14.3.1-4  
Number of suspected drug-related TEAEs by SOC and PT  by treatment 


 
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group 
SAF population 
Table 14.3.1-5  
Number of serious TEAEs by SOC and PT by treatment group 
SAF population 
Table 14.3.1-6  
Number of TEAEs leading to treatment discontinuation by SOC and PT by 
treatment group 
SAF population 
 
 
Listings of Deaths, Other Serious and Significant Adverse Events 
Table 14.3.2-1  
List of Deaths 
SAF population  
Table 14.3.2-2  
List of patients with at least one serious adverse event  
SAF population  
Table 14.3.2-3  
List of patients with a fatal adverse event 
SAF population  
Table 14.3.2-4  
List of subjects with an adverse event leading to treatment discontinuation 
SAF population 
 
 


 
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Liver and Renal Events 
Table 14.3.2-1  
Liver Events 
SAF population  
Table 14.3.2-2  
Renal Events  
SAF population  
 
 
Laboratory data 
 
Table 14.3-4.1  
Laboratory data: absolute values and changes from baseline by visit and 
treatment group 
SAF population  
Table 14.3-4.2  
Hemoglobin: notable values at any time post-baseline by treatment group 
SAF population  
Table 14.3-4.3  
ALT: notable values at any time post-baseline by treatment group 
SAF population 
Table 14.3-4.4  
AST: notable values at any time post-baseline by treatment group 
SAF population 
Table 14.3-4.5  
Creatinine: notable values at any time post-baseline by treatment group 
SAF population 
Table 14.3-4.6  
Potassium: notable values at any time post-baseline by treatment group 
SAF population 
Table 14.3-4.7  
Potassium Clearance: notable values at any time post-baseline by 
treatment group 
SAF population 
Table 14.3-4.8  
Laboratory data: Shift from baseline by treatment group 
SAF population 
 
Vital signs  
 
Table 14.3-6.1  
Blood pressure: absolute values and changes from baseline by visit and 
treatment group 
SAF population  
Table 14.3-6.2  
Pulse rate: absolute values and changes from baseline by visit and 
treatment group 
SAF population 
 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
35 (37) 
Treatment exposure 
 
Table 14.3-7.1  
Treatment exposure 
SAF population 
Table 14.3-7.2  
Treatment compliance 
SAF population 
 
NYHA class 
Table 14.3-8.1  
NYHA class by visit and treatment group 
SAF population 
 
 
Concomitant therapy 
 
Table 14.3-11.1  
Concomitant medication  
SAF population 
 
 
8.2 
Graphs (Section 14.2-14.3 in ICH E3) 
Figure 14.2-1 
6-minute walking test at baseline, week 4, week 8 and week 12 by 
treatment group. 
FAS population/PP population/FAS population subset patients without 
AE/SAE 
Figure 14.2-2 
Mean daily non-sedentary daytime activity in weekly intervals by treatment 
group. 
FAS population 
Figure 14.2-3 
Mean daily non-sedentary daytime activity in two-weekly intervals by 
treatment group. 
FAS population 
Figure 14.2-4 
PGA score at baseline, week 4, week 8 and week 12 by treatment group. 
FAS population 
Figure 14.2-5 
Total weekly time spent in non-sedentary daytime physical activity in 
weekly intervals by treatment group. 
FAS population 
Figure 14.2-6 
Total weekly time spent in light non-sedentary daytime physical activity in 
weekly intervals by treatment group. 
FAS population 
Figure 14.2-7 
Total weekly time spent in moderate-to-vigorous non-sedentary daytime 
physical activity in weekly intervals by treatment group. 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
36 (37) 
FAS population 
Figure 14.2-8 
M6min at baseline, week 4, week 8 and week 12 by treatment group. 
FAS population 
 
8.3 
Listings of Individual Subject Data and other Information to be Produced for 
the Clinical Study Report (Sections 16.1 and 16.2 according to ICH E3) 
(Listing numbers refer to Appendix number in ICH E3. CRF check questions/reminders will 
not be listed.) 
 
Listing 16.2.1-1.1  
Discontinued Subjects, Reason for Discontinuation 
Listing 16.2.1-1.2  
Visit Dates  
Listing 16.2.1-1.3  
Study Termination 
Listing 16.2.1-1.4  
Screening failure subjects, Reason for SF 
Listing 16.2.2-1.1  
Protocol deviations 
Listing 16.2.3-1.1  
Patients excluded from the efficacy analysis 
Listing 16.2.4-1.1  
Demographic data 
Listing 16.2.4-1.2  
Medical History 
Listing 16.2.4-1.3  
Physical Examination at visit 1 
Listing 16.2.4-1.4  
Inclusion Criteria Not Met and Exclusion Criteria Met 
Listing 16.2-5-1.1  
Compliance and/or Drug Concentration Data 
Listing 16.2.6-1.1  
Variables from Actigraphy  
Listing 16.2.6-1.2  
NYHA class 
Listing 16.2.6-1.3  
PGA 
Listing 16.2.6-1.4  
6 minute walking test 
  
 
  
 
  
 
  
 
Listing 16.2.7-1.1  
Adverse events 
Listing 16.2.7-1.2  
Liver events 
Listing 16.2.7-1.3  
Renal events 
Listing 16.2.8-1.1  
Listing of Individual Laboratory Measurements by Subject (according to 
layout in section 12.4.1 in ICH E3, abnormal values should be flagged) 
Listing 16.2.8-1.2  
Vital signs 
Listing 16.2.8-1.3  
ECG 
Listing 16.2.11-1.1 Concomitant medications 


 
Statistical Analysis Plan 
Version: Final 4 
Date: 12th Dec 2018 
Sponsor: Novartis 
Study Code: CLCZ696B3301 
EudraCT No.: 2016 – 0085 - 32 
 
ST_Form_Statistical Analysis Plan_03 
37 (37) 
 
8.4 
US Archival Listings (Appendix 16.4 according to ICH E3) 
Not applicable 
 
8.5 
Multiple Imputation: To select the most appropriate MI method 
 
Missing Data 
Pattern 
Imputed Variable 
Type  
Method  
PROC MI Statement  
Monotone 
Continous 
Linear regression 
MONOTONE REG 
 
 
Predictive mean matching 
MONOTONE REGPMM 
Propensity score 
MONOTONE 
PROPENSITY 
Binary/ordinal 
Logistic regression 
MONOTONE LOGISTIC 
Nominal 
Discriminant function 
MONOTONE DISCRIM 
Arbitrary 
Continuous 
With continuous covariates:  
MCMC monotone method 
MCMC full-data imputation  
With mixed covariates:  
FCS regression  
FCS predictive mean matching 
  
MCMC monotone method  
MCMC full-data imputation  
  
FCS REG 
FCS REGPMM 
Binary/ordinal 
FCS logistic regression 
FCS LOGISTIC 
Nominal 
FCS discriminant function 
FCS DISCRIM 
 
Notes: 
MCMC:  Markov chain Monte Carlo method.  
FCS    : Fully conditional specification  
Table extracted from the SAS/STAT PROC MI documentation