Conditions: Heart Failure Heart Failure, Systolic Erectile Dysfunction
Keywords: heart failure systolic heart failure heart failure with reduced ejection fraction erectile dysfunction Enalapril Enalaprilat LCZ696 Sacubitril/valsartan
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine the effect of sacubitril/valsartan (LCZ696) vs. Enalapril on improvement in erectile function and ability in male patients with chronic heart failure with reduced ejection fraction and erectile dysfunction.

Detailed description:
The purpose of this study was to evaluate the effect of sacubitril/valsartan in improving erectile function in male patients with chronic heart failure (NYHA II) and reduced ejection fraction (HFrEF) and erectile dysfunction (ED). Data from this study was intended to provide a thorough understanding of the impact of sacubitril/valsartan on male sexual function and therefore quality of life.

Arms:
arm 1: LCZ696 200 mg (sacubitril/valsartan 97 mg/103 mg bid) arm 2: Enalapril 10 mg

Interventions: intervention 1: LCZ696 intervention 2: Enalapril matching placebo intervention 3: Enalapril intervention 4: LCZ696 matching placebo
Intervention descriptions: intervention 1: sacubitril/valsartan 200 mg = 97 mg/103 mg bid sacubitril/valsartan film-coated tablets intervention 2: Placebo to Enalapril 10 mg film-coated tablets intervention 3: Enalapril 10 mg film-coated tablets intervention 4: Placebo to LCZ696 200 mg = 97 mg/103 mg bid sacubitril/valsartan film-coated tablets

Protocol document:
Prot_000.pdf: 
Official Title: 
NCT Number: 
Document Dates: 
A Randomized, Double-blind, Active-controlled Study to Assess the Effect of 
Sacubitril/Valsartan Compared With Enalapril to Improve Erectile Function in 
Patients With Heart Failure With Reduced Ejection Fraction and Erectile Dysfunction
NCT03917459
Original Protocol : 07 August 2018
Protocol Version 01: 15 January 2019


Appendix 16.1.1 
Protocol and protocol amendments 
History of changes 
Version 
Summary of changes 
1.0 
Original version 
1 
Protocols and protocol amendments 
Table 1-1 
List of protocols, protocol amendments and post text supplements 
. 
Document 
Effective Date 
Original Protocol 
07-Aug-2018
 
Amended Protocol Version 01 (clean version) 
15-Jan-2019
 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
1 
Introduction ....................................................................................................................... 14 
1.1 
Background ............................................................................................................ 14 
1.2 
Purpose .................................................................................................................. 15 
2 
Study objectives and endpoints ......................................................................................... 16 
3 
Investigational plan ........................................................................................................... 17 
3.1 
Study design........................................................................................................... 17 
3.2 
Rationale for study design ..................................................................................... 20 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 21 
3.4 
Rationale for choice of comparator ....................................................................... 21 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 22 
3.6 
Risks and benefits .................................................................................................. 22 
4 
Population .......................................................................................................................... 22 
4.1 
Inclusion criteria .................................................................................................... 23 
4.2 
Exclusion criteria ................................................................................................... 24 
5 
Treatment ........................................................................................................................... 26 
5.1 
Study treatment ...................................................................................................... 26 
5.1.1 
Investigational and control drugs .......................................................... 26 
5.1.2 
Additional treatment .............................................................................. 27 
5.2 
Treatment arms ...................................................................................................... 27 
5.3 
Treatment assignment and randomization ............................................................. 27 
5.4 
Treatment blinding ................................................................................................. 27 
5.5 
Treating the patient ................................................................................................ 28 
5.5.1 
Patient numbering ................................................................................. 28 
5.5.2 
Dispensing the study drug ..................................................................... 28 
5.5.3 
Handling of study and additional treatment .......................................... 28 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 29 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 30 
5.5.6 
Rescue medication ................................................................................ 32 
5.5.7 
Concomitant medication ....................................................................... 32 
5.5.8 
Prohibited medication ........................................................................... 34 
5.5.9 
Emergency breaking of assigned treatment code .................................. 35 
5.6 
Study completion and discontinuation ................................................................... 36 
 
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5.6.1 
Study completion and post-study treatment .......................................... 36 
5.6.2 
Discontinuation of study treatment ....................................................... 36 
5.6.3 
Withdrawal of informed consent ........................................................... 37 
5.6.4 
Loss to follow-up .................................................................................. 38 
5.6.5 
Early study termination by the sponsor ................................................. 38 
6 
Visit schedule and assessments ......................................................................................... 38 
6.1 
Information to be collected on screening failures .................................................. 41 
6.2 
Patient demographics/other baseline characteristics ............................................. 41 
6.3 
Treatment exposure and compliance ..................................................................... 41 
6.4 
Efficacy .................................................................................................................. 41 
6.4.1 
IIEF-15 questionnaire ............................................................................ 41 
6.4.2 
Patient-reported frequency of sexual activity ....................................... 42 
6.4.3 
NT-proBNP ........................................................................................... 42 
 
 42 
6.4.5 
Appropriateness of efficacy assessments .............................................. 42 
6.5 
Safety ..................................................................................................................... 43 
6.5.1 
Physical examination ............................................................................ 43 
6.5.2 
Vital signs.............................................................................................. 43 
6.5.3 
Height and weight ................................................................................. 44 
6.5.4 
Laboratory evaluations .......................................................................... 44 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 45 
6.5.6 
Pregnancy and assessments of fertility ................................................. 45 
6.5.7 
Angioedema .......................................................................................... 45 
6.5.8 
Cognitive Impairment ........................................................................... 45 
6.5.9 
Statin-related Events ............................................................................. 46 
6.5.10 
Appropriateness of safety measurements .............................................. 46 
6.6 
Other assessments .................................................................................................. 46 
6.6.1 
Patient Reported Outcomes (PRO) ....................................................... 46 
6.6.2 
Pharmacokinetics .................................................................................. 48 
6.6.3 
Other biomarkers ................................................................................... 48 
7 
Safety monitoring .............................................................................................................. 48 
7.1 
Adverse events ....................................................................................................... 48 
7.2 
Serious adverse events ........................................................................................... 50 
7.2.1 
Definition of SAE ................................................................................. 50 
7.2.2 
SAE reporting........................................................................................ 51 
7.3 
Liver safety monitoring ......................................................................................... 51 
 
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7.4 
Renal safety monitoring ......................................................................................... 52 
7.5 
Reporting of study treatment errors including misuse/abuse ................................ 53 
7.6 
Pregnancy reporting ............................................................................................... 53 
7.7 
Prospective suicidality assessment ........................................................................ 53 
8 
Data review and database management ............................................................................. 53 
8.1 
Site monitoring ...................................................................................................... 53 
8.2 
Data collection ....................................................................................................... 54 
8.3 
Database management and quality control ............................................................ 54 
8.4 
Data Monitoring Committee .................................................................................. 55 
8.5 
Angioedema Adjudication Committee .................................................................. 55 
9 
Data analysis ...................................................................................................................... 56 
9.1 
Analysis sets .......................................................................................................... 56 
9.2 
Patient demographics and other baseline characteristics ....................................... 56 
9.3 
Treatments ............................................................................................................. 56 
9.4 
Analysis of the primary variable(s) ....................................................................... 57 
9.4.1 
Primary Variable(s) ............................................................................... 57 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 57 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 57 
9.4.4 
Sensitivity analyses ............................................................................... 58 
9.5 
Analysis of secondary variables ............................................................................ 58 
9.5.1 
Efficacy variables .................................................................................. 58 
9.5.2 
Safety variables ..................................................................................... 58 
9.5.3 
Resource utilization ............................................................................... 59 
9.5.4 
Pharmacokinetics .................................................................................. 59 
9.5.5 
DNA ...................................................................................................... 59 
9.5.6 
Biomarkers ............................................................................................ 59 
9.5.7 
PK/PD ................................................................................................... 59 
 
 59 
9.7 
Interim analyses ..................................................................................................... 59 
9.8 
Sample size calculation .......................................................................................... 59 
10 Ethical considerations ........................................................................................................ 60 
10.1 
Regulatory and ethical compliance ........................................................................ 60 
10.2 
Informed consent procedures ................................................................................. 60 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 61 
10.4 
Publication of study protocol and results............................................................... 61 
10.5 
Quality Control and Quality Assurance ................................................................. 61 
 
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11 Protocol adherence ............................................................................................................ 61 
11.1 
Protocol amendments ............................................................................................. 62 
12 References ......................................................................................................................... 62 
13 Appendix 1: Clinically notable laboratory values ............................................................. 65 
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 66 
15 Appendix 3: Specific Renal Alert Criteria and Actions .................................................... 68 
16 Appendix 4: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.5 mmol/L) ..................................................................................................... 68 
17 Appendix 5: Guidelines for the management of blood pressure ....................................... 70 
18 Appendix 6: Guidelines for the management of renal dysfunction ................................... 70 
 71 
20 Appendix 8: IIEF-5 ............................................................................................................ 73 
21 Appendix 9: IIEF-15 .......................................................................................................... 74 
22 Appendix 10: Sexual activity diary ................................................................................... 80 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 16 
Table 3-1               
Minimum required pre-study daily doses of commonly prescribed 
ACEIs and ARBs .................................................................................. 18 
Table 5-1  
Study drug dispensed during the double-blind period .......................... 30 
Table 5-2 
Prohibited medication ........................................................................... 35 
Table 6-1 
Assessment schedule ............................................................................. 39 
Table 7-1  
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 53 
Table 14-1 
Liver Event and Laboratory Trigger Definitions .................................. 66 
Table 14-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 66 
Table 15-1 
Specific Renal Alert Criteria and Actions ............................................. 68 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 20 
 
 
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List of abbreviations 
 
ACE 
ACEI 
AE 
ALT 
Angiotensin-converting-enzyme 
Angiotensin-converting-enzyme inh bitor 
Adverse Event 
Alanine aminotransferase 
ANP 
ARB 
AST 
Atrial natriuretic peptide 
Angiotensin receptor blocker 
Aspartate aminotransferase 
bid 
BNP 
BUN 
cGMP 
cHF 
CNP 
CPK 
twice a day 
Brain natriuretic peptide 
Blood urea nitrogen 
Cyclic guanosine monophosphate 
Chronic heart failure 
C-type natriuretic peptide 
Creatine phosphokinase 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTRD  
Clinical Trial Results Database  
d 
day 
ED 
Erectile dysfunction 
EDC 
eGFR 
EMA 
eGFR 
EOS 
Electronic Data Capture 
Estimated glomerular filtration rate 
European Medicines Agency  
Estimated glomerular filtration rate 
End of study 
eSource 
GC 
Electronic Source 
Guanyl cyclase 
GCP 
HF 
HFrEF 
Good Clinical Practice 
Heart failure 
Heart failure with reduced ejection fraction 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
IIEF 
INR 
Independent Ethics Committee 
International Index of Erectile Function 
International normalized ratio 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LFT 
LVEF 
MDRD 
Liver function test  
Left ventricular ejection fraction 
Modification of Diet in Renal Disease 
MedDRA 
Mg 
Medical dictionary for regulatory activities  
Milligram 
 
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mmHg 
MRA 
NEP 
NO 
NYHA 
Millimeter mercury 
Mineralocorticoid Receptor Antagonist 
Neutral endopeptidase/neprilysin 
Nitric oxide 
New York Heart Association 
od 
pGC 
once a day 
particulate guanyl cyclase 
p.o. 
PSD 
QoL 
RAAS 
oral(ly) 
Premature subject/patient discontinuation 
Quality of Life 
Renin angiotensin aldosterone system 
SAE 
SBP 
SMC 
SmPC 
SUSAR 
TBL 
Serious Adverse Event 
Systolic blood pressure 
Smooth muscle cell 
Summary of product characteristics 
Suspected Unexpected Serious Adverse Reactions 
Total bilirubin 
TD 
UACR 
ULN 
w 
WBC 
Study Treatment Discontinuation 
Urinary albumin to creatinine 
Upper limit of normal 
Week(s) 
White blood cell 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
 
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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
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) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care. 
eSource DDE 
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits.  
eSource combines source documents and case report forms (eCRFs) 
into one application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate. 
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 descr bed in the 
protocol) 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product”. 
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  
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis 
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource. 
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 
 
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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 study 
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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Protocol summary 
 
Protocol number 
CLCZ696BDE03 
Full title 
A randomized, double-blind, active-controlled study to assess the 
effect of sacubitril/valsartan compared with enalapril to improve 
erectile function in patients with heart failure with reduced ejection 
fraction (HFrEF) and erectile dysfunction (ED)   
Brief title 
 
COmparing arNi and ace For Improving erectile Dysfunction in 
mEN with reduCed Ejection fraction heart failure  
Sponsor and Clinical 
Phase 
Novartis  
Phase IV 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale Heart failure (HF) patients typically display various symptoms 
including peripheral congestion, low exercise tolerance, fatigue and 
dyspnea, which contribute to a progressive worsening of quality of 
life (QoL). Additionally, sexual activity remains an essential aspect 
of QoL, since, contrary to common belief, seriously ill patients 
mostly do not lose their interest in intimacy. An estimated 70% of 
male HF patients experience erectile dysfunction (ED).  
Decreasing left ventricular function is associated with significantly 
reduced erectile function in cardiovascular high-risk patients and ED 
was shown to precede cardiovascular events in these patients.  
A secondary analysis of the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) used in the PARADIGM-HF trial 
demonstrated that patients treated with sacubitril/valsartan 
significantly improved nearly all criteria at the physical limitation 
and social limitation section when compared with enalapril, with the 
most significant changes in intimate/sexual relationships after 8 
months of double-blind treatment. 
Based on these beneficial effects and the potential positive influence 
of enhanced CNP levels under sacubitril/valsartan treatment in 
erectile tissue, we hypothesize that sacubitril/valsartan may also 
enhance erectile function in male HFrEF patients, thereby 
contributing to improvement of QoL. Enhancement in erectile 
function will be evaluated using the renowned International Index of 
Erectile Function (IIEF). 
Primary Objective(s)  
To demonstrate the superiority of sacubitril/valsartan compared to 
enalapril regarding improvement in erectile function and ability in 
 
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male patients with chronic heart failure and erectile dysfunction 
using the questionnaire International index of erectile function 
(IIEF-15) at the end of the study. 
Secondary Objectives 
• To assess the early-onset effect as well as the effect at the end of 
the study of sacubitril/valsartan versus enalapril regarding 
improvement in sexual activity assessed using patient’s self-
reported frequency of sexual activity per month 
• To assess the early-onset effect as well as the effect at the end of 
the study of sacubitril/valsartan versus enalapril regarding NT-
proBNP levels 
Study design 
This is a randomized, double-blind, double-dummy, multi-center, 
active-controlled, 
interventional 
study 
to 
compare 
sacubitril/valsartan to enalapril in improving erectile function in 
male patients with chronic heart failure (NYHA II) and reduced 
ejection fraction (HFrEF) and erectile dysfunction (ED). 
Population 
The study population will consist of a representative group of adult 
(≥18 and ≤ 75) male HFrEF patients in NYHA class II with mild to 
moderate ED. Eligible patients should be on a stable dose of an 
ACEI or an ARB as well as bisoprolol/metoprolol for at least 4 
weeks prior to randomization. The targeted projected sample size is 
200 patients (100 patients in each arm). It is expected that 286 
patients will be screened at up to approximately 40 study sites, as a 
screen failure rate of 30% is anticipated. 
Key Inclusion criteria 
• Patients must give written informed consent before any assessment 
is performed and must be willing and capable to comply with all 
study procedures  
• Male Outpatients ≥ 18 and ≤ 75 years of age 
• Patients with a diagnosis of CHF NYHA class II and reduced 
ejection fraction (< 40%) at Visit 1 
• Plasma NT-proBNP level of ≥ 300 pg/mL at Visit 1(Screening)  
• Patients must be living in a stable and sexually active 
heterosexual partnership for at least 6 months prior to Visit 1  
• Patients must have a mild to moderate erectile dysfunction 
determined using the IIEF-5 questionnaire (> 7 and ≤ 21 IIEF 
units) at Visit 1 (Screening) and Visit 2 (Randomization) 
• Patients must be on an ACEI or ARB at a stable dose for at least 
2 weeks prior to Visit 1 and 4 weeks prior to Visit 2 
• Patients 
must 
be 
treated 
with 
a 
stable 
dose 
of 
bisoprolol/metoprolol for at least 2 weeks prior to Visit 1 and 4 
weeks prior to Visit 2 
• No usage of any available drug for erectile dysfunction (e.g. 
sildenafil, tadalafil) for at least 2 weeks prior to Visit 1 and 4 
weeks prior to Visit 2 
 
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Key Exclusion criteria 
• History of hypersensitivity or allergy to any of the study drugs, 
drugs of similar chemical classes, ACEIs, ARBs, or NEP 
inhibitors as well as known or suspected contraindications to the 
study drugs 
• Previous history of intolerance to recommended target doses of 
ACEIs or ARBs 
• Known history of angioedema  
• Requirement of treatment with both ACEIs and ARBs 
• Current acute decompensated HF (exacerbation of chronic HF 
manifested by signs and symptoms that may require intravenous 
therapy) 
• Symptomatic hypotension and SBP ≤100 mm Hg at Visit 1 
(Screening) or Visit 2 (Randomization) 
• Estimated 
glomerular 
filtration 
rate 
(eGFR) 
below 
30mL/min/1.73m2 at Visit 
1 
(Screening) 
or 
Visit 
2 
(Randomization) 
• Serum potassium level of more than 5.2 mmol/L at Visit 1 
(Screening) or Visit 2 (Randomization) 
• History of severe pulmonary disease 
• Penile anatomical defects and Peyronie’s disease 
• Foreseeable usage of any available drug for erectile dysfunction 
(e.g. sildenafil, tadalafil) during the trial 
• Prostate-specific antigen (PSA) levels higher than 4 ng/mL at 
Visit 1 or known prostate cancer 
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 
• IIEF-15 questionnaire  
• Patient-reported frequency of sexual activity 
• Changes in NT-proBNP 
 
 
Key safety 
assessments 
• Adverse event monitoring 
• Physical examinations and blood pressure monitoring 
 
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• Monitoring of laboratory markers in blood (potassium, 
creatinine, AST/ALT) 
Other assessments 
Not applicable 
Data analysis 
The primary variable will be analyzed using a mixed model for 
repeated measures (MMRM). The response variable will be the 
Erectile function score IIEF-15. Treatment (sacubitril/valsartan 
versus enalapril), visit and treatment-by-visit interaction will be 
included as fixed-effect factors; baseline IIEF-15 will be included as 
a covariate. 
Secondary endpoints will be analyzed descriptively. 
Key words 
Erectile dysfunction, heart failure, reduced ejection fraction, 
sacubitril/valsartan, enalapril, randomized controlled trial 
 
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1 
Introduction 
1.1 
Background  
Heart failure (HF) patients typically display various symptoms including peripheral congestion, 
low exercise tolerance, fatigue and dyspnea, which contribute to a progressive worsening of 
quality of life (QoL). Additionally, sexual activity remains an essential aspect of QoL, since, 
contrary to common belief, seriously ill patients mostly do not lose their interest in intimacy 
(Alberti et al., 2013). The American Heart Association asserts that sexual activity is appropriate 
and safe for patients with compensated and/or mild HF (NYHA I/II) (Levine et al., 2012) but 
unfortunately, an estimated 70% of male HF patients experience erectile dysfunction (ED) 
(Alberti et al., 2013). ED describes the persistent inability to achieve and/or maintain a penile 
erection sufficient for satisfactory sexual performance (Lue, 2000). 
ED and HF share common risk factors including age, atherosclerosis, hyperlipidemia, 
hypertension, diabetes mellitus, smoking, obesity and sedentary lifestyle (Rastogi et al., 2005). 
Decreasing left ventricular function is associated with significantly reduced erectile function in 
cardiovascular high-risk patients and ED was shown to precede cardiovascular events in these 
patients (Baumhakel and Bohm, 2007). In addition, common underlying pathophysiological 
mechanisms such as atherosclerosis causing reduced blood-flow, arterial insufficiency and 
endothelial dysfunction are anticipated to contribute to both ED and HF progression (Rastogi 
et al., 2005). Furthermore, ED is also influenced by depression, exercise tolerance impairment, 
anabolic deficiency and pharmacological treatment (Alberti et al., 2013).  
Several physiological pathways contribute to developing an erection. Contracted penile smooth 
muscle cells (SMC) in cavernosal arterioles and sinuses have to be transferred into the relaxed 
state in order to facilitate vasodilation and blood influx into the corpora cavernosa. With the 
increased intracorporal pressure, the surrounding fibrous tunica albuginea is stretched and thus 
compresses the subtunical venules. Thereby, the venous outflow is tremendously reduced 
contributing to initiation and maintenance of an erection (Fraga-Silva et al., 2013). 
Sexual stimulation triggers nitric oxide (NO) release from penile nerves and activates the 
soluble guanyl cyclase (GC) in penile SMC to catalyze the conversion of GTP to cGMP. This 
results in the relaxation of SMCs and an increased blood flow into penile tissue.  
Besides this well-known mechanism, the particulate guanyl cyclase (pGC), a cytoplasmic 
membrane-bound GC, additionally plays a pivotal role in erectile tissue. pGC is activated by 
binding of the C-type natriuretic peptide (CNP) to its receptor NPR-B. Subsequently, active 
pGC converts GTP to cGMP in penile SMCs (Kuthe et al., 2003). Additionally, CNP acts as an 
endothelium-derived hyperpolarizing factor (EDHF) and binding to its other receptor NPR-C 
elicits an activation of the inward rectifier K+ channel mediating the hyperpolarization and 
relaxation of penile SMCs (Kun et al., 2008). Thus, CNP essentially contributes to maintaining 
SMCs dilated and the penile tissue erect. ED patients display significantly lower NT-proCNP 
levels, which correlates with the erectile function assessed using the International index of 
erectile function (IIEF-5) (Vlachopoulos et al., 2010).  
Furthermore, the RAAS system has been identified to play a paracrine role in penile tissue and 
interestingly, the physiological amount of angiotensin II produced in erectile tissues exceeds 
that found in the systemic plasma (Fraga-Silva et al., 2013). Angiotensin II elicits penile SMC 
 
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2 
Study objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
• 
To demonstrate the superiority of 
sacubitril/valsartan compared to enalapril 
regarding improvement in erectile function 
and ability in male patients with chronic 
heart failure and erectile dysfunction using 
the questionnaire International Index of 
Erectile Function (IIEF-15) at the end of the 
study 
• 
Erectile function score at 3 months 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the early-onset effect as well as 
the effect at the end of the study of 
sacubitril/valsartan 
versus 
enalapril 
regarding improvement in sexual activity 
assessed 
using 
patient’s 
self-reported 
frequency of sexual activity per month 
• 
To assess the early-onset effect as well as 
the effect at the end of the study of 
sacubitril/valsartan versus enalapril 
regarding NT-proBNP levels  
• 
Self-reported frequency of sexual activity 
per month at months 1 and 3 
 
 
 
 
• 
NT-proBNP levels at months 1 and 3 
 
 
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3 
Investigational plan 
3.1 
Study design 
This is a randomized, double-blind, double-dummy, multi-center, active-controlled, 
interventional study to compare sacubitril/valsartan 97 mg/103 mg bid to enalapril 10 mg bid 
in improving erectile function in male patients with chronic heart failure (NYHA II) and 
reduced ejection fraction (HFrEF) and erectile dysfunction (ED). 
The study comprises five obligatory and one optional visit over a period of approximately 14 
weeks. Once patients’ eligibility has been ascertained at Visit 1 (Screening), patients will be 
randomized at Visit 2 (Randomization) to receive either sacubitril/valsartan or enalapril in a 1:1 
allocation during the double-blind period. At Visit 2, all efficacy assessments will be collected 
and used as baseline values. Double-blind treatment will be initiated with 5 mg bid enalapril or 
49 mg/51 mg bid sacubitril/valsartan and up-titrated after 2 weeks to the final dose of 10mg bid 
enalapril or 97 mg/103 mg bid sacubitril/valsartan. According to the sacubitril/valsartan SmPC, 
initiation of treatment is recommended with the 24 mg/26 mg bid sacubitril/valsartan or 2.5 mg 
bid enalapril dose for certain patients. For these patients, an optional visit 4B after achieving 
the target dose of 97 mg /103 mg bid sacubitril/valsartan or 10 mg bid enalapril is mandatory. 
For allowed investigational treatment dose adjustments during double-blind period refer to 
Section 5.5.4.  
All laboratory evaluations for planned visits and for unscheduled visits will be performed by 
the central laboratory. In order to have the results from the central laboratory available and 
enable a competent decision on randomization or up-titration at the respective visits, patients 
should come to the site approximately 3 to 4 days prior to the scheduled visit date for a blood 
draw (applies for Visit 2 (Randomization), Visit 3 and Visit 4 (Cave: Visit 4: safety lab only for 
patients who started with dose level 1)).  
Further information on the visit schedule and data collection scheme can be found inTable 6-
1. 
 
Visit 1 (Screening) 
At Visit 1 (-2 to -1 weeks) after signing informed consent, the inclusion and exclusion criteria 
will be checked for each patient to ascertain eligibility (see Section 4). Among other criteria, 
they have been on a stable dose of enalapril of at least 10 mg/d, or equivalent ACEI or ARB for 
at least 4 weeks prior to visit 1 (see Table 2-1). A complete physical examination is required at 
Visit 1. Mild to moderate ED will be determined using a short form of the International Index 
of Erectile Function (IIEF-5). Screening potassium levels and eGFR as well as the biomarker 
NT-proBNP will be assessed by sending blood samples to the central laboratory and only 
patients with the required values per entry criteria will be eligible for entering the study. 
Detailed HF history and other relevant CV medical history will be recorded on eCRFs 
separately from other medical history.  
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 potentially be eligible. A minimum of 2 
 
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weeks must elapse between re-screenings and a patient may be re-screened once only (see 
Section 6.1). 
Patients will continue stable intake of their current ACEI/ARB as well as concomitant 
medication until Visit 2 (Randomization). They should be reminded to come without taking 
their usual ACEI to Visit 2. For ACEI a wash-out period of ≥ 36 hours before first application 
of investigational treatment is mandatory.  
 
Table 3-1              Minimum required pre-study daily doses of commonly prescribed 
ACEIs and ARBs 
ACEIs 
Minmum dose 
ARBs 
Minimum dose 
Enalapril 
10 mg 
Candesartan 
16 mg 
Benazepril 
20 mg 
Eprosartan 
400 mg 
Captopril 
100 mg 
Irbesartan 
150 mg 
Cilazapril 
2.5 mg 
Losartan 
50 mg 
Fosinopril 
20 mg 
Olmesartan 
10 mg 
Lisinopril 
10 mg 
Telmisartan 
40 mg 
Moexipril 
7.5 mg 
Valsartan 
160 mg  
Perindopril 
4 mg 
 
 
Quinapril 
20 mg 
 
 
Ramipril 
5 mg 
 
 
Trandolapril 
2 mg 
 
 
Zofenopril 
30 mg 
 
 
 
Visit 2 (Randomization) 
At Visit 2 (timepoint 0), patients who meet all relevant entry criteria, including the required 
clinical laboratory values and safety criteria, will be randomized to one of the two treatment 
arms sacubitril/valsartan or enalapril bid, respectively. Patients should continue to take their 
background medication for heart failure during the study, with the exception of ACEI or ARBs 
which are replaced by the investigational treatment and must be discontinued before first 
application of the study drug (washout period of ≥ 36 hours is mandatory for ACEI). The 
first application of the study drug is planned for the day after Visit 2 (Randomization) – 
therefore, patients taking an ACEI should have discontinued their ACEI medical therapy in the 
evening before Visit 2 (e.g. if Visit 2 is scheduled for Wednesday the last ACEI medication 
should be taken by the patient on Tuesday evening. The patient will then start to take the first 
dose of double blind study medication (sacubitril/valsartan or enalapril) on Thursday morning). 
If the patient continued to take their usual ACEI, the start of study drug has to be postponed to 
assure a ≥ 36 hours washout before first application of the study drug.  
 
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Patients taking an ARB should discontinue their ARB medical therapy the day of Visit 2 (e.g. 
if Visit 2 is scheduled for Wednesday the last ARB medication should be taken on Wednesday. 
The patient will then start to take the first dose of double blind study medication 
(sacubitril/valsartan or enalapril) on Thursday morning). 
Patients will start study treatment at dose level 2 (enalapril 5 mg bid or sacubitril/valsartan 49 
mg/51 mg bid) unless the patients are suffering from moderate hepatic impairment, moderate 
renal impairment or patients with SBP ≥100 to 110 mmHg. These patients should be initiated 
at dose level 1, according to the the sacubitril/valsartan SmPC and the investigator’s medical 
judgement (for these patients Visit 4B is neccessary). All patients must be stabilized on the 
chosen dose for 2 weeks.  
At Visit 2, baseline IIEF-15, 
 and the sexual activity log need to be performed by the 
patients.  
Visit 3 and 4 
After 2 weeks of treatment (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. A blood draw for the safety lab  needs to be performed 3-4 days prior to Visit 3 in 
order to have the results on the day of the visit to up-titrate the patient (for patients starting with 
dose level 1 an additonal safety lab is performed 3-4 days before Visit 4). The titration steps for 
the three dose levels are described in detail in Section 5.5.3 (see Table 5-1). Every attempt 
should be made to keep the patients stable on dose level 3 in accordance with all safety 
parameters, which are symptomatic hypotension, renal dysfunction and/or hyperkalemia and 
should be handled according to the respective guidelines for management (see Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, Appendix 5 and Appendix 6). In case of lab deviations 
an unscheduled visit may be scheduled at the discretion of the investigator to re-assess lab 
parameters and evaluate the efficacy of taken measures. Measurements showing an elevation 
of potassium levels above the predefined values should be repeated and confirmed in a non-
hemolyzed sample before any action is taken (for a serum potassium concentration greater than 
or equal to 6.0 mmol/L please refer to Appendix 4) . 
For the following visits (no up-titration), a blood draw for lab assessments has to be done during 
the visit. 
At Visit 3 and Visit 4, IIEF-15, a physical examination and the current NYHA status is 
documented, as well as safety monitoring and adverse events. At Visit 4, the questionnaires 
IIEF-15 
 will be applied as well as a blood draw for the biomarker NT-proBNP. 
Visit 4B – Optional 
For patients achieving target dose at Visit 4, Visit 4B is needed to evaluate safety criteria and 
ensure adequate medical management. Investigator’s clinical judgement and discretion is 
advised. For patients who started with dose level 1, this visit is mandatory. 
 
 
 
 
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Visit 5 (End of Study) 
After 3 months of treatment, a final assessment of patients is performed at Visit 5. IIEF-15 
 
questionnaires will be completed by patients at Visit 5. A blood draw for NT-proBNP 
assessment has to be done during the visit. 
 
Unscheduled visits  
In addition to the protocol-required visits, patients may be seen at any time throughout the study 
at the discretion of the investigator to follow any new lab abnormalities or AEs. All randomized 
patients, including any patient who has experienced a health event, should continue to receive 
double-blind treatment until the trial is completed, if possible in the opinion of the investigator. 
Unscheduled visits may also be performed throughout the study at the discretion of the 
investigator for up-titration of the study medication. 
 
Figure 3-1 
Study design  
 
 
 
3.2 
Rationale for study design  
Sexual activity remains an essential aspect of QoL for patients with CHF. Unfortunately, 
erectile dysfunction is a common diagnosis in male patients with CHF constituting a substantial 
burden for the patients. Inhibition of neprilysin with sacubitrilat may enhance CNP levels in 
erectile tissue and contribute to maintaining an erection. It was already demonstrated that 
sacubitril/valsartan improved QoL in HFrEF patients including the intimate/sexual 
relationships section in a PARADIGM-HF post-hoc analysis (Chandra et al., 2018). Thus, the 
aim of the present study is to assess differences between sacubitril/valsartan versus enalapril in 
improving erectile function as assessed by the International Index of Erectile Function (IIEF-
15) questionnaire in patients with HFrEF and ED. The questionnaire is established for assessing 
sexual function in ED patients and has been used in numerous clinical trials. For such a 
subjective endpoint as erectile function, a randomized, actively controlled, double-blind 
 
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interventional trial with a balanced study population is the state of the art and allows controlling 
the patients’ treatment and thus reducing bias. Moreover, the study design is reasonable and 
adapted from recent studies for treatment of patients with CHF in terms of investigational 
treatment, duration of assessment period and the comparator. The study design is also in line 
with all required safety assessments and follow-ups for patients with CHF and for the treatment 
with sacubitril/valsartan and in compliance with the effective risk management plan for the 
product. Thus, events of angioedema, liver events, statin related events, and events of cognitive 
impairment are followed up by targeted questionnaires. Please refer to Section 6.5 (safety 
assessments) for further details. Known risks of hypotension, renal impairment, and 
hyperkalemia are closely monitored to prevent severe events and are subject to separate 
guidance should such events occur. Please refer to Sections 6.5.2 and 6.5.4 for assessments of 
blood pressure and laboratory assessments, respectively; and to Appendix 1, Appendix 2, 
Appendix 3, Appendix 4 and Appendix 5 for guidance to manage these risks. 
Taken together, the present randomized, actively-controlled, double-blind, double-dummy 
approach is the most suitable design for achieving the study objective of demonstrating the 
superiority of sacubitril/valsartan versus enalapril in improving erectile function in patients with 
HFrEF and ED. 
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 twice-daily dosing regimen of 
sacubitril/valsartan also ensures a sustained neprilysin (NEP) inhibition over 24 hours. The 
sacubitril/valsartan target dose of 97 mg/103 mg twice daily delivers a daily dose of valsartan 
equivalent to Diovan® 160 mg bid, the dose commonly recommended by current HF 
management guidelines (Ponikowski et al., 2016). With the purpose of this study to demonstrate 
the superiority of sacubitril/valsartan compared to enalapril in improving erectile function in 
patients with HFrEF and ED, we assume a measurable effect using the IIEF-15 questionnaire 
after 3 months of treatment. 
3.4 
Rationale for choice of comparator  
Enalapril, the comparator chosen for this study, is an ACE inhibitor - the drug class considered 
first-line treatment by the current European 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. Since sacubitril/valsartan is tested in this study according to its label in treatment of patients 
with CHF, a standard-of-care comparator is thought to be most appropriate. 
As a well-studied ACEI in HF, enalapril is used as the comparator in this study. Enalapril was 
studied in a number of previous large, outcome-driven studies, such as CONSENSUS (Group, 
 
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1987), SOLVD-Treatment (Investigators, 1991), and SOLVD-Prevention (Investigators et al., 
1992).  
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 (Investigators et al., 1992). 
3.5 
Purpose and timing of interim analyses/design adaptations  
Not applicable. 
3.6 
Risks and benefits  
Both sacubitril/valsartan and enalapril are approved in the indication investigated within this 
study. Please refer to the corresponding Summary of Product Characteristics (SmPC) of each 
product as well as the Investigator’s Brochure (IB) for sacubitril/valsartan for known adverse 
reactions, or special precautions on both IMPs (provided to all participating sites). 
Patients will be instructed not to take any renin angiotensin aldosterone system (RAAS) 
blocking agents (ACEIs or ARBs) before start of study treatment in order to avoid excess RAAS 
blockade. For ACEI a ≥ 36h washout period is mandatory. The risk of temporary 
discontinuation of concomitant ACEIs or ARBs will be minimal as it will be reflective of the 
typical dosing schedule of most ACEIs and ARBs.  
All patients will be allowed to continue receiving their other background CV medications. 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
close clinical monitoring. 
If there is any question that the patient will not reliably comply, the patient should not be entered 
in the study. Participating patients will benefit from careful monitoring and follow-up during 
the entire study duration. 
4 
Population 
This is an outpatient multi-center clinical study to be conducted in Germany. The goal is to 
randomize 200 patients in about 40 centers. Since a 30% screening failure rate is expected, 
approximately 286 patients will be screened. The study population will consist of a 
representative group of adult (≥18 and ≤ 75) male HFrEF patients in NYHA class II with mild 
to moderate ED. Eligible patients should be on a stable dose of an ACEI or an ARB as well as 
bisoprolol/metoprolol for at least 4 weeks prior to entering into the study.  
The investigator must ensure that all patients who meet the inclusion criteria and do not fulfill 
any of the exclusion criteria are offered enrollment in the study. No additional parameter can 
be applied by the investigator. 
 
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4.1 
Inclusion criteria 
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. 
Patients must give written informed consent before any assessment is performed and 
must be willing and capable to comply with all study procedures  
2. 
Male Outpatients ≥ 18 and ≤ 75 years of age 
3. 
Patients with a diagnosis of CHF NYHA class II and reduced ejection fraction (< 40%) 
(assessed by any local measurement using echocardiography, CT scanning, MRI or 
ventricular angiography ≤ 6 months prior to Visit 1) 
4. 
Plasma NT-proBNP level of ≥ 300 pg/mL at Visit 1  
5. 
Patients must be living in a stable and sexually active heterosexual partnership for at 
least 6 months prior to Visit 1 
6. 
Patients must have a mild to moderate erectile dysfunction determined using the IIEF-5 
questionnaire (> 7 and ≤ 21 IIEF units) at Visit 1 and Visit 2 
7. 
No usage of any available drug for erectile dysfunction (e.g. sildenafil, tadalafil) for at 
least 2 weeks prior to Visit 1 and 4 weeks prior to Visit 2 
8. 
Patients must be on an ACEI or an ARB at a stable dose for at least 2 weeks prior to 
Visit 1 and 4 weeks prior to Visit 2 
9. 
Patients must be treated with a stable dose of bisoprolol/metoprolol, unless the use of β-
blockers is contraindicated or not tolerated (reason should be documented) for at least 2 
weeks prior to Visit 1 and 4 weeks prior to Visit 2 (β-blockers other than 
bisoprolol/metoprolol are not allowed per protocol) 
10. 
Patients must be literate in German 
 
 
 
 
 
 
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4.2 
Exclusion criteria 
Patients/subjects 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 during the study and within 30 days or 5 half-lives, 
whichever is longer before enrolment and at enrolment 
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes, ACEIs, ARBs or NEP inhibitors, as well as known or suspected 
contraindications to the study drugs 
3. Previous history of intolerance to recommended target doses of ACEIs or ARBs 
4. Known history of angioedema 
5. Requirement of treatment with a dual RAAS blockade, e.g. a treatment with both, ACEIs 
and ARBs or concomitant treatment with aliskiren 
6. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy) 
7. Symptomatic hypotension and/or a systolic blood pressure (SBP) ≤100 mm Hg at Visit 1 
(Screening) or Visit 2 (Randomization) 
8. Estimated glomerular filtration rate (eGFR) < 30mL/min/1.73m2 at Visit 1 (Screening) or 
Visit 2 (Randomization) as calculated by MDRD formula 
9. Serum potassium level > 5.2mmol/L at Visit 1 (Screening) or Visit 2 (Randomization) 
10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major 
CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 
months prior to Visit 1 
11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 3 months after Visit 1 
12. Implantation of a pacemaker, implantable cardioverter defibrillator (ICD), cardiac 
resynchronization therapy pacemaker / defibrillator (CRT-P/D), or upgrade of an existing 
device or revision of device leads within 3 months prior Visit 1 or intent to implant such a 
device during the study 
13. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on 
transplant list) or implant a VAD 
14. History of severe pulmonary disease including COPD (Patients with significant chronic 
obstructive pulmonary disease contributing to dyspnea or patients whose COPD 
medication has been altered within 2 weeks prior to Visit 1 and 4 weeks prior to Visit 2) 
15. Diagnosis of chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1 
16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months 
prior to Visit 1 
17. Known symptomatic bradycardia or second or third degree heart block without a 
pacemaker 
18. Known presence of hemodynamically significant mitral and/or aortic valve disease, except 
mitral regurgitation due to left ventricular dilatation 
 
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19. Presence of other hemodynamically significant obstructive lesions of left ventricular 
outflow tract, including aortic and sub-aortic stenosis 
20. Known history of familial long QT syndrome or known family history of Torsades de 
Pointes 
21. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of study drugs, including but not limited to any of 
the following: 
• AST or ALT values exceeding 2 x upper limit of normal (ULN)  
• History of active inflammatory bowel disease during the 12 months before Visit 1 
• Current duodenal or gastric ulcers during the 3 months prior to Visit 1 
• Gastric bypass 
• Evidence of severe hepatic impairment, biliary cirrhosis or cholestasis, classified as 
Child-Pugh C 
• History of hepatic encephalopathy, history of  esophageal varices, history of 
portocaval shunt 
• Active treatment with bile sequestering agents such as cholestyramine or colestipol 
resins 
22. Presence of any other disease with a life expectancy of < 1 years 
23. Presence of known bilateral renal artery stenosis 
24. Penile anatomical defects and Peyronie’s disease 
25. Foreseeable usage of any available drug for erectile dysfunction (e.g. sildenafil, tadalafil) 
during the study 
26. Co-Medication with an influence on erectile function such as digoxin, anticholinergic anti-
depressants, alpha blockers finasteride and calcium channel blockers 
27. Recent (4 weeks prior to Visit 1) or planned (within the 14 weeks after Visit 1) change in 
statin or spironolactone therapy 
28. Diabetes mellitus Type I or insulin-dependent Type II  
29. Prostate-specific antigen (PSA) levels higher than 4 ng/mL at Visit 1 or known prostate 
cancer 
30. Spinal cord injury, ileostomy, prior surgery or radio therapy for rectal or prostate cancer 
and radical prostatectomy  
31. Presence of peripheral artery occlusive disease and/or stenosis of the common and internal 
iliac artery 
32. Patients with ongoing alcohol and/or drug abuse and/or severe depression (defined as 
patients with altered medication or hospitalization within 4 weeks prior to Visit 1 and 
Visit 2) 
33. Presence of any neurodegenerative disease or polyneuropathy 
34. Hormonal abnormalities such as hypogonadism, hyperprolactinemia, hyper- and 
hypocortisolism and medically untreated hyper- and hypothyroidism  
35. Obesity based on a body mass index ≥35 kg/m2, frail patients or patients with cardiac 
cachexia or a body mass index <18.5 kg/m2  
 
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36. Any surgical or medical condition, which in the opinion of the investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study. 
5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
Double blind treatment 
All eligible patients will be randomized in a 1:1 allocation to receive either sacubitril/valsartan 
or enalapril in addition to optimal CHF therapy, as considered appropriate by the investigator 
and in accordance with standard therapy guidelines, but with the exception of an ACEI or ARB, 
as this will be replaced by investigational treatment at Visit 2 (Randomization). The use of an 
ACEI or an ARB in addition to investigational treatment is strictly prohibited. For ACEIs a 
washout period of ≥ 36 hour is mandatory. During the dosing of study medication, i.e. beyond 
randomization until the end of the study, the intake of ACEIs or ARBs remains prohibited (in 
case of treatment interruption/discontinuation see Section 5.5.5 and Section 5.5.6). 
The following study drugs will be provided: 
• Sacubitril/valsartan 24 mg/26 mg film-coated tablets (sacubitril/valsartan dose level 1) 
• Placebo to match sacubitril/valsartan 24 mg/26 mg film-coated tablets (placebo matching 
sacubitril/valsartan dose level 1) 
• Sacubitril/valsartan 49 mg/51 mg bid film-coated tablets (sacubitril/valsartan dose level 2) 
• Placebo to match sacubitril/valsartan 49 mg/51 mg bid film-coated tablets (placebo 
matching sacubitril/valsartan dose level 2) 
• Sacubitril/valsartan 97 mg/103 mg film-coated tablets (sacubitril/valsartan dose level 3) 
• Placebo to match sacubitril/valsartan 97 mg/103 mg film-coated tablets (placebo matching 
sacubitril/valsartan dose level 3) 
• Enalapril 2.5 mg film-coated tablets (enalapril dose level 1) 
• Placebo to match enalapril 2.5 mg tablets (placebo matching enalapril dose level 1) 
• Enalapril 5 mg film-coated tablets (enalapril dose level 2) 
• Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2) 
• Enalapril 10 mg film-coated tablets (enalapril dose level 3) 
• Placebo to match enalapril 10 mg tablets (placebo matching enalapril dose level 3) 
Target doses: Sacubitril/valsartan 97 mg/103 mg bid and enalapril 10 mg bid 
All tablets have different shapes and colors. Therefore, the study will be designed as a double-
blind, double-dummy trial to ensure the blinding during the entire course of the study. To 
 
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maintain the blinding, patients will be required to take their assigned active treatment tablet 
along with placebo matching the opposite treatment twice daily (morning and evening dose) in 
addition to their conventional concomitant therapy. 
Sacubitril/valsartan and its matching placebo will be provided in HDPE bottles and/or blister 
packs. Enalapril and its matching placebo will be provided in HDPE bottles and/or 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 bid and placebo matching enalapril bid 
• enalapril bid and placebo matching sacubitril/valsartan bid. 
5.3 
Treatment assignment and randomization  
At Visit 2, all eligible patients/subjects 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 using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s).  
The randomization scheme for patients/subjects will be reviewed and approved by a member 
or delegate of the Randomization Group. 
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:  
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) 
 
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• 
Drug supply management 
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.  
5.5 
Treating the patient  
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a Patient-ID Number assigned by Novartis. The Patient-
ID Number is composed of a site number and a sequential number. Once assigned to a patient, 
the Patient-ID Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in the electronic data capture (EDC) system. The investigator or his/her staff will 
contact the IRT and provide the requested identifying information for the patient to register 
them into the IRT. The site must select the CRF book with a matching Subject Number in the 
EDC system to enter data.  
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate 
Screening period CRF. 
5.5.2 
 Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 2 treatment arms and a specific dose. 
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. 
 
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Medication labels will be in German language and comply with the legal requirements of 
Germany. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
5.5.3.2 
Handling of additional treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he is 
unable for any reason to take the study treatment as prescribed. 
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. 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. Table 5.1 summarizes the study drug that will be taken during the double-blind 
period. 
Patients will begin treatment with dose level 2 for 2 weeks. At Visit 3, patients will be up-
titrated to dose level 3 unless safety monitoring criteria prevent up-titration. According to the 
sacubitril/valsartan SmPC and the investigator’s medical judgement, patients suffering from 
moderate hepatic impairment (Child Pugh B), moderate renal impairment or patients with SBP 
≥100 to 110 mmHg should be initiated at dose level 1. They will be up-titrated every 2 weeks 
(unless safety monitoring criteria prevent up-titration) until they reach dose level 3. Visit 4B is 
a mandatory visit for patients achieving target dose (dose level 3) at visit 4 to evaluate safety 
criteria and ensure adequate medical management.  
 
 
 
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Table 5-1  
Study drug dispensed during the double-blind period 
Dose 
level  
Sacubitril/valsartan  
Enalapril 
3* 
97 mg/103 mg or matching 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.  
 
Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 
AM) and their evening study drug doses at approximately 19:00 (7 PM). The study medications 
should be taken with a glass of water with or without food. If the patient misses taking any 
study drug dose, he should take it as soon as possible, unless if it is almost time for the following 
scheduled dose. In this case, the patient should skip the missed dose and return back to his 
regular study drug administration schedule. 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF. 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
For patients 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:  
Once patients achieve the target study drug dose, every attempt should be made to maintain the 
target study drug dose level (dose level 3) 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. 
diuretics, nitrates) 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 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 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. 
 
 
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Study drug dose level adjustments should be based on overall safety and tolerability with a 
special focus on 
• Hyperkalemia (see Appendix 4)  
• Symptomatic hypotension (see Appendix 5) 
• Clinically significant decrease in eGFR or clinically significant increase in serum 
Creatinine (see Appendix 6) 
• Worsening hepatic function (see Appendix 2) 
After randomization, temporary study drug discontinuation for any reason does not 
automatically constitute withdrawal from the study and should not lead to the patient being 
withdrawn from the study. 
 
Adjustment of study drug dose level  
If despite adjustment of concomitant medications per the guidance provided above the situation 
is not rectified, the investigator may consider adjusting the study medication according the 
following instructions.  
During the double-blind treatment period down-titration of the study drug at any time will be 
allowed based on the safety and tolerability criteria defined in Appendix 1, Appendix 2, 
Appendix 3, and Appendix 4. If down-titration is necessary, the patient should be down titrated 
to the next dose level (see Table 5-1). The patient may continue receiving the lower dose level 
for a recommended period of 1 to 2 weeks before re-challenging the patient with the next higher 
dose level. For example, a patient who encounters tolerability problems at the target dose level 
(dose level 3), should receive the study drug at dose level 2 for 1 to 2 weeks. Then, he should 
be re-challenged with up-titration back to dose level 3.  
If the tolerability issues are not alleviated, the investigator may lower the study drug dose 
further to the next lower level for 1 to 2 weeks, up to temporary withdrawal of the study drug. 
Again, once stable, the patient should be re-challenged with up-titration to the next higher 
dose level every 1 to 2 weeks in an attempt to bring back the patient gradually to the target 
study drug dose level (dose level 3). The investigator may choose the next dose level for 
down- or up-titration according to his or her judgment (Table 5-1).  
In some cases, according to the safety and tolerability criteria and the investigator’s judgment, 
dose level 1 or 2 could be maintained if he/she considers that the patient’s condition would not 
allow an up-titration to the target dose of study medication (level 3). In this case, it would be 
acceptable to maintain the patient at dose level 2 (or lower), to assure treatment with the highest 
dose level tolerated by the patient. 
 
Study drug restart after temporary treatment interruption  
Study drug should be reintroduced after 1-2 weeks in those who temporarily discontinue as 
soon as medically justified in the opinion of the investigator.  
Once the investigator considers the patient’s condition appropriate for receiving the study drug, 
the investigator should re-start the patient on the study drug at the most appropriate and 
allowable dose level (Table 5-1) per his/her medical judgment. If tolerated based on the safety 
 
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and tolerability criteria in Appendix 1, Appendix 2, Appendix 3, and Appendix 4 the patient 
should be up-titrated to the next dose level (up to dose level 3) every 1 to 2 weeks, as per the 
investigator’s judgment.  
Patients re-started on the study drug will retain their original randomization and study 
identification numbers. Should the patient not tolerate the re-start study drug dose level, he may 
be down-titrated again (if appropriate) or discontinue the study medication. Up-titration or 
reintroducing the study drug could be considered by the investigator as soon as medically 
justified in his/her medical judgment.  
Study visits should occur as close as possible to the time points indicated in Table 6-1. The 
timeframe between the regular visits should be maintained as scheduled, irrespective of the 
number of unscheduled visits that may be performed in between, according to the visit and time 
schedule described in Table 6-1.  
Any changes in the study drug dose level, including temporary/permanent withdrawal or re-
start of the study drug, must be recorded on the Dosage Administration Record CRF. 
5.5.6 
Rescue medication 
Guidance on handling hyperkalemia, hypotension and renal dysfunction are provided in 
Appendix 1, 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 (in case the patient is switched to an ACEI), but also for any ACEI before (re-)introducing 
study drug. 
Use of rescue medication must be recorded on the appropriate CRF. 
5.5.7 
Concomitant medication  
The investigator must instruct the patient to notify the study site about any new medications he 
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. 
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 hyperkalemia. The investigators are 
encouraged to assess patients’ potassium levels regularly, especially during the up-titration and 
in those receiving such medications. 
 
 
 
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ACEIs and ARBS 
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 2 and should remain on a stable regimen, if medically justified, throughout the entire 
study duration.  
The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient 
is receiving study medication. If the investigator believes that addition of an ACEI or ARB is 
necessary, then study drug must be discontinued. Study medication should be stopped ≥ 36 
hours prior to addition of open-label ACEI. If not already treated with an aldosterone 
antagonist, consideration should be given to adding this therapy rather than an ACEI or ARB. 
Similarly, if study medication is to be restarted, the open-label ACEI should be discontinued 
≥ 36 hours prior to resuming study medication. 
 
Phosphodiesterase-5 (PDE-5) inhibitors 
The use of Phoshodiesterase-5 inhibitors (e.g. sildenafil, vardenafil, tadalafil and compounds 
with similar characteristics) is not allowed during the study.  
However, there is a risk that patients make use of PDE5i, despite being not allowed by the study 
protocol. For this reason, investigators are advised to make all efforts to make the patient aware 
that use of PDE5i is not allowed. The investigator should educate the patient concerning the 
increased possibility of the occurrence of hypotension.  
 
Statins 
Caution should be exercised upon co-administration of statins such as atorvastatin, simvastatin, 
pravastatin and/or pitavastatin and study medication, due to potential interactions between 
statins and sacubitril/valsartan.  
 
Other drugs with a potential impact on erectile function 
The treatment with the following medications with a potential influence on erectile function are 
not allowed: 
• Digitoxin, Digoxin (e.g. Digacin, Lanicor, Lenoxin and compounds with similar 
characteristics) 
• Calcium channel blockers (e.g. Verapamil, Gallopamil, Diltiazem, Amlodipin, 
Nitrendipin, Felodipin, Nidedipin and compounds with similar characteristics) 
• Alpha blockers (e.g. Alfuzosin, Tamsulosin, Doxazosin, Phentolamin, Prazosin, 
Uradipil, Ergotamin and compounds with similar characteristics)  
• Anticholinergic anti-depressants (e.g. amitriptyline, doxepin and compounds with 
similar characteristics)  
• Finasteride  
 
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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. 
 
Medications known to raise potassium levels 
Potassium-sparing diuretics, potassium supplements, aldosterone antagonists, and any other 
medications known to raise potassium levels should be used with caution while the patient is 
receiving the study medication due to the increased possibility of occurrence of hyperkalemia. 
The investigator is encouraged to assess patients’ potassium levels regularly, especially in those 
who are receiving these medications. Guidelines for the management of hyperkalemia can be 
found in Appendix 4.  
5.5.8 
Prohibited medication 
Use of the treatments displayed in the Table 5-2 is NOT allowed after the start of the 
investigational drug. For ACEI a washout period of ≥ 36 hours is mandatory.  
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 
hyperkalemia.  
Bile acid sequestering agents are prohibited due to potential interference with the absorption of 
study drugs. 
β-blockers other than bisoprolol/metoprolol are not allowed per protocol due to interference 
with erectile function.  
 
 
 
 
 
 
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Table 5-2 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Any ACEI, ARB or Renin 
inhibitors 
 
 
Double blind period 
(≥ 36h washout 
period for ACEI) 
 
Prohibited until at least 36 hours after study 
drug discontinuation/interruption/end of study 
(for ACEI). In case these drugs are taken / 
need to be taken during the double-blind 
treatment period of the study, discontinue 
study drug 
PDE5i 
Double blind period 
Discontinue before randomization, proh bited 
throughout the study. No action required with 
study medication 
Bile acid sequestering 
agents (e.g. 
Cholestyramine, 
Colestipol) 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
Calcium channel blockers 
(e.g. Verapamil, 
Amlodipin) 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
Alpha blockers (e.g. 
Tamsulozin, Prazosin, 
Ergotamin) 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
Anticholinergic anti-
depressants (e.g. 
Amitryptiline, Doxepin) 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
Digitoxin 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
Digoxin (e.g. Digacin, 
Lanicor) 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
β-blockers other than 
bisoprolol/metoprolol 
Double blind period 
Prohibited throughout the study. No action 
required with study medication 
Finasteride 
Double blind period 
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication 
 
5.5.9 
Emergency breaking of assigned treatment code  
Emergency 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 
 
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patient and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the Study Team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name (if available) 
• patient number 
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.  
5.6 
Study completion and discontinuation  
5.6.1 
Study completion and post-study treatment  
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol. 
Continuing care should be provided by investigator and/or referring physician based on patient 
availability for follow-up.  
For all patients/subjects a safety follow-up visit should be conducted (e.g. by telephone) 30 days 
after last visit (Visit 5) or PD, or TSD. The information to be collected at this follow up visit 
includes concomitant medications, adverse events, and survival status. 
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  
• Any situation in which study participation might result in a safety risk to the patient 
• Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator and constitute a 
reason for temporary or permanent discontinuation of study treatment 
• Use of prohibited treatment as per Table 5-2. In case of initiation of open-label ACEI during 
the double blind treatment period, study medication must be stopped for ≥36 hours prior to 
initiation of open-label ACEI. The open label ACEI must be stopped for ≥36 hours prior to 
re-initiation of study drug 
• Depending on the serum potassium, blood pressure, or eGFR, patients may need to have 
their study drug dose or the dose of another concomitant medication reduced or 
discontinued, or, if appropriate, have potentially contributing agents adjusted. Please refer 
 
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to Appendix 4, Appendix 5, and Appendix 6 for treatment guidelines for hyperkalemia, 
hypotension, or renal dysfunction, respectively. 
 
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 study drug, for a study treatment discontinuation visit. Treatment discontinuation visit 
assessments detailed in the “unplanned treatment discontinuation visit” 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 on the 
appropriate CRF.  
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. 
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/subjects 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 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. 
 
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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 must 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 planned 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 specified in the clinical trial 
study contract. This may include reasons related to the benefit risk assessment of participating 
in the study, practical reasons, or for regulatory or medical reasons (including slow enrolment). 
Should this be necessary, the patient must be seen as soon as possible and treated as a 
prematurely discontinued patient. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The sponsor will be responsible for informing the Institutional Review 
Board/Independent Ethics Committee (IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed. 
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF. 
 
 
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Table 6-1 
Assessment schedule 
 
Visit  
1 
2 
3 
4 
4B 
5 
 TD 
and/or 
PSD 
 
Time  
-2w to -1w 
0 
2w 
4w 
6w 
12w 
 
 
Obtain informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Some exclusion criteria apply for both Visit 1 and Visit 2 
Demography 
X 
 
 
 
 
 
 
 
Medical History 
X 
X1 
 
 
 
 
 
 
NYHA Classification 
X 
X 
X 
X 
(X) 
X 
X 
 
Previous and concomitant 
drug/non-drug treatments 
X 
X 
X 
X 
(X) 
X 
X 
 
Physical Exam 
X 
X 
S 
S 
(S) 
X 
S 
At Visit 1 (Screening), 2 (Randomization), and 5 (EOS) 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 
X 
 
 
Vital signs 
X 
 
 
 
 
X 
X 
 
IIEF-15 
 
X 
X 
X 
 
X 
X 
 
IIEF-5 
X 
X 
 
 
 
 
 
 
Dispense Sexual Activity Log 
 
X 
 
 
 
 
 
 
Sexual Activity Log 
 
X 
X4 
X4 
X4 
X4 
X 
Sexual activity Log is completed by the patient once a week. Baseline 
value is assessed at Visit 2  
Diagnostic and Laboratory 
evaluations 
X2 
X3 
 
X 
 
X 
X 
Hematology and Biochemistry 
NT-proBNP 
X 
X3 
 
X 
 
X 
X 
 
Laboratory assessment 
 
 
X3 
(X3,5) 
(X) 
 
 
Abbreviated assessment for Potassium, AST and ALT and 
Creatinine/eGFR.  
Dispense Study Medication 
 
X 
X 
X 
 
 
 
 
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Visit  
1 
2 
3 
4 
4B 
5 
 TD 
and/or 
PSD 
 
Time  
-2w to -1w 
0 
2w 
4w 
6w 
12w 
 
 
Drug accountability 
 
 
X 
X 
(X) 
X 
X 
 
Adverse event monitoring 
X 
X 
X 
X 
(X) 
X 
X 
 
Contact IVRS/IWRS 
S 
S 
S 
S 
(S) 
S 
S 
 
Study Completion form 
 
 
 
 
 
 
X 
 
TD = Study treatment discontinuation; PSD = Premature subject/patient discontinuation 
X = assessment to be recorded on clinical data base 
S = assessment to be recorded on source documentation only 
“( )” = Assessments for Visit 4B are in brackets, as Visit 4B is a visit not applying to all patients 
IIEF = International Index of Erectile Function 
 
1 = Medical history as far as needed for inclusion and exclusion criteria 
2 = PSA level will be determined at Visit 1  
3 = Blood draw 3-4 days before Study Visit (central lab) 
4 = sexual activity log is completed once a week by the patient  
5 = The laboratory assessment (safety lab) only applies for patients who started with dose level 1 (Cave: these patients need to come 3-4  
 days before Visit 4 for the blood draw). The Diagnostic and Laboratory Evaluations at Visit 4 are performed at the regular visit.  
 
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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 period will 
have the study completion CRF for the screening period, 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. 
 
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, 
rescreening will only be possible for inclusion criteria 4, 6, 7, 8 and 9 and exclusion criteria 1, 
7, 8, 9, 14, 25, 26 and 27. In this case, a completely new patient number will be allocated to the 
patient and all Visit 1 assessments will be performed again. A patient may be re-screened once 
only.  
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, 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 and 2), 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  
Compliance 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. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. 
6.4 
Efficacy  
• 
IIEF-15 questionnaire 
• 
Patient-reported frequency of sexual activity  
• 
NT-proBNP 
 
 
6.4.1 
IIEF-15 questionnaire  
The International Index of Erectile Function (IIEF-15) is a patient self-reported questionnaire 
to assess ED in male patients (see annex for detailed information). It consists of 15 questions 
assessing five main principles associated with ED: erectile function, orgasmic function, sexual 
 
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Patient-reported sexual activity 
Although the IIEF-15 questionnaire is assessing erectile function, it is not measuring sexual 
activity other than intercourse with vaginal penetration, or the attempt to vaginal intercourse. 
However, sexual activity can also include sexual actions like masturbation, sexual foreplay or 
intimacy with a partner. Sexual activity other than intercourse is also an important part of 
Quality of Life (McCabe, 1997). Therefore, a sexual activity diary was developed to assess the 
patients’ sexual activity and QoL associated with the patients’sexual activity.  
 
NT-proBNP 
NT-proBNP is a biomarker relevant to the pathophysiology of cardiovascular disease and has 
shown prognostic value in large clinical trials. Therefore, NT-proBNP is an appropriate readout 
for the progression of cHF (Zile et al., 2016, McMurray et al., 2014).  
6.5 
Safety  
The Sponsor may request additional information on specific adverse events 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 additional information will be de-identified prior to 
collection by Novartis or its agents. 
6.5.1 
Physical examination  
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vasculature and neurological function. 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 [SBP and DBP] and pulse). A short physical exam will be at all visits starting from 
Visit 3 except where a complete physical examination is required (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 CRF capturing Medical History. Significant findings made after first 
administration of investigational drug which meet the definition of an Adverse Event must be 
recorded on the appropriate CRF capturing AEs. 
6.5.2 
Vital signs  
Vital signs include BP and pulse measurements. BP will be measured by using a standard 
sphygmomanometer with an appropriate size cuff and the non-dominant arm in the sitting 
position after 5 minutes of rest. 
Guidelines for the management of BP are provided in Appendix 5. 
 
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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 all visits, until the EOS visit. 
6.5.4 
Laboratory evaluations  
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. 
Clinically notable laboratory findings are defined in Appendix 1. 
The investigator or his/her designee should review the central laboratory results as soon as they 
become available to decide on whether any adjustments in the patient’s study drug or non-study 
drug regimen are needed. Therefore, unscheduled visits are possible based on investigator’s 
discretion.  
 
All central laboratory results will be communicated to the investigators and the sponsor. Details 
on the collection, shipment of samples and reporting of results by the central laboratory will be 
provided to investigators in the laboratory manual. 
 
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator in the Comments screen of the patient's eCRF and additional 
laboratory evaluations should be performed, as judged appropriate by the investigator. If the 
laboratory abnormality induces clinical signs or symptoms, or requires therapeutic intervention, 
then the diagnosis or medical condition must be entered on the AEs screen of the patient's eCRF. 
If the laboratory abnormality is the primary reason for an unforeseen hospitalization or 
otherwise fulfills the seriousness category of an AE, then the procedure for rapid notification 
of SAEs must be followed. Likewise, if the laboratory abnormality leads to discontinuation 
from the study drug (temporarily or permanently), the patient must be followed until the 
abnormality resolves or until it is judged to be permanent. 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be measured at Visits 1, 2, 4, 5 and in case of study treatment 
discontinuation (TD) or premature subject/patient discontinuation (PSD). 
6.5.4.2 
Clinical chemistry 
Glucose, blood urea nitrogen (BUN), Blood urea, creatinine, creatinine kinase, total bilirubin, 
AST, ALT, alkaline phosphatase, INR, GFR, HbA1c absolute, HbA1c relative, sodium, 
potassium, chloride, calcium, total protein, albumin, HDL, LDL, triglycerides, and uric acid 
will be measured at visits 1, 2, 4, 5 and in case of TD or PSD. 
BUN, creatinine, GFR, potassium and urea will be obtained from patients at every visit when a 
complete laboratory test is not done (i.e., Visit 3, 4 and 4B, please see Table 6-1 for details). 
The latter is true for all unscheduled visits done with up-titration intention. 
 
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6.5.4.3 
Urine analysis  
Not applicable 
6.5.5 
Electrocardiogram (ECG)  
Not applicable.  
6.5.6 
Pregnancy and assessments of fertility  
Not applicable. 
6.5.7 
Angioedema 
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise. 
Although the mechanism is not fully understood, bradykinin has been implicated as the putative 
mediator. Therefore, medications that raise the levels of endogenous bradykinin by inhibiting 
the enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and NEP, may 
result in this potentially dangerous side effect.  
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an Angioedema-
like Event form (provided by Novartis) to summarize the event, its treatment, and its ultimate 
outcome. This report along with the requisite medical documentation must be submitted to 
Novartis as soon as possible. Follow-up reports must be communicated to Novartis as soon as 
new information regarding the event becomes available. All hospital records related to the event 
must be communicated to Novartis. The investigator may be also be contacted by Novartis 
regarding AEs that may resemble an angioedema-like event. A list of terms that are considered 
“angioedema-like” (e.g., periorbital swelling) will be provided to sites in a manual. The 
investigator or his/her delegated staff must complete the required forms and provide the 
required medical records for all such events, regardless of whether the investigator views the 
event in question as angioedema or not.  
All angioedema reports will be forwarded to an Angioedema Adjudication Committee by 
Novartis for assessment. Information regarding this committee is outlined in Section 8.5. 
Details on the procedures for reporting angioedema events will be provided to investigators in 
a manual. 
6.5.8 
Cognitive Impairment 
Angiotensin receptor blockade has been suggested to improve cognitive function, as might 
overall improvement in cardiac and vascular function. Thus, improvements in cardiac function 
and cerebral blood flow by LCZ696 are hypothesized to potentially improve vascular effects 
and, thereby, cognition. However, neprilysin is one of multiple enzymes involved in the 
breakdown of amyloid β, a peptide linked to cognitive impairment. Thus, cognitive function 
resulting from combined angiotensin receptor blockade and neprilysin inhibition with LCZ696 
is subject to standardized follow-up.  
It is important that the investigator pays attention to any events of cognitive impairment or 
related events that may be reported by patients. If such an event occurs that meets criteria for 
 
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serious adverse event, the investigator will complete a separate questionnaire for a Dementia-
related Event form (provided by Novartis) to summarize the event, its further diagnostic tests 
performed, and its related information. A list of terms that are considered “dementia-like” (e.g., 
presenile dementia, memory impairment) will be provided to sites in a manual. 
6.5.9 
Statin-related Events 
Statin-related events are subject to additional safety assessments and thus are followed with a 
standardized questionnaire. A list of terms that are considered “statin-related” (e.g., 
rhabdomyolysis, acute pancreatitis, myalgia and muscle spasm) will be provided to sites in a 
manual.  
If such an event occurs that meets criteria for serious adverse event, the investigator will 
complete a separate questionnaire for a Hepatotoxicity and Statin-related Event form (provided 
by Novartis) to summarize the event, its further diagnostic tests performed, and its related 
information. 
6.5.10 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 
6.6.1 
Patient Reported Outcomes (PRO) 
The following Patient reported outcomes (PROs) will be used in the study: 
6.6.1.1 
IIEF-5  
The IIEF-5 score will be used in male patients with heart failure with reduced ejection fraction 
to determine the patients’/subjects’ eligibility for study participation. The IIEF-5 consists of 5 
items. For every item, 5 possible response options are available (score 1-5) adding up to a 
maximum total score of 25. Erectile function will be determined by study personnel by adding 
individual scores to a total score. 
22-25   
No erectile dysfunction 
17-21  
Mild erectile dysfunction 
12-16  
Mild to moderate erectile dysfunction 
8-11   
Moderate erectile dysfunction 
5-7  
 
Severe erectile dysfunction. 
 
The estimated completion time is 5-10 minutes. The IIEF-5 score will be assessed at Visit 1 and 
Visit 2.  
6.6.1.2 
IIEF-15  
The IIEF-15 score will be used in male patients with heart failure with reduced ejection fraction. 
The IIEF-15 is a validated, multi-dimensional, self-administered questionnaire for the 
 
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All PRO measures will be performed as ePROs on an electronic device (tablet). All these 
questionnaires should be completed by patients/subjects before they see the study physician 
where applicable. All questionnaires will be completed in German language. IIEF-15 
will be assessed at the planned study visits 2, 3 and 5 and ideally prior to the patient seeing 
the investigator for any clinical assessment or evaluation. The patient should be given sufficient 
instruction, space, time and privacy to complete the questionnaire.  
If patients/subjects experience any difficulties with submission after they complete the PROs, 
the study staff should assist them with submitting their PRO responses. All attempts should be 
made to collect responses to all PROs for all patients/subjects, including from those who 
prematurely discontinue prior to the study evaluation completion visit, however, if 
patients/subjects refuse to complete PROs, this should be documented in study source records. 
Patient’s refusal to complete study PROs are not protocol deviations. 
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). If AEs or SAEs are confirmed, then the physician must record the events as per 
instructions given in Section 7.1 and Section 7.2 of the protocol.  
6.6.2 
Pharmacokinetics  
Not applicable. 
6.6.3 
Other biomarkers  
Not applicable. 
7 
Safety monitoring  
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
 
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• 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 
patients and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.  
Adverse events must be recorded in the appropriate CRF capturing AEs 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  
• 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 adverse events must be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (e.g. further observation only)  
• [investigational] treatment dosage increased/reduced 
• [investigational] treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given  
• 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 
 
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updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient. 
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
7.2 
Serious adverse events  
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• 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). 
 
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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting  
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30-day period after the last study visit should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information. 
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.  
 
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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 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring should be entered 
into the appropriate CRFs. Please refer to Table 14-1 in Appendix 2 for complete 
definitions of liver laboratory triggers and liver events.  
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. LFT repeats must then be performed at central laboratory as soon as possible. If a liver 
event is subsequently reported, any local LFTs previously conducted that are associated with 
this event must be reported on the appropriate CRFs. 
• 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 the appropriate CRFs. 
7.4 
Renal safety monitoring  
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
• Serum event: 
• confirmed (after ≥24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status 
• Urine event 
• new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable) 
 
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• new onset (≥1+), hematuria or glycosuria  
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 4.  
7.5 
Reporting of study treatment errors including misuse/abuse  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the appropriate CRF, 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 CRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes  
Yes, even if not 
associated with a SAE 
7.6 
Pregnancy reporting  
Not applicable.  
7.7 
Prospective suicidality assessment  
All SAEs relating to suicidal behavior must be reviewed by the Safety Management Team or 
early project teams. 
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 data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
 
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of data capture/data entry, 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 data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the 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 (eCRFs) using fully validated secure web-enabled software that conforms 
to US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access 
to the system until they have been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control  
The study will use electronic source documents and source data, and data entry will be done by 
the sites directly into eSource DDE. 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data.  
 
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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. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Diary data will be entered into an electronic diary by the patient and patients will fill in their 
PRO data in a site based tablet. The system will be supplied by a vendor, who will also manage 
the database. The database will be sent electronically to Novartis personnel (or designated 
CRO). 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The data 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 Trial 
Statistician and Statistical Reporting and the Clinical Trial Leader. 
8.4 
Data Monitoring Committee  
Not required. 
8.5 
Angioedema Adjudication Committee 
If an angioedema or angioedema-like event occurs, the investigator will complete an 
Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis). Details 
on the process of reporting angioedema and angioedema like events are outlined in a manual 
provided to investigators. 
Submission of an angioedema report is not a substitution for the submission of an AE or SAE 
report. If an angioedema-like event satisfies the definition of an AE or SAE, the investigator 
must submit an AE or SAE report according to the respective processes in addition to the 
Adjudication Questionnaire for an Angioedema-like Event. 
The membership and responsibilities of the Angioedema Adjudication Committee are defined 
in a separate document that will be provided to the sites. 
 
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9 
Data analysis  
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation. 
9.1 
Analysis sets  
The following analysis sets will be used for the statistical analyses: 
The full analysis set (FAS) will consist of all randomized patients who received at least one 
dose of study drug. Following the intent-to-treat principle, patients will be analyzed according 
to the treatment which they were assigned to at randomization. Efficacy variables will be 
analyzed based on the FAS. 
The safety set (SAF) will consist of all randomized patients who received at least one dose of 
study drug. Patients will be analyzed according to the treatment actually received. The SAF will 
be used for the analyses of safety variables. 
9.2 
Patient demographics and other baseline characteristics  
Baseline value is defined as the last non-missing assessment prior to the first dose of 
randomized study medication.  
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (<65 years vs. ≥65 years), sex, race, weight, height, 
body mass index (BMI), category of prior CHF medication, prior HF hospitalization, NYHA 
class, and vital signs. BMI will be calculated as weight (kg) / height2 (m2) from the collected 
height and weight at Visit 1 (Screening). Continuous variables will be summarized using n, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using frequency and percentage. The FAS will be the patient population for the 
above analyses. 
9.3 
Treatments  
The overall duration on the double-blind study drug will be summarized by treatment group 
using mean, standard deviation, median, minimum, and maximum. Additionally, the number 
and percentage of patients will be summarized by treatment group for duration category.  
Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date respectively, will be summarized by therapeutic class, preferred term, and 
treatment group for the safety population.  
The number and percentage of patients on different CHF background medications (β-blockers, 
diuretics) will be tabulated by treatment at baseline and during the double-blind stage. 
The FAS will be used for the above analyses. 
 
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9.4 
Analysis of the primary variable(s) 
9.4.1 
Primary Variable(s) 
The primary endpoint is the Erectile function score IIEF-15 at 3 months. The trial aims to 
estimate the effect of the treatment policy, irrespective of intercurrent events such as dose 
changes or adherence to randomized treatment. The following estimand will be used: 
• Population – Full Analysis Set (FAS) 
• Variable of Interest – Erectile function score IIEF-15 at 3 months 
• Intervention effect – effect between sacubitril/valsartan versus enalapril at 3 months 
regardless of adherence to randomized treatment. 
• Summary measure –difference in means 
For patients who permanently discontinue study treatment, values collected after study drug 
discontinuation will generally be included in the analysis. 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary variable will be analyzed using a mixed model for repeated measures (MMRM), 
The response variable will be the Erectile function score IIEF-15. Treatment 
(sacubitril/valsartan versus enalapril), visit and treatment-by-visit interaction will be included 
as fixed-effect factors; baseline IIEF-15 will be included as a covariate; the within-patient 
covariance will be modeled using an unstructured covariance matrix (a common matrix for the 
two treatment groups). The analysis will include all (two) scheduled post-baseline visits and 
will be performed based on the likelihood method with an assumption of missing at random 
(MAR) for missing data. 
The null-hypothesis to be rejected is that there is no difference in mean IIEF-15 scores at 3 
months between the two treatment arms, in mathematical terms: H0: μ1 = μ2 vs. Ha: μ1 ≠ μ2, 
where μ1 and μ2 are mean IIEF-15 scores at 3 months for the treatment groups of 
sacubitril/valsartan versus enalapril, respectively. 
The statistical test will be performed at the two-sided significance level of 0.05 based on the 
MMRM model. The estimates and the corresponding 95% confidence intervals will be provided 
for the difference in adjusted means at month 3 between the two treatment groups based on the 
MMRM model. Although this test is defined as two-sided, superiority of sacubitril/valsartan 
versus enalapril will be claimed only, if the difference is in favor of sacubitril/valsartan. 
The FAS will be used for the above primary analyses. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Patients will be followed up and all scheduled visits should be performed, even if study drug is 
discontinued for that respective patient prematurely. Therefore, missing values should only 
 
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occur in case of death, withdrawal of informed consent or loss to follow up. In these cases, 
patients will be included with their available values into the statistical MMRM model. 
9.4.4 
Sensitivity analyses  
A ‘while on treatment’ estimand might be meaningful to explore the effect of drop-outs on the 
primary estimand. This estimand will include drop-outs with their last observed value and will 
not (like the MMRM model of the primary estimand) extrapolate a possible improvent that 
might have been observed if the patient had continued. The following estimand will be used: 
• Population – Full Analysis Set (FAS) 
• Variable of Interest – Erectile function score IIEF-15 at last observed visit 
• Intervention effect – effect between sacubitril/valsartan versus enalapril at last observed 
visit regardless of adherence to randomized treatment. 
• Summary measure – difference in means 
For patients for whom an IIEF-15 at month 3 is available, this value will be used, regardless of 
adherence to treatment. Analysis will be performed using an Analysis of Covariance model for 
IIEF-15 at last observed visit with factor treatment group and covariate baseline IIEF-15. 
In case of substantial/early drop-out, additional estimands may be explored as post-hoc 
analyses.  
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables  
Self-reported frequency of sexual activity per month will be analyzed using a MMRM model 
analogous to the one used for the primary endpoint, NT-proBNP levels at months 1 and 3 will 
be summarized descriptively using n, mean, standard deviation, median, minimum, and 
maximum. 
9.5.2 
Safety variables 
Safety assessments will be based mainly on the frequency of adverse events. Adverse events 
will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). An adverse event related to study drug is 
defined as one considered by the investigator to have a suspected relationship with the study 
drug. The adverse events will be summarized by the number and percentage of patients in each 
primary system organ class and preferred term. For summaries by severity of event, the most 
severe occurrence for a particular preferred term will be used for a given patient. Summary 
tables of adverse events by treatment and severity will be provided. 
Multiple occurrences of the same AE or SAE in the same patient will be counted only once, 
using the worst severity and drug relationship. 
In the data listings of adverse events, the severity of an AE, whether or not an AE is study drug 
related, and whether or not it is a serious AE, will be indicated. 
 
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a double-blind randomized trial and the beneficial effect of sacubitril/valsartan will likely be 
driven not by valsartan but by the neprilysin inhibition introduced by sacubitril. For sample size 
calculation the shorter study period, differing patient population (heart failure versus 
hypertension) as well as the use of bisoprolol/metoprolol have to be taken into account. Beta-
blocker have differing effects on erectile function. While propranolol and atenolol are well-
known to reduce sexual function, nebivolol has vasodilating effects, which may even be 
beneficial in erectile dysfuntion (Baumhakel et al., 2011). Bisoprolol/metoprolol have been 
suggested to have a neutral effect on erectile dysfunction (Baumhakel et al., 2011) and were 
thus chosen as the allowed concomitant beta-blockers within the study.  
Therefore, a treatment effect of sacubitril/valsartan compared to enalapril of 3.5 IIED units was 
estimated. Assuming a standard deviation of 7 IIEF units and a two-sided alpha of 0.05, 86 
patients per arm would confer a 90% power to detect a conservative treatment difference of 3.5 
IIEF units. This is in accordance with the minimal clinically important difference of the erectile 
function domain of IIEF-15 of 2 and 5 IIEF units in patients with mild and moderate erectile 
dysfunction, respectively (Rosen et al., 2011). 
To compensate for some drop-out and other protocol deviations, 100 patients/arm (200 in total) 
should be randomized into this trial. There will be no additional recruitment in case some 
patients will not be able to achieve the target dose since based on PARADIGM-HF and a shorter 
trial duration, no substantial influence on the power of the trial is expected. 
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 (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after such 
consent has been provided by a legally acceptable representative(s) of the patient. 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.  
For trials using an Electronic Informed Consent system where a date/timestamp is automatically 
generated, the system-generated date/timestamp is sufficient; additional input of the date at the 
time of consent is not required by the patient.  
Novartis will provide to investigators in a separate document an informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study.  
 
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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, 
informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients/subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
10.4 
Publication of study protocol and results  
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
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, 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 including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 
not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants. 
 
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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.  
11.1 
Protocol amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients/subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 
12 
References 
References are available upon request 
 
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KIM, K. S., KOZAN, O., LLAMAS, E. B., MARTINEZ, F., MERKELY, B., 
MENDOZA, I., MOSTERD, A., NEGRUSZ-KAWECKA, M., PEUHKURINEN, K., 
RAMIRES, F. J., REFSGAARD, J., ROSENTHAL, A., SENNI, M., SIBULO, A. S., 
JR., SILVA-CARDOSO, J., SQUIRE, I. B., STARLING, R. C., TEERLINK, J. R., 
VANHAECKE, J., VINEREANU, D., WONG, R. C., INVESTIGATORS, P.-H. & 
COORDINATORS 2015. Angiotensin receptor neprilysin inhibition compared with 
 
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enalapril on the risk of clinical progression in surviving patients with heart failure. 
Circulation, 131, 54-61. 
PONIKOWSKI, P., VOORS, A. A., ANKER, S. D., BUENO, H., CLELAND, J. G., COATS, 
A. J., FALK, V., GONZALEZ-JUANATEY, J. R., HARJOLA, V. P., JANKOWSKA, 
E. A., JESSUP, M., LINDE, C., NIHOYANNOPOULOS, P., PARISSIS, J. T., PIESKE, 
B., RILEY, J. P., ROSANO, G. M., RUILOPE, L. M., RUSCHITZKA, F., RUTTEN, 
F. H. & VAN DER MEER, P. 2016. 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: The Task Force for the diagnosis and 
treatment of acute and chronic heart failure of the European Society of Cardiology 
(ESC). Developed with the special contribution of the Heart Failure Association (HFA) 
of the ESC. Eur J Heart Fail. 
RASTOGI, S., RODRIGUEZ, J. J., KAPUR, V. & SCHWARZ, E. R. 2005. Why do patients 
with heart failure suffer from erectile dysfunction? A critical review and suggestions on 
how to approach this problem. Int J Impot Res, 17 Suppl 1, S25-36. 
ROSEN, R. C., RILEY, A., WAGNER, G., OSTERLOH, I. H., KIRKPATRICK, J. & 
MISHRA, A. 1997. The international index of erectile function (IIEF): a 
multidimensional scale for assessment of erectile dysfunction. Urology, 49, 822-30. 
SENNI, M., MCMURRAY, J. J., WACHTER, R., MCINTYRE, H. F., REYES, A., 
MAJERCAK, I., ANDREKA, P., SHEHOVA-YANKOVA, N., ANAND, I., YILMAZ, 
M. B., GOGIA, H., MARTINEZ-SELLES, M., FISCHER, S., ZILAHI, Z., COSMI, F., 
GELEV, V., GALVE, E., GOMEZ-DOBLAS, J. J., NOCIAR, J., RADOMSKA, M., 
SOKOLOVA, B., VOLTERRANI, M., SARKAR, A., REIMUND, B., CHEN, F. & 
CHARNEY, A. 2016. Initiating sacubitril/valsartan (LCZ696) in heart failure: results 
of TITRATION, a double-blind, randomized comparison of two uptitration regimens. 
Eur J Heart Fail, 18, 1193-202. 
VLACHOPOULOS, C., IOAKEIMIDIS, N., TERENTES-PRINTZIOS, D., AZNAOURIDIS, 
K., BAOU, K., BRATSAS, A., LAZAROS, G. & STEFANADIS, C. 2010. Amino-
terminal pro-C-type natriuretic peptide is associated with arterial stiffness, endothelial 
function and early atherosclerosis. Atherosclerosis, 211, 649-55. 
WILTINK, J., HAUCK, E. W., PHADAYANON, M., WEIDNER, W. & BEUTEL, M. E. 2003. 
Validation of the German version of the International Index of Erectile Function (IIEF) 
in patients with erectile dysfunction, Peyronie's disease and controls. Int J Impot Res, 
15, 192-7. 
ZILE, M. R., CLAGGETT, B. L., PRESCOTT, M. F., MCMURRAY, J. J., PACKER, M., 
ROULEAU, J. L., SWEDBERG, K., DESAI, A. S., GONG, J., SHI, V. C. & 
SOLOMON, S. D. 2016. Prognostic Implications of Changes in N-Terminal Pro-B-
Type Natriuretic Peptide in Patients With Heart Failure. J Am Coll Cardiol, 68, 2425-
2436. 
 
 
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13 
Appendix 1: Clinically notable laboratory values  
 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline:  
 
Hematology  
RBC count  
 
 
>50% increase, >20% decrease  
Hemoglobin   
 
>50% increase, >20% decrease  
Hematocrit  
 
 
>50% increase, >20% decrease  
WBC count  
 
 
>50% increase, >50% decrease  
Platelet count   
 
>75% increase, >50% decrease  
 
Blood Chemistry  
ALT (SGPT)   
 
>150% increase  
AST (SGOT)   
 
>150% increase  
BUN   
 
 
>50% increase  
Creatinine 
 
 
>50% increase  
Total bilirubin   
 
>100% increase  
CPK   
 
 
>300% increase  
Alkaline phosphatase  
>100% increase  
Potassium 
 
 
>20% increase, >20% decrease  
Chloride  
 
 
>10% increase, >10% decrease  
Calcium  
 
 
>10% increase, >10% decrease  
Uric acid  
 
 
>50% increase  
 
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14 
Appendix 2: 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 he study treatment 
immediately 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Record liver events to the appropriate 
CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue he study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Record liver events to the appropriate 
CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 3 × ULN and 
INR > 1.5 
• 
Discontinue he study treatment 
immediately 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Record liver events to the appropriate 
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 
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 
• 
Establish causality 
• 
Record liver events to the appropriate 
CRF 
> 3 × ULN 
accompanied by 
symptomsb 
• 
Discontinue he study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Record liver events to the appropriate 
CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator’s 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’s 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 
• 
Record liver events to the appropriate 
CRF 
Investigator’s 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 
• 
Record liver events to the appropriate 
CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator’s 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’s discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
Jaundice 
• 
Discontinue he study treatment 
immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Record liver events to the appropriate 
CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator’s discretion) 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study treatment interruption or 
discontinuation  
• 
Hospitalization if clinically appropriate 
• 
Establish causality 
• 
Record liver events to the appropriate 
CRF 
Investigator’s discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 
 
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Appendix 3: 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 diagnos ic 
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. 
 
16 
Appendix 4: Treatment guidelines for hyperkalemia (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: 
 
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• Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 
• Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 
• Potassium supplements, e.g., potassium chloride 
• Salt substitutes 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors 
• Trimethoprim 
and 
trimethoprim-containing 
combination 
products, 
such 
as 
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. 
• If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 3-5 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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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 increases 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 
 
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• Urinary tract obstruction 
• Study medication 
 
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. 
 
 
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20 
Appendix 8: IIEF-5 
 
 
 INTERNATIONAL INDEX FOR ERECTILE DYSFUNCTION (IIEF-5) 
 
  
 
 Over the past 4 weeks: 
 
 
1. How do you rate your 
confidence that you could get 
and keep an erection? 
1 
Very low 
2 
Low 
3 
Moderate 
4 
High 
5 
Very high 
 
 
2. When you had erections with 
sexual stimulation, how often 
were your erections hard 
enough for penetration? 
1 
Almost 
never/never 
 
 
2 
A few times 
(much less 
than half  
the time) 
3 
Sometimes 
(about half  
the time) 
 
4 
Most times 
(much more 
than half  
the time) 
5 
Almost 
always/always 
 
 
 
 
3. During sexual intercourse,  
how often were you able to 
maintain your erection after you 
had penetrated (entered)  
your partner? 
1 
Almost 
never/never 
 
 
2 
A few times 
(much less 
than half  
the time) 
3 
Sometimes 
(about half  
the time) 
 
4 
Most times 
(much more 
than half  
the time) 
5 
Almost 
always/always 
 
 
 
 
4. During sexual intercourse,  
how difficult was it to maintain 
your erection to completion  
of intercourse? 
1 
Extremely 
difficult 
 
 
2 
Very  
difficult 
 
 
3 
Difficult 
 
 
 
4 
Slightly 
difficult 
 
 
5 
Not difficult 
 
 
 
 
 
5. When you attempted sexual 
intercourse, how often was it 
satisfactory for you? 
1 
Almost 
never/never 
 
 
2 
A few times 
(much less 
than half  
the time) 
3 
Sometimes 
(about half  
the time) 
 
4 
Most times 
(much more 
than half  
the time) 
5 
Almost 
always/always 
 
 
 
aThe IIEF-5 score is the sum of the ordinal responses to the five items; thus, the score can range from 5 to 25. 
 
 
 
 
 
 
 
 
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21 
Appendix 9: IIEF-15 
 
 
 INTERNATIONAL INDEX FOR ERECTILE DYSFUNCTION (IIEF-15) 
 
  
 
 
These questions ask about the effect your erection problems have had on your sex 
life over the past 4 weeks. Please answer these questions as honestly and as clearly 
as possible.  Please answer every question by checking the appropriate box []. If 
you are unsure about how to answer, please give the most accurate answer you can.  
 
In answering these questions, the following 
definitions apply: 
 
 
 
 
 
 
 
 
 
 
 
 
 
*  
Sexual intercourse 
 
Is defined as vaginal penetration (entry) of the partner. 
 
 
**  
Sexual Activity 
 
Includes sexual intercourse, caressing, foreplay and masturbation. 
 
 
***  Ejaculate 
 
Is defined as the ejection of semen from the penis (or the sensation of this). 
 
 
****  Sexual stimulation 
 
Includes situations such as loveplay with a partner, looking at erotic pictures, etc. 
 
 
1. Over the past 4 weeks how often were you able to get an erection during sexual activity**? 
Please check one box only. 
No sexual activity .............................................................................. 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ........................................................ 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
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2. Over the past 4 weeks when you had erections with sexual stimulation****, how often were 
your erections hard enough for penetration?  
Please check one box only. 
No sexual stimulation ........................................................................ 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ........................................................ 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
The next 3 questions will ask about the erections you may have had during sexual 
intercourse*. 
 
 
3. Over the past 4 weeks when you attempted sexual intercourse* how often were you able to 
penetrate (enter) your partner?  
Please check one box only. 
Did not attempt to initiate sexual intercourse .................................... 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ....................................................... 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
4. Over the past 4 weeks during sexual intercourse* how often were you able to maintain your 
erection after you had penetrated (entered) your partner?  
Please check one box only. 
Did not attempt to initiate sexual intercourse .................................... 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ....................................................... 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
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5. Over the past 4 weeks during sexual intercourse* how difficult was it to maintain your 
erection to completion of intercourse?  
Please check one box only. 
Did not attempt to initiate sexual intercourse .................................... 
 
Extremely difficult ............................................................................ 
 
Very difficult ..................................................................................... 
 
Difficult ............................................................................................. 
 
Slightly difficult ................................................................................ 
 
Not difficult ....................................................................................... 
 
 
 
 
 
 
 
 
 
*  
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner   
**  
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation   
***  
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)   
****  
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc  
 
  
 
 
6. Over the past 4 weeks how many times have you attempted sexual intercourse*?  
Please check one box only. 
No attempts ....................................................................................... 
 
1-2 attempts ....................................................................................... 
 
3-4 attempts ....................................................................................... 
 
5-6 attempts ....................................................................................... 
 
7-10 attempts ..................................................................................... 
 
11 and more attempts ........................................................................ 
 
 
 
 
7. Over the past 4 weeks when you attempted sexual intercourse* how often was it  
satisfactory for you?  
Please check one box only. 
Did not attempt to initiate sexual intercourse .................................... 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ....................................................... 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
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8. Over the past 4 weeks how much have you enjoyed sexual intercourse*?  
Please check one box only. 
No sexual intercourse ........................................................................ 
 
Very highly enjoyable ....................................................................... 
 
Highly enjoyable ............................................................................... 
 
Fairly enjoyable ................................................................................. 
 
Not very enjoyable ............................................................................ 
 
Not enjoyable .................................................................................... 
 
 
 
 
 
 
 
 
 
*  
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner   
**  
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation   
***  
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)   
****  
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc  
 
  
 
 
9. Over the past 4 weeks when you had sexual stimulation**** or had sexual intercourse* how 
often did you ejaculate***?  
Please check one box only. 
No sexual stimulation or intercourse ................................................. 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ....................................................... 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
10. Over the past 4 weeks when you had sexual stimulation**** or had sexual intercourse* how 
often did you have the feeling of orgasm with or without ejaculation***?  
Please check one box only. 
No sexual stimulation or intercourse ................................................. 
 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ....................................................... 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
*  
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner   
**  
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation   
***  
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)   
****  
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc  
 
 
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The next 2 questions ask about sexual desire.  Let's define sexual desire as a feeling 
that may include wanting to have a sexual experience (e.g. masturbation or 
intercourse*), thinking about sex, or feeling frustrated due to lack of sex. 
 
 
11. Over the past 4 weeks how often have you felt sexual desire?  
Please check one box only. 
Almost always or always ................................................................... 
 
Most times (much more than half the time) ...................................... 
 
Sometimes (about half the time) ....................................................... 
 
A few times (much less than half the time) ....................................... 
 
Almost never or never ....................................................................... 
 
 
 
 
12. Over the past 4 weeks how would you assess your level of sexual desire?  
Please check one box only. 
Very high ........................................................................................... 
 
High ................................................................................................... 
 
Moderate ............................................................................................ 
 
Low .................................................................................................... 
 
Very low or none at all ...................................................................... 
 
 
 
 
 
 
 
 
 
*  
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner   
**  
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation   
***  
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)   
****  
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc  
 
13. Over the past 4 weeks how satisfied on average have you been with your sex life?  
Please check one box only. 
Very satisfied ..................................................................................... 
 
Moderately satisfied .......................................................................... 
 
About equally satisfied and dissatisfied ............................................ 
 
Moderately dissatisfied ..................................................................... 
 
Very dissatisfied ................................................................................ 
 
 
 
 
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14. Over the past 4 weeks how satisfied have you been with your sexual relationship with a 
partner?  
Please check one box only. 
Very satisfied ..................................................................................... 
 
Moderately satisfied .......................................................................... 
 
About equally satisfied and dissatisfied ............................................ 
 
Moderately dissatisfied ..................................................................... 
 
Very dissatisfied ................................................................................ 
 
 
 
 
15. Over the past 4 weeks how would you rate your confidence that you could get and keep  
an erection?  
Please check one box only. 
Very high ........................................................................................... 
 
High ................................................................................................... 
 
Moderate ............................................................................................ 
 
Low .................................................................................................... 
 
Very low ............................................................................................ 
 
 
 
 
 
 
 
 
 
*  
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner   
**  
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation   
***  
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)   
****  
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc  
 
 
 
 
 
 
 
 
 
 
 
 
 
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22 
Appendix 10: Sexual activity diary 
 
1. Within the past 7 days, how often did you try to have sexual intercourse (attempted vaginal 
penetration) with your partner? 
□ 
not at all (no attempted sexual intercourse within the past 7 days) 
□ 
once 
□ 
twice 
□ 
three times 
□ 
> three times 
 
 
2. Within the past 7 days, how often have you tried to masturbate? 
□ 
not at all (no attempt to masturbate within the past 7 days) 
□ 
once 
□ 
twice 
□ 
three times 
□ 
> three times 
 
3. Within the past 7 days, how often did you have an erection at night or in the morning (if both 
apply, please only count once)? 
□ 
not at all (no erection at night or in the morning) 
□ 
once 
□ 
2-3 times 
□ 
4-5 times 
□ 
> 5 times 
 
4. Within the past 7 days, how often have you had intimate physical activity with your partner 
other than having vaginal intercourse (exchange of affection, foreplay, petting, oral 
intercourse)? 
□ 
not at all (no other sexual activity) 
□ 
once 
□ 
2-3 times 
□ 
4-5 times 
□ 
> 5 times 
 
5. Within the past 7 days, did you avoid physical intimacy with your partner because of your 
diminished erectile capability?  
□ 
yes 
□ 
no 
 
6. Within the past 7 days, how would you rate your affection/emotions towards your partner? 
□ 
non existent  
□ 
little 
 
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□ 
satisfactory 
□ 
strong  
□ 
very strong 
 
7. Within the past 7 days, to which extent did your sexual desire influence your mood? 
□ 
very negatively affected 
□ 
negative affected 
□ 
not affected 
□ 
positive affected  
□ 
very positive affected 
 
 
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Global Clinical Development - General Medicine 
sacubitril/valsartan
Clinical Trial Protocol CLCZ696BDE03 
A randomized, double-blind, active-controlled study to assess the 
effect of sacubitril/valsartan compared with enalapril to improve 
erectile function in patients with heart failure with reduced 
ejection fraction (HFrEF) and erectile dysfunction (ED)
Document type:
EUDRACT number:
Clinical Trial Protocol
2018-000220-33
Version number:
V01 
Clinical trial phase:
IIIB
Release date:
15-Jan-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.4 (May 2017)
 
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
Amendment 1 ......................................................................................................................9
1.
Introduction .......................................................................................................................10
1.1
Background............................................................................................................10
1.2
Purpose ..................................................................................................................11
2.
Study objectives and endpoints .........................................................................................11
3.
Investigational plan ...........................................................................................................13
3.1
Study design...........................................................................................................13
3.2
Rationale for study design .....................................................................................16
3.3
Rationale for dose/regimen, route of administration and duration of treatment....17
3.4
Rationale for choice of comparator .......................................................................17
3.5
Purpose and timing of interim analyses/design adaptations..................................18
3.6
Risks and benefits..................................................................................................18
4.
Population..........................................................................................................................18
4.1
Inclusion criteria ....................................................................................................18
4.2
Exclusion criteria...................................................................................................19
5.
Treatment...........................................................................................................................22
5.1
Study treatment......................................................................................................22
5.1.1
Investigational and control drugs..........................................................22
5.1.2
Additional treatment..............................................................................23
5.2
Treatment arms......................................................................................................23
5.3
Treatment assignment and randomization.............................................................23
5.4
Treatment blinding.................................................................................................23
5.5
Treating the patient................................................................................................23
5.5.1
Patient numbering .................................................................................23
5.5.2
Dispensing the study drug.....................................................................23
5.5.3
Handling of study and additional treatment..........................................23
5.5.4
Instructions for prescribing and taking study treatment........................23
5.5.5
Permitted dose adjustments and interruptions of study treatment ........24
5.5.6
Rescue medication ................................................................................26
5.5.7
Concomitant medication .......................................................................26
5.5.8
Prohibited medication ...........................................................................28
5.5.9
Emergency breaking of assigned treatment code..................................29
 
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5.6
Study completion and discontinuation...................................................................29
5.6.1
Study completion and post-study treatment..........................................29
5.6.2
Discontinuation of study treatment .......................................................29
5.6.3
Withdrawal of informed consent...........................................................29
5.6.4
Loss to follow-up ..................................................................................30
5.6.5
Early study termination by the sponsor.................................................30
6.
Visit schedule and assessments .........................................................................................30
6.1
Information to be collected on screening failures..................................................33
6.2
Patient demographics/other baseline characteristics .............................................33
6.3
Treatment exposure and compliance .....................................................................33
6.4
Efficacy..................................................................................................................33
6.4.1
IIEF-15 questionnaire............................................................................33
6.4.2
Patient-reported frequency of sexual activity .......................................33
6.4.3
NT-proBNP...........................................................................................34
34
6.4.5
Appropriateness of efficacy assessments..............................................34
6.5
Safety.....................................................................................................................35
6.5.1
Physical examination ............................................................................35
6.5.2
Vital signs..............................................................................................35
6.5.3
Height and weight .................................................................................35
6.5.4
Laboratory evaluations..........................................................................35
6.5.5
Electrocardiogram (ECG) .....................................................................36
6.5.6
Pregnancy and assessments of fertility .................................................36
6.5.7
Angioedema ..........................................................................................36
6.5.8
Cognitive Impairment ...........................................................................36
6.5.9
Statin-related Events .............................................................................37
6.5.10
Appropriateness of safety measurements..............................................37
6.6
Other assessments..................................................................................................37
6.6.1
Patient Reported Outcomes (PRO) .......................................................37
6.6.2
Pharmacokinetics ..................................................................................37
6.6.3
Other biomarkers...................................................................................37
7.
Safety monitoring..............................................................................................................37
7.1
Adverse events.......................................................................................................37
7.2
Serious adverse events...........................................................................................38
7.2.1
Definition of SAE .................................................................................38
7.2.2
SAE reporting........................................................................................38
 
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7.3
Liver safety monitoring .........................................................................................38
7.4
Renal safety monitoring.........................................................................................38
7.5
Reporting of study treatment errors including misuse/abuse ................................38
7.6
Pregnancy reporting...............................................................................................38
7.7
Prospective suicidality assessment ........................................................................38
8.
Data review and database management.............................................................................38
8.1
Site monitoring ......................................................................................................38
8.2
Data collection.......................................................................................................38
8.3
Database management and quality control............................................................38
8.4
Data Monitoring Committee..................................................................................38
8.5
Angioedema Adjudication Committee ..................................................................38
9.
Data analysis......................................................................................................................38
9.1
Analysis sets ..........................................................................................................38
9.2
Patient demographics and other baseline characteristics.......................................38
9.3
Treatments .............................................................................................................38
9.4
Analysis of the primary variable(s) .......................................................................38
9.4.1
Primary Variable(s)...............................................................................38
9.4.2
Statistical model, hypothesis, and method of analysis..........................39
9.4.3
Handling of missing values/censoring/discontinuations.......................39
9.4.4
Sensitivity analyses ...............................................................................39
9.5
Analysis of secondary variables ............................................................................40
9.5.1
Efficacy variables..................................................................................40
9.5.2
Safety variables .....................................................................................40
9.5.3
Resource utilization...............................................................................40
9.5.4
Pharmacokinetics ..................................................................................40
9.5.5
DNA......................................................................................................40
9.5.6
Biomarkers ............................................................................................40
9.5.7
PK/PD ...................................................................................................40
40
9.7
Interim analyses.....................................................................................................40
9.8
Sample size calculation..........................................................................................41
10. Ethical considerations........................................................................................................42
10.1
Regulatory and ethical compliance........................................................................42
10.2
Informed consent procedures.................................................................................42
10.3
Responsibilities of the investigator and IRB/IEC..................................................42
10.4
Publication of study protocol and results...............................................................42
 
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10.5
Quality Control and Quality Assurance.................................................................42
11. Protocol adherence ............................................................................................................42
11.1
Protocol amendments.............................................................................................42
12. References .........................................................................................................................42
13. Appendix 1: Clinically notable laboratory values.............................................................45
14. Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up
Requirements.....................................................................................................................46
15. Appendix 3: Specific Renal Alert Criteria and Actions....................................................47
16. Appendix 4: Treatment guidelines for hyperkalemia (serum potassium greater than
or equal to 5.5 mmol/L).....................................................................................................47
17. Appendix 5: Guidelines for the management of blood pressure .......................................48
18. Appendix 6: Guidelines for the management of renal dysfunction...................................49
50
20. Appendix 8: IIEF-5............................................................................................................51
21. Appendix 9: IIEF-15..........................................................................................................52
22. Appendix 10: Sexual activity diary...................................................................................58
List of tables
Table 2-1
Objectives and related endpoints ..........................................................11
Table 3-1              
Minimum required pre-study daily doses of commonly prescribed 
ACEIs and ARBs ..................................................................................14
Table 5-1 
Study drug dispensed during the double-blind period ..........................24
Table 5-2
Prohibited medication ...........................................................................28
Table 6-1
Assessment schedule.............................................................................31
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................38
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................46
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...46
Table 15-1
Specific Renal Alert Criteria and Actions.............................................47
List of figures
Figure 3-1
Study design..........................................................................................16
 
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COmparing arNi and ace For Improving erectile Dysfunction in 
mEN with reduCed Ejection fraction heart failure
Heart failure (HF) patients typically display various symptoms 
including peripheral congestion, low exercise tolerance, fatigue and 
dyspnea, which contribute to a progressive worsening of quality of 
life (QoL). Additionally, sexual activity remains an essential aspect 
of QoL, since, contrary to common belief, seriously ill patients 
mostly do not lose their interest in intimacy. An estimated 70% of 
male HF patients experience erectile dysfunction (ED). 
Decreasing left ventricular function is associated with significantly 
reduced erectile function in cardiovascular high-risk patients and ED 
was shown to precede cardiovascular events in these patients. 
A
secondary
analysis of the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) used in the PARADIGM-HF trial 
demonstrated that patients treated with sacubitril/valsartan 
significantly improved nearly all criteria at the physical limitation 
and social limitation section when compared with enalapril, with the 
most significant changes in intimate/sexual relationships after 8 
months of double-blind treatment.
Based on these beneficial effects and the potential positive influence 
of enhanced CNP levels under sacubitril/valsartan treatment in 
erectile tissue, we hypothesize that sacubitril/valsartan may also 
enhance erectile function in male HFrEF patients, thereby 
contributing to improvement of QoL. Enhancement in erectile 
function will be evaluated using the renowned International Index of 
Erectile Function (IIEF).
To demonstrate the superiority of sacubitril/valsartan compared to
enalapril regarding improvement in erectile function and ability in 
male patients with chronic heart failure and erectile dysfunction 
using the questionnaire International index of erectile function 
(IIEF-15) at the end of the study.
To assess the early-onset effect as well as the effect at the end of 
the study of sacubitril/valsartan versus enalapril regarding 
improvement in sexual activity assessed using patient’s self-
reported frequency of sexual activity per month
To assess the early-onset effect as well as the effect at the end of 
the study of sacubitril/valsartan versus enalapril regarding NT-
proBNP levels
This is a randomized, double-blind, double-dummy, multi-center, 
active-controlled, 
interventional 
study 
to 
compare 
sacubitril/valsartan to enalapril in improving erectile function in 
 
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male patients with chronic heart failure (NYHA II) and reduced 
ejection fraction (HFrEF) and erectile dysfunction (ED).
The study population will consist of a representative group of adult 
(≥18 and ≤ 75) male HFrEF patients in NYHA class II with mild to 
moderate ED. Eligible patients should be on a stable dose of an 
ACEI or an ARB as well as bisoprolol/metoprolol for at least 4 
weeks prior to randomization. The targeted projected sample size is 
200 patients (100 patients in each arm). It is expected that 286
patients will be screened at up to approximately 40 study sites, as a 
screen failure rate of 30% is anticipated.

Patients must give written informed consent before any assessment 
is performed and must be willing and capable to comply with all 
study procedures 

Male Outpatients ≥ 18 and ≤ 75 years of age

Patients with a diagnosis of CHF NYHA class II and reduced 
ejection fraction (< 40%) at Visit 1

Plasma NT-proBNP level of ≥ 300 pg/mL at Visit 1(Screening) 

Patients must be living in a stable and sexually active 
heterosexual partnership for at least 6 months prior to Visit 1 

Patients must have a mild to moderate erectile dysfunction 
determined using the IIEF-5 questionnaire (> 7 and ≤ 21 IIEF 
units) at Visit 1 (Screening) and Visit 2 (Randomization)

Patients must be on an ACEI or ARB at a stable dose for at least 
2 weeks prior to Visit 1 and 4 weeks prior to Visit 2

Patients 
must 
be 
treated 
with 
a 
stable 
dose 
of 
bisoprolol/metoprolol for at least 2 weeks prior to Visit 1 and 4 
weeks prior to Visit 2

No usage of any available drug for erectile dysfunction (e.g. 
sildenafil, tadalafil) for at least 2 weeks prior to Visit 1 and 4 
weeks prior to Visit 2

History of hypersensitivity or allergy to any of the study drugs, 
drugs of similar chemical classes, ACEIs, ARBs, or NEP 
inhibitors as well as known or suspected contraindications to the 
study drugs

Previous history of intolerance to recommended target doses of 
ACEIs or ARBs

Known history of angioedema 

Requirement of treatment with both ACEIs and ARBs

Current acute decompensated HF (exacerbation of chronic HF 
manifested by signs and symptoms that may require intravenous 
therapy)
 
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
Symptomatic hypotension and SBP ≤100 mm Hg at Visit 1
(Screening) or Visit 2 (Randomization)

Estimated 
glomerular 
filtration 
rate 
(eGFR) 
below 
30mL/min/1.73m2 at Visit 
1
(Screening) 
or 
Visit 
2
(Randomization)

Serum potassium level of more than 5.2 mmol/L at Visit 1
(Screening) or Visit 2 (Randomization)

History of severe pulmonary disease

Penile anatomical defects and Peyronie’s disease

Foreseeable usage of any available drug for erectile dysfunction 
(e.g. sildenafil, tadalafil) during the trial

Prostate-specific antigen (PSA) levels higher than 4 ng/mL at 
Visit 1 or known prostate cancer

Placebo to match sacubitril/valsartan at all dose levels

Enalapril (target dose 10 mg bid)

Placebo to match enalapril at all dose levels

IIEF-15 questionnaire 

Patient-reported frequency of sexual activity

Changes in NT-proBNP

Adverse event monitoring

Physical examinations and blood pressure monitoring

Monitoring of laboratory markers in blood (potassium, 
creatinine, AST/ALT)
The primary variable will be analyzed using a mixed model for 
repeated measures (MMRM). The response variable will be the 
Erectile function score IIEF-15. Treatment (sacubitril/valsartan 
versus enalapril), visit and treatment-by-visit interaction will be 
included as fixed-effect factors; baseline IIEF-15 will be included as 
a covariate.
Secondary endpoints will be analyzed descriptively.
 
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Amendment 1 
Amendment Rationale
This amendment is being introduced as a consequence of feedback from Health Authorities. In 
summary, the classification of the clinical phase of the trial was adjusted. In addition, exclusion 
criterion 33 was modified and the end of the study was defined in more detail. 
A copy of this amended protocol will be sent to the Independent Ethics Committee and Health 
Authorities.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underlined for insertions.
Clinical Trial Phase: 
This trial is classified as a phase IIIB trial instead of phase IV
Section 4.2 
Exclusion criterion 33 was modified, extending the exclusion also to patients in which any 
neurodegenerative disease or polyneuropathy is suspected. 
Section 5.6.1 
The end of the study was defined in more detail. The trial as a whole will be considered 
completed when the last visit of the last subject occurred. 
 
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1.
Introduction
1.1
Background 
Heart failure (HF) patients typically display various symptoms including peripheral congestion, 
low exercise tolerance, fatigue and dyspnea, which contribute to a progressive worsening of 
quality of life (QoL). Additionally, sexual activity remains an essential aspect of QoL, since, 
contrary to common belief, seriously ill patients mostly do not lose their interest in intimacy
(Alberti et al., 2013). The American Heart Association asserts that sexual activity is appropriate 
and safe for patients with compensated and/or mild HF (NYHA I/II) (Levine et al., 2012) but 
unfortunately, an estimated 70% of male HF patients experience erectile dysfunction (ED) 
(Alberti et al., 2013). ED describes the persistent inability to achieve and/or maintain a penile 
erection sufficient for satisfactory sexual performance (Lue, 2000).
ED and HF share common risk factors including age, atherosclerosis, hyperlipidemia, 
hypertension, diabetes mellitus, smoking, obesity and sedentary lifestyle (Rastogi et al., 2005). 
Decreasing left ventricular function is associated with significantly reduced erectile function in 
cardiovascular high-risk patients and ED was shown to precede cardiovascular events in these 
patients (Baumhakel and Bohm, 2007). In addition, common underlying pathophysiological 
mechanisms such as atherosclerosis causing reduced blood-flow, arterial insufficiency and 
endothelial dysfunction are anticipated to contribute to both ED and HF progression (Rastogi 
et al., 2005). Furthermore, ED is also influenced by depression, exercise tolerance impairment, 
anabolic deficiency and pharmacological treatment (Alberti et al., 2013). 
Several physiological pathways contribute to developing an erection. Contracted penile smooth 
muscle cells (SMC) in cavernosal arterioles and sinuses have to be transferred into the relaxed 
state in order to facilitate vasodilation and blood influx into the corpora cavernosa. With the 
increased intracorporal pressure, the surrounding fibrous tunica albuginea is stretched and thus 
compresses the subtunical venules. Thereby, the venous outflow is tremendously reduced 
contributing to initiation and maintenance of an erection (Fraga-Silva et al., 2013).
Sexual stimulation triggers nitric oxide (NO) release from penile nerves and activates the 
soluble guanyl cyclase (GC) in penile SMC to catalyze the conversion of GTP to cGMP. This 
results in the relaxation of SMCs and an increased blood flow into penile tissue. 
Besides this well-known mechanism, the particulate guanyl cyclase (pGC), a cytoplasmic 
membrane-bound GC, additionally plays a pivotal role in erectile tissue. pGC is activated by 
binding of the C-type natriuretic peptide (CNP) to its receptor NPR-B. Subsequently, active 
pGC converts GTP to cGMP in penile SMCs (Kuthe et al., 2003). Additionally, CNP acts as an 
endothelium-derived hyperpolarizing factor (EDHF) and binding to its other receptor NPR-C 
elicits an activation of the inward rectifier K+ channel mediating the hyperpolarization and 
relaxation of penile SMCs (Kun et al., 2008). Thus, CNP essentially contributes to maintaining 
SMCs dilated and the penile tissue erect. ED patients display significantly lower NT-proCNP 
levels, which correlates with the erectile function assessed using the International index of 
erectile function (IIEF-5) (Vlachopoulos et al., 2010). 
Furthermore, the RAAS system has been identified to play a paracrine role in penile tissue and 
interestingly, the physiological amount of angiotensin II produced in erectile tissues exceeds 
that found in the systemic plasma (Fraga-Silva et al., 2013). Angiotensin II elicits penile SMC 
 
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contraction by binding to its AT1 receptor. Consequently, angiotensin II contributes to the 
detumescence of the penis and termination of an erection. A hyperactivity of this peptide is 
known to augment the pathogenesis of ED (Becker et al., 2001). 
Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI), which 
both blocks the RAAS and augments natriuretic peptides, and was developed for the treatment 
of chronic HF. The clinical efficacy of sacubitril/valsartan in HF with reduced ejection fraction 
(HFrEF) patients has been demonstrated in the PARADIGM-HF study (McMurray et al., 2014). 
Sacubitril/valsartan not only established a significant benefit over enalapril in reducing 
cardiovascular death and hospitalizations due to HF as well as all-cause mortality, it also 
improved both health-related QoL, measured by Kansas City Cardiomyopathy Questionnaire 
(KCCQ) and EQ-5D, as well as symptom burden measured by NYHA class (Packer et al., 2015, 
McMurray et al., 2014). Furthermore, a post-hoc analysis of KCCQ demonstrated that patients 
treated with sacubitril/valsartan significantly improved nearly all criteria at the physical 
limitation and social limitation section when compared with enalapril, with the most significant 
changes in intimate/sexual relationships after 8 months of double-blind treatment persisting 
throughout 36 months (Chandra et al., 2018). 
Based on these beneficial effects and the potential positive influence of enhanced CNP levels 
in erectile tissue, we hypothesize that sacubitril/valsartan may also enhance erectile function in 
male HFrEF patients, thereby contributing to improvement of QoL. Enhancement in erectile 
function will be evaluated using the renowned International Index of Erectile Function (IIEF), 
which was developed and validated in the 1990s and used in various clinical trials (Rosen et al., 
1997, Wiltink et al., 2003). Since the questionnaire was developed for heterosexual men with 
the assumption of vaginal sex, homosexuals unfortunately cannot be included in this trial. 
 
urpose
The purpose of this study is to evaluate the effect of sacubitril/valsartan in improving erectile 
function in male patients with chronic heart failure (NYHA II) and reduced ejection fraction 
(HFrEF) and erectile dysfunction (ED). Data from this study are intended to provide a thorough 
understanding of the impact of sacubitril/valsartan on male sexual function and therefore quality 
of life.
2.
Study objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 
 
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Objective(s)
Endpoint(s)
•
To demonstrate the superiority of 
sacubitril/valsartan compared to enalapril 
regarding improvement in erectile function 
and ability in male patients with chronic 
heart failure and erectile dysfunction using 
the questionnaire International Index of 
Erectile Function (IIEF-15) at the end of the 
study
•
Erectile function score at 3 months
Secondary Objective(s)
Endpoint(s) for secondary objective(s)
•
To assess the early-onset effect as well as 
the effect at the end of the study of 
sacubitril/valsartan 
versus 
enalapril 
regarding improvement in sexual activity 
assessed 
using 
patient’s 
self-reported 
frequency of sexual activity per month
•
To assess the early-onset effect as well as 
the effect at the end of the study of 
sacubitril/valsartan versus enalapril 
regarding NT-proBNP levels 
•
Self-reported frequency of sexual activity 
per month at months 1 and 3
•
NT-proBNP levels at months 1 and 3
 
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3.
Investigational plan
3.1
Study design
This is a randomized, double-blind, double-dummy, multi-center, active-controlled, 
interventional study to compare sacubitril/valsartan 97 mg/103 mg bid to enalapril 10 mg bid 
in improving erectile function in male patients with chronic heart failure (NYHA II) and 
reduced ejection fraction (HFrEF) and erectile dysfunction (ED).
The study comprises five obligatory and one optional visit over a period of approximately 14 
weeks. Once patients’ eligibility has been ascertained at Visit 1 (Screening), patients will be 
randomized at Visit 2 (Randomization) to receive either sacubitril/valsartan or enalapril in a 1:1 
allocation during the double-blind period. At Visit 2, all efficacy assessments will be collected 
and used as baseline values. Double-blind treatment will be initiated with 5 mg bid enalapril or 
49 mg/51 mg bid sacubitril/valsartan and up-titrated after 2 weeks to the final dose of 10mg bid 
enalapril or 97 mg/103 mg bid sacubitril/valsartan. According to the sacubitril/valsartan SmPC, 
initiation of treatment is recommended with the 24 mg/26 mg bid sacubitril/valsartan or 2.5 mg 
bid enalapril dose for certain patients. For these patients, an optional visit 4B after achieving 
the target dose of 97 mg /103 mg bid sacubitril/valsartan or 10 mg bid enalapril is mandatory. 
For allowed investigational treatment dose adjustments during double-blind period refer to
Section 5.5.4. 
All laboratory evaluations for planned visits and for unscheduled visits will be performed by 
the central laboratory. In order to have the results from the central laboratory available and 
enable a competent decision on randomization or up-titration at the respective visits, patients 
should come to the site approximately 3 to 4 days prior to the scheduled visit date for a blood 
draw (applies for Visit 2 (Randomization), Visit 3 and Visit 4 (Cave: Visit 4: safety lab only for 
patients who started with dose level 1)). 
Further information on the visit schedule and data collection scheme can be found inTable 6-1.
Visit 1 (Screening)
At Visit 1 (-2 to -1 weeks) after signing informed consent, the inclusion and exclusion criteria 
will be checked for each patient to ascertain eligibility (see Section 4). Among other criteria, 
they have been on a stable dose of enalapril of at least 10 mg/d, or equivalent ACEI or ARB for 
at least 4 weeks prior to visit 1 (see Table 2-1). A complete physical examination is required at 
Visit 1. Mild to moderate ED will be determined using a short form of the International Index 
of Erectile Function (IIEF-5). Screening potassium levels and eGFR as well as the biomarker 
NT-proBNP will be assessed by sending blood samples to the central laboratory and only 
patients with the required values per entry criteria will be eligible for entering the study. 
Detailed HF history and other relevant CV medical history will be recorded on eCRFs 
separately from other medical history. 
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 potentially be eligible. A minimum of 2 
weeks must elapse between re-screenings and a patient may be re-screened once only (see 
Section 6.1).
 
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Patients will continue stable intake of their current ACEI/ARB as well as concomitant 
medication until Visit 2 (Randomization). They should be reminded to come without taking 
their usual ACEI to Visit 2. For ACEI a wash-out period of ≥ 36 hours before first application 
of investigational treatment is mandatory.
Table 3-1              Minimum required pre-study daily doses of commonly prescribed 
ACEIs and ARBs
ACEIs
Minmum dose
ARBs
Minimum dose
Enalapril
10 mg
Candesartan
16 mg
Benazepril
20 mg
Eprosartan
400 mg
Captopril
100 mg
Irbesartan
150 mg
Cilazapril
2.5 mg
Losartan
50 mg
Fosinopril
20 mg
Olmesartan
10 mg
Lisinopril
10 mg
Telmisartan
40 mg
Moexipril
7.5 mg
Valsartan
160 mg 
Perindopril
4 mg
Quinapril
20 mg
Ramipril
5 mg
Trandolapril
2 mg
Zofenopril
30 mg
Visit 2 (Randomization)
At Visit 2 (timepoint 0), patients who meet all relevant entry criteria, including the required 
clinical laboratory values and safety criteria, will be randomized to one of the two treatment 
arms sacubitril/valsartan or enalapril bid, respectively. Patients should continue to take their 
background medication for heart failure during the study, with the exception of ACEI or ARBs 
which are replaced by the investigational treatment and must be discontinued before first 
application of the study drug (washout period of ≥ 36 hours is mandatory for ACEI). The 
first application of the study drug is planned for the day after Visit 2 (Randomization) –
therefore, patients taking an ACEI should have discontinued their ACEI medical therapy in the 
evening before Visit 2 (e.g. if Visit 2 is scheduled for Wednesday the last ACEI medication 
should be taken by the patient on Tuesday evening. The patient will then start to take the first 
dose of double blind study medication (sacubitril/valsartan or enalapril) on Thursday morning). 
If the patient continued to take their usual ACEI, the start of study drug has to be postponed to 
assure a ≥ 36 hours washout before first application of the study drug. 
Patients taking an ARB should discontinue their ARB medical therapy the day of Visit 2 (e.g. 
if Visit 2 is scheduled for Wednesday the last ARB medication should be taken on Wednesday. 
 
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The patient will then start to take the first dose of double blind study medication 
(sacubitril/valsartan or enalapril) on Thursday morning).
Patients will start study treatment at dose level 2 (enalapril 5 mg bid or sacubitril/valsartan 49 
mg/51 mg bid) unless the patients are suffering from moderate hepatic impairment, moderate 
renal impairment or patients with SBP ≥100 to 110 mmHg. These patients should be initiated 
at dose level 1, according to the the sacubitril/valsartan SmPC and the investigator’s medical 
judgement (for these patients Visit 4B is neccessary). All patients must be stabilized on the 
chosen dose for 2 weeks. 
At Visit 2, baseline IIEF-15,
and the sexual activity log need to be performed by the 
patients.
Visit 3 and 4
After 2 weeks of treatment (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. A blood draw for the safety lab needs to be performed 3-4 days prior to Visit 3 in 
order to have the results on the day of the visit to up-titrate the patient (for patients starting with 
dose level 1 an additonal safety lab is performed 3-4 days before Visit 4). The titration steps for 
the three dose levels are described in detail in Section 5.5.3 (see Table 5-1). Every attempt 
should be made to keep the patients stable on dose level 3 in accordance with all safety 
parameters, which are symptomatic hypotension, renal dysfunction and/or hyperkalemia and 
should be handled according to the respective guidelines for management (see Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, Appendix 5 and Appendix 6). In case of lab deviations 
an unscheduled visit may be scheduled at the discretion of the investigator to re-assess lab 
parameters and evaluate the efficacy of taken measures. Measurements showing an elevation 
of potassium levels above the predefined values should be repeated and confirmed in a non-
hemolyzed sample before any action is taken (for a serum potassium concentration greater than 
or equal to 6.0 mmol/L please refer to Appendix 4) .
For the following visits (no up-titration), a blood draw for lab assessments has to be done during 
the visit.
At Visit 3 and Visit 4, IIEF-15, a physical examination and the current NYHA status is 
documented, as well as safety monitoring and adverse events. At Visit 4, the questionnaires 
IIEF-15 
 will be applied as well as a blood draw for the biomarker NT-proBNP.
Visit 4B – Optional
For patients achieving target dose at Visit 4, Visit 4B is needed to evaluate safety criteria and 
ensure adequate medical management. Investigator’s clinical judgement and discretion is 
advised. For patients who started with dose level 1, this visit is mandatory.
Visit 5 (End of Study)
 
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After 3 months of treatment, a final assessment of patients is performed at Visit 5. IIEF-15 
 
 questionnaires will be completed by patients at Visit 5. A blood draw for NT-proBNP 
assessment has to be done during the visit.
Unscheduled visits 
In addition to the protocol-required visits, patients may be seen at any time throughout the study 
at the discretion of the investigator to follow any new lab abnormalities or AEs. All randomized 
patients, including any patient who has experienced a health event, should continue to receive 
double-blind treatment until the trial is completed, if possible in the opinion of the investigator.
Unscheduled visits may also be performed throughout the study at the discretion of the 
investigator for up-titration of the study medication.
Figure 3-1
Study design 
3.2
Rationale for study design
Sexual activity remains an essential aspect of QoL for patients with CHF. Unfortunately, 
erectile dysfunction is a common diagnosis in male patients with CHF constituting a substantial
burden for the patients. Inhibition of neprilysin with sacubitrilat may enhance CNP levels in 
erectile tissue and contribute to maintaining an erection. It was already demonstrated that 
sacubitril/valsartan improved QoL in HFrEF patients including the intimate/sexual 
relationships section in a PARADIGM-HF post-hoc analysis (Chandra et al., 2018). Thus, the 
aim of the present study is to assess differences between sacubitril/valsartan versus enalapril in 
improving erectile function as assessed by the International Index of Erectile Function (IIEF-
15) questionnaire in patients with HFrEF and ED. The questionnaire is established for assessing 
sexual function in ED patients and has been used in numerous clinical trials. For such a 
subjective endpoint as erectile function, a randomized, actively controlled, double-blind 
interventional trial with a balanced study population is the state of the art and allows controlling
 
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the patients’ treatment and thus reducing bias. Moreover, the study design is reasonable and 
adapted from recent studies for treatment of patients with CHF in terms of investigational 
treatment, duration of assessment period and the comparator. The study design is also in line 
with all required safety assessments and follow-ups for patients with CHF and for the treatment 
with sacubitril/valsartan and in compliance with the effective risk management plan for the 
product. Thus, events of angioedema, liver events, statin related events, and events of cognitive 
impairment are followed up by targeted questionnaires. Please refer to Section 6.5 (safety 
assessments) for further details. Known risks of hypotension, renal impairment, and 
hyperkalemia are closely monitored to prevent severe events and are subject to separate 
guidance should such events occur. Please refer to Sections 6.5.2 and 6.5.4 for assessments of 
blood pressure and laboratory assessments, respectively; and to Appendix 1, Appendix 2, 
Appendix 3, Appendix 4 and Appendix 5 for guidance to manage these risks.
Taken together, the present randomized, actively-controlled, double-blind, double-dummy 
approach is the most suitable design for achieving the study objective of demonstrating the
superiority of sacubitril/valsartan versus enalapril in improving erectile function in patients with 
HFrEF and EDRationale 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 twice-daily dosing regimen of 
sacubitril/valsartan also ensures a sustained neprilysin (NEP) inhibition over 24 hours. The 
sacubitril/valsartan target dose of 97 mg/103 mg twice daily delivers a daily dose of valsartan 
equivalent to Diovan® 160 mg bid, the dose commonly recommended by current HF 
management guidelines (Ponikowski et al., 2016). With the purpose of this study to demonstrate 
the superiority of sacubitril/valsartan compared to enalapril in improving erectile function in 
patients with HFrEF and ED, we assume a measurable effect using the IIEF-15 questionnaire 
after 3 months of treatment.
3.4
Rationale for choice of comparator
Enalapril, the comparator chosen for this study, is an ACE inhibitor - the drug class considered 
first-line treatment by the current European 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. Since sacubitril/valsartan is tested in this study according to its label in treatment of patients 
with CHF, a standard-of-care comparator is thought to be most appropriate.
As a well-studied ACEI in HF, enalapril is used as the comparator in this study. Enalapril was 
studied in a number of previous large, outcome-driven studies, such as CONSENSUS (Group, 
1987), SOLVD-Treatment (Investigators, 1991), and SOLVD-Prevention (Investigators et al., 
1992). 
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 
 
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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 (Investigators et al., 1992).
3.5
Purpose and timing of interim analyses/design adaptations
3.6
Risks and benefits 
Both sacubitril/valsartan and enalapril are approved in the indication investigated within this 
study. Please refer to the corresponding Summary of Product Characteristics (SmPC) of each 
product as well as the Investigator’s Brochure (IB) for sacubitril/valsartan for known adverse 
reactions, or special precautions on both IMPs (provided to all participating sites).
Patients will be instructed not to take any renin angiotensin aldosterone system (RAAS) 
blocking agents (ACEIs or ARBs) before start of study treatment in order to avoid excess RAAS 
blockade. For ACEI a ≥ 36h washout period is mandatory. The risk of temporary 
discontinuation of concomitant ACEIs or ARBs will be minimal as it will be reflective of the 
typical dosing schedule of most ACEIs and ARBs.
All patients will be allowed to continue receiving their other background CV medications.
The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
close clinical monitoring.
If there is any question that the patient will not reliably comply, the patient should not be entered 
in the study. Participating patients will benefit from careful monitoring and follow-up during 
the entire study duration.
4.
Population
This is an outpatient multi-center clinical study to be conducted in Germany. The goal is to 
randomize 200 patients in about 40 centers. Since a 30% screening failure rate is expected, 
approximately 286 patients will be screened. The study population will consist of a 
representative group of adult (≥18 and ≤ 75) male HFrEF patients in NYHA class II with mild 
to moderate ED. Eligible patients should be on a stable dose of an ACEI or an ARB as well as 
bisoprolol/metoprolol for at least 4 weeks prior to entering into the study. 
The investigator must ensure that all patients who meet the inclusion criteria and do not fulfill 
any of the 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.
Patients must give written informed consent before any assessment is performed and 
must be willing and capable to comply with all study procedures
2.
Male Outpatients ≥ 18 and ≤ 75 years of age
 
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3.
Patients with a diagnosis of CHF NYHA class II and reduced ejection fraction (< 40%)
(assessed by any local measurement using echocardiography, CT scanning, MRI or 
ventricular angiography ≤ 6 months prior to Visit 1)
4.
Plasma NT-proBNP level of ≥ 300 pg/mL at Visit 1 
5.
Patients must be living in a stable and sexually active heterosexual partnership for at 
least 6 months prior to Visit 1
6.
Patients must have a mild to moderate erectile dysfunction determined using the IIEF-5 
questionnaire (> 7 and ≤ 21 IIEF units) at Visit 1 and Visit 2
7.
No usage of any available drug for erectile dysfunction (e.g. sildenafil, tadalafil) for at 
least 2 weeks prior to Visit 1 and 4 weeks prior to Visit 2
8.
Patients must be on an ACEI or an ARB at a stable dose for at least 2 weeks prior to 
Visit 1 and 4 weeks prior to Visit 2
9.
Patients must be treated with a stable dose of bisoprolol/metoprolol, unless the use of β-
blockers is contraindicated or not tolerated (reason should be documented) for at least 2 
weeks prior to Visit 1 and 4 weeks prior to Visit 2 (β-blockers other than 
bisoprolol/metoprolol are not allowed per protocol)
10.
Patients must be literate in German
4.2
Exclusion criteria
Patients/subjects 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 during the study and within 30 days or 5 half-lives, 
whichever is longer before enrolment and at enrolment
 
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2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes, ACEIs, ARBs or NEP inhibitors, as well as known or suspected 
contraindications to the study drugs
3. Previous history of intolerance to recommended target doses of ACEIs or ARBs
4. Known history of angioedema
5. Requirement of treatment with a dual RAAS blockade, e.g. a treatment with both, ACEIs 
and ARBs or concomitant treatment with aliskiren
6. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy)
7. Symptomatic hypotension and/or a systolic blood pressure (SBP) ≤100 mm Hg at Visit 1 
(Screening) or Visit 2 (Randomization)
8. Estimated glomerular filtration rate (eGFR) < 30mL/min/1.73m2 at Visit 1 (Screening) or 
Visit 2 (Randomization) as calculated by MDRD formula
9. Serum potassium level > 5.2mmol/L at Visit 1 (Screening) or Visit 2 (Randomization)
10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major 
CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 
months prior to Visit 1
11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention 
within the 3 months after Visit 1
12. Implantation of a pacemaker, implantable cardioverter defibrillator (ICD), cardiac 
resynchronization therapy pacemaker / defibrillator (CRT-P/D), or upgrade of an existing 
device or revision of device leads within 3 months prior Visit 1 or intent to implant such a 
device during the study
13. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on 
transplant list) or implant a VAD
14. History of severe pulmonary disease including COPD (Patients with significant chronic 
obstructive pulmonary disease contributing to dyspnea or patients whose COPD 
medication has been altered within 2 weeks prior to Visit 1 and 4 weeks prior to Visit 2)
15. Diagnosis of chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1
16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months 
prior to Visit 1
17. Known symptomatic bradycardia or second or third degree heart block without a 
pacemaker
18. Known presence of hemodynamically significant mitral and/or aortic valve disease, except 
mitral regurgitation due to left ventricular dilatation
19. Presence of other hemodynamically significant obstructive lesions of left ventricular 
outflow tract, including aortic and sub-aortic stenosis
20. Known history of familial long QT syndrome or known family history of Torsades de 
Pointes
21. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of study drugs, including but not limited to any of 
the following:

AST or ALT values exceeding 2 x upper limit of normal (ULN) 
 
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
History of active inflammatory bowel disease during the 12 months before Visit 1

Current duodenal or gastric ulcers during the 3 months prior to Visit 1

Gastric bypass

Evidence of severe hepatic impairment, biliary cirrhosis or cholestasis, classified as 
Child-Pugh C

History of hepatic encephalopathy, history of  esophageal varices, history of
portocaval shunt

Active treatment with bile sequestering agents such as cholestyramine or colestipol 
resins
22. Presence of any other disease with a life expectancy of < 1 years
23. Presence of known bilateral renal artery stenosis
24. Penile anatomical defects and Peyronie’s disease
25. Foreseeable usage of any available drug for erectile dysfunction (e.g. sildenafil, tadalafil) 
during the study
26. Co-Medication with an influence on erectile function such as digoxin, anticholinergic anti-
depressants, alpha blockers finasteride and calcium channel blockers
27. Recent (4 weeks prior to Visit 1) or planned (within the 14 weeks after Visit 1) change in 
statin or spironolactone therapy
28. Diabetes mellitus Type I or insulin-dependent Type II 
29. Prostate-specific antigen (PSA) levels higher than 4 ng/mL at Visit 1 or known prostate 
cancer
30. Spinal cord injury, ileostomy, prior surgery or radio therapy for rectal or prostate cancer 
and radical prostatectomy 
31. Presence of peripheral artery occlusive disease and/or stenosis of the common and internal 
iliac artery
32. Patients with ongoing alcohol and/or drug abuse and/or severe depression (defined as 
patients with altered medication or hospitalization within 4 weeks prior to Visit 1 and 
Visit 2)
33. Presence and suspicion of any neurodegenerative disease or polyneuropathy
34. Hormonal abnormalities such as hypogonadism, hyperprolactinemia, hyper- and 
hypocortisolism and medically untreated hyper- and hypothyroidism 
35. Obesity based on a body mass index ≥35 kg/m2, frail patients or patients with cardiac 
cachexia or a body mass index <18.5 kg/m2
36. Any surgical or medical condition, which in the opinion of the investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study.
 
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5.
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Double blind treatment
All eligible patients will be randomized in a 1:1 allocation to receive either sacubitril/valsartan 
or enalapril in addition to optimal CHF therapy, as considered appropriate by the investigator 
and in accordance with standard therapy guidelines, but with the exception of an ACEI or ARB,
as this will be replaced by investigational treatment at Visit 2 (Randomization). The use of an 
ACEI or an ARB in addition to investigational treatment is strictly prohibited. For ACEIs a 
washout period of ≥ 36 hour is mandatory. During the dosing of study medication, i.e. beyond 
randomization until the end of the study, the intake of ACEIs or ARBs remains prohibited (in 
case of treatment interruption/discontinuation see Section 5.5.5 and Section 5.5.6).
The following study drugs will be provided:

Sacubitril/valsartan 24 mg/26 mg film-coated tablets (sacubitril/valsartan dose level 1)

Placebo to match sacubitril/valsartan 24 mg/26 mg film-coated tablets (placebo matching 
sacubitril/valsartan dose level 1)

Sacubitril/valsartan 49 mg/51 mg bid film-coated tablets (sacubitril/valsartan dose level 2)

Placebo to match sacubitril/valsartan 49 mg/51 mg bid film-coated tablets (placebo 
matching sacubitril/valsartan dose level 2)

Sacubitril/valsartan 97 mg/103 mg film-coated tablets (sacubitril/valsartan dose level 3)

Placebo to match sacubitril/valsartan 97 mg/103 mg film-coated tablets (placebo matching 
sacubitril/valsartan dose level 3)

Enalapril 2.5 mg film-coated tablets (enalapril dose level 1)

Placebo to match enalapril 2.5 mg tablets (placebo matching enalapril dose level 1)

Enalapril 5 mg film-coated tablets (enalapril dose level 2)

Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2)

Enalapril 10 mg film-coated tablets (enalapril dose level 3)

Placebo to match enalapril 10 mg tablets (placebo matching enalapril dose level 3)
Target doses: Sacubitril/valsartan 97 mg/103 mg bid and enalapril 10 mg bid
All tablets have different shapes and colors. Therefore, the study will be designed as a double-
blind, double-dummy trial to ensure the blinding during the entire course of the study. To 
maintain the blinding, patients will be required to take their assigned active treatment tablet 
along with placebo matching the opposite treatment twice daily (morning and evening dose) in 
addition to their conventional concomitant therapy.
 
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Sacubitril/valsartan and its matching placebo will be provided in HDPE bottles and/or blister 
packs. Enalapril and its matching placebo will be provided in HDPE bottles and/or 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 bid and placebo matching enalapril bid

enalapril bid and placebo matching sacubitril/valsartan bid.
5.3
Treatment assignment and randomization 
5.4
Treatment blinding
5.5
Treating the patient 
5.5.1
Patient numbering
5.5.2
Dispensing the study drug
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment
5.5.3.2
Handling of additional treatment 
5.5.4
Instructions for prescribing and taking study treatment
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. 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. Table 5.1 summarizes the study drug that will be taken during the double-blind 
period.
Patients will begin treatment with dose level 2 for 2 weeks. At Visit 3, patients will be up-
titrated to dose level 3 unless safety monitoring criteria prevent up-titration. According to the 
sacubitril/valsartan SmPC and the investigator’s medical judgement, patients suffering from 
moderate hepatic impairment (Child Pugh B), moderate renal impairment or patients with SBP 
≥100 to 110 mmHg should be initiated at dose level 1. They will be up-titrated every 2 weeks 
(unless safety monitoring criteria prevent up-titration) until they reach dose level 3. Visit 4B is 
 
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a mandatory visit for patients achieving target dose (dose level 3) at visit 4 to evaluate safety 
criteria and ensure adequate medical management.
Table 5-1 
Study drug dispensed during the double-blind period
Dose 
level 
Sacubitril/valsartan 
Enalapril
3*
97 mg/103 mg or matching 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. 
Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 
AM) and their evening study drug doses at approximately 19:00 (7 PM). The study medications 
should be taken with a glass of water with or without food. If the patient misses taking any 
study drug dose, he should take it as soon as possible, unless if it is almost time for the following 
scheduled dose. In this case, the patient should skip the missed dose and return back to his 
regular study drug administration schedule.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
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 (dose level 3) 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. 
diuretics, nitrates) 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 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 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.
 
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Study drug dose level adjustments should be based on overall safety and tolerability with a 
special focus on

Hyperkalemia (see Appendix 4) 

Symptomatic hypotension (see Appendix 5)

Clinically significant decrease in eGFR or clinically significant increase in serum
Creatinine (see Appendix 6)

Worsening hepatic function (see Appendix 2)
After randomization, temporary study drug discontinuation for any reason does not 
automatically constitute withdrawal from the study and should not lead to the patient being 
withdrawn from the study.
Adjustment of study drug dose level 
If despite adjustment of concomitant medications per the guidance provided above the situation 
is not rectified, the investigator may consider adjusting the study medication according the 
following instructions. 
During the double-blind treatment period down-titration of the study drug at any time will be 
allowed based on the safety and tolerability criteria defined in Appendix 1, Appendix 2,
Appendix 3, and Appendix 4. If down-titration is necessary, the patient should be down titrated
to the next dose level (see Table 5-1). The patient may continue receiving the lower dose level 
for a recommended period of 1 to 2 weeks before re-challenging the patient with the next higher 
dose level. For example, a patient who encounters tolerability problems at the target dose level 
(dose level 3), should receive the study drug at dose level 2 for 1 to 2 weeks. Then, he should 
be re-challenged with up-titration back to dose level 3. 
If the tolerability issues are not alleviated, the investigator may lower the study drug dose 
further to the next lower level for 1 to 2 weeks, up to temporary withdrawal of the study drug. 
Again, once stable, the patient should be re-challenged with up-titration to the next higher 
dose level every 1 to 2 weeks in an attempt to bring back the patient gradually to the target 
study drug dose level (dose level 3). The investigator may choose the next dose level for 
down- or up-titration according to his or her judgment (Table 5-1). 
In some cases, according to the safety and tolerability criteria and the investigator’s judgment, 
dose level 1 or 2 could be maintained if he/she considers that the patient’s condition would not 
allow an up-titration to the target dose of study medication (level 3). In this case, it would be 
acceptable to maintain the patient at dose level 2 (or lower), to assure treatment with the highest
dose level tolerated by the patient.
Study drug restart after temporary treatment interruption 
Study drug should be reintroduced after 1-2 weeks in those who temporarily discontinue as 
soon as medically justified in the opinion of the investigator. 
Once the investigator considers the patient’s condition appropriate for receiving the study drug, 
the investigator should re-start the patient on the study drug at the most appropriate and 
 
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allowable dose level (Table 5-1) per his/her medical judgment. If tolerated based on the safety 
and tolerability criteria in Appendix 1, Appendix 2, Appendix 3, and Appendix 4 the patient 
should be up-titrated to the next dose level (up to dose level 3) every 1 to 2 weeks, as per the 
investigator’s judgment. 
Patients re-started on the study drug will retain their original randomization and study 
identification numbers. Should the patient not tolerate the re-start study drug dose level, he may 
be down-titrated again (if appropriate) or discontinue the study medication. Up-titration or 
reintroducing the study drug could be considered by the investigator as soon as medically 
justified in his/her medical judgment. 
Study visits should occur as close as possible to the time points indicated in Table 6-1. The 
timeframe between the regular visits should be maintained as scheduled, irrespective of the 
number of unscheduled visits that may be performed in between, according to the visit and time 
schedule described in Table 6-1.
Any changes in the study drug dose level, including temporary/permanent withdrawal or re-
start of the study drug, must be recorded on the Dosage Administration Record CRF.
5.5.6
Rescue medication
Guidance on handling hyperkalemia, hypotension and renal dysfunction are provided in 
Appendix 1, 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 (in case the patient is switched to an ACEI), but also for any ACEI before (re-)introducing 
study drug.
Use of rescue medication must be recorded on the appropriate CRF.
5.5.7
Concomitant medication 
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 hyperkalemia. The investigators are 
encouraged to assess patients’ potassium levels regularly, especially during the up-titration and 
in those receiving such medications.
ACEIs and ARBS
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 2 and should remain on a stable regimen, if medically justified, throughout the entire 
study duration. 
The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient 
is receiving study medication. If the investigator believes that addition of an ACEI or ARB is 
 
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necessary, then study drug must be discontinued. Study medication should be stopped ≥ 36 
hours prior to addition of open-label ACEI. If not already treated with an aldosterone 
antagonist, consideration should be given to adding this therapy rather than an ACEI or ARB.
Similarly, if study medication is to be restarted, the open-label ACEI should be discontinued
≥ 36 hours prior to resuming study medication.
Phosphodiesterase-5 (PDE-5) inhibitors
The use of Phoshodiesterase-5 inhibitors (e.g. sildenafil, vardenafil, tadalafil and compounds 
with similar characteristics) is not allowed during the study. 
However, there is a risk that patients make use of PDE5i, despite being not allowed by the study 
protocol. For this reason, investigators are advised to make all efforts to make the patient aware 
that use of PDE5i is not allowed. The investigator should educate the patient concerning the 
increased possibility of the occurrence of hypotension.
Statins
Caution should be exercised upon co-administration of statins such as atorvastatin, simvastatin, 
pravastatin and/or pitavastatin and study medication, due to potential interactions between 
statins and sacubitril/valsartan. 
Other drugs with a potential impact on erectile function
The treatment with the following medications with a potential influence on erectile function are
not allowed:

Digitoxin, Digoxin (e.g. Digacin, Lanicor, Lenoxin and compounds with similar 
characteristics)

Calcium channel blockers (e.g. Verapamil, Gallopamil, Diltiazem, Amlodipin, 
Nitrendipin, Felodipin, Nidedipin and compounds with similar characteristics)

Alpha blockers (e.g. Alfuzosin, Tamsulosin, Doxazosin, Phentolamin, Prazosin, 
Uradipil, Ergotamin and compounds with similar characteristics) 

Anticholinergic anti-depressants (e.g. amitriptyline, doxepin and compounds with 
similar characteristics) 

Finasteride 
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 
 
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followed up to ensure adequate management of their diabetes according to investigators 
discretion.
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements, aldosterone antagonists, and any other 
medications known to raise potassium levels should be used with caution while the patient is 
receiving the study medication due to the increased possibility of occurrence of hyperkalemia. 
The investigator is encouraged to assess patients’ potassium levels regularly, especially in those 
who are receiving these medications. Guidelines for the management of hyperkalemia can be 
found in Appendix 4. 
5.5.8
Prohibited medication
Use of the treatments displayed in the Table 5-2 is NOT allowed after the start of the 
investigational drug. For ACEI a washout period of ≥ 36 hours is mandatory. 
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 
hyperkalemia. 
Bile acid sequestering agents are prohibited due to potential interference with the absorption of 
study drugs.
β-blockers other than bisoprolol/metoprolol are not allowed per protocol due to interference 
with erectile function. 
Table 5-2
Prohibited medication
Medication
Prohibition period
Action taken
Any ACEI, ARB or Renin 
inhibitors
Double blind period 
(≥ 36h washout 
period for ACEI)
Prohibited until at least 36 hours after study 
drug discontinuation/interruption/end of study
(for ACEI). In case these drugs are taken / 
need to be taken during the double-blind 
treatment period of the study, discontinue 
study drug
PDE5i
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
 
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Medication
Prohibition period
Action taken
Bile acid sequestering 
agents (e.g. 
Cholestyramine, 
Colestipol)
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
Calcium channel blockers 
(e.g. Verapamil, 
Amlodipin)
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
Alpha blockers (e.g. 
Tamsulozin, Prazosin, 
Ergotamin)
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
Anticholinergic anti-
depressants (e.g. 
Amitryptiline, Doxepin)
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
Digitoxin
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
Digoxin (e.g. Digacin, 
Lanicor)
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
β-blockers other than 
bisoprolol/metoprolol
Double blind period
Prohibited throughout the study. No action 
required with study medication
Finasteride
Double blind period
Discontinue before randomization, prohibited 
throughout the study. No action required with 
study medication
5.5.9
Emergency breaking of assigned treatment code 
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
5.6.2
Discontinuation of study treatment 

Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator and constitute a 
reason for temporary or permanent discontinuation of study treatmentUse of prohibited 
treatment as per Table 5-2. In case of initiation of open-label ACEI during the double blind 
treatment period, study medication must be stopped for ≥36 hours prior to initiation of open-
label ACEI. The open label ACEI must be stopped for ≥36 hours prior to re-initiation of 
study drugDepending on the serum potassium, blood pressure, or eGFR, patients may need 
to have their study drug dose or the dose of another concomitant medication reduced or 
discontinued, or, if appropriate, have potentially contributing agents adjusted. Please refer 
to Appendix 4, Appendix 5, and Appendix 6 for treatment guidelines for hyperkalemia, 
hypotension, or renal dysfunction, respectively.Withdrawal of informed consent
 
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5.6.4
Loss to follow-up
5.6.5
Early study termination by the sponsor 
6.
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed.
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled and the adverse event and 
concomitant medications reconciled on the CRF.
 
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Table 6-1
Assessment schedule
Visit
1
2
3
4
4B
5
TD 
and/or 
PSD
Time
-2w to -1w
0
2w
4w
6w
12w
Obtain informed consent
X
Inclusion/Exclusion criteria
X
X
Some exclusion criteria apply for both Visit 1 and Visit 2
Demography
X
Medical History
X
X1
NYHA Classification
X
X
X
X
(X)
X
X
Previous and concomitant
drug/non-drug treatments
X
X
X
X
(X)
X
X
Physical Exam
X
X
S
S
(S)
X
S
At Visit 1 (Screening), 2 (Randomization), and 5 (EOS) 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
X
Vital signs
X
X
X
IIEF-15
X
X
X
X
X
IIEF-5
X
X
Dispense Sexual Activity Log
X
Sexual Activity Log
X
X4
X4
X4
X4
X
Sexual activity Log is completed by the patient once a week. Baseline 
value is assessed at Visit 2
Diagnostic and Laboratory
evaluations
X2
X3
X
X
X
Hematology and Biochemistry
NT-proBNP
X
X3
X
X
X
Laboratory assessment
X3
(X3,5)
(X)
Abbreviated assessment for Potassium, AST and ALT and 
Creatinine/eGFR. 
Dispense Study Medication
X
X
X
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Visit
1
2
3
4
4B
5
TD 
and/or 
PSD
Time
-2w to -1w
0
2w
4w
6w
12w
Drug accountability
X
X
(X)
X
X
Adverse event monitoring
X
X
X
X
(X)
X
X
Contact IVRS/IWRS
S
S
S
S
(S)
S
S
Study Completion form
X
TD = Study treatment discontinuation; PSD = Premature subject/patient discontinuation
X = assessment to be recorded on clinical data base
S = assessment to be recorded on source documentation only
“( )” = Assessments for Visit 4B are in brackets, as Visit 4B is a visit not applying to all patients
IIEF = International Index of Erectile Function
1 = Medical history as far as needed for inclusion and exclusion criteria
2 = PSA level will be determined at Visit 1 
3 = Blood draw 3-4 days before Study Visit (central lab)
4 = sexual activity log is completed once a week by the patient
5 = The laboratory assessment (safety lab) only applies for patients who started with dose level 1 (Cave: these patients need to come 3-4
days before Visit 4 for the blood draw). The Diagnostic and Laboratory Evaluations at Visit 4 are performed at the regular visit. 
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6.1
Information to be collected on screening failures 
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, 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 and 2), 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 
Compliance 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. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log.
6.4
Efficacy
•
Patient-reported frequency of sexual activity 
•
NT-proBNP
6.4.1
IIEF-15 questionnaire The International Index of Erectile Function (IIEF-15) is 
a patient self-reported questionnaire to assess ED in male patients (see annex for 
detailed information). It consists of 15 questions assessing five main principles 
associated with ED: erectile function, orgasmic function, sexual desire, intercourse 
satisfaction and overall satisfaction. For each question, 0-5 points can be achieved 
with 5 being the best outcome (Rosen et al., 1997). In this study, the IIEF-15 will 
be completed by patients at baseline (Visit 2), as well as at 2 weeks (Visit 3), at 1
month (Visit 4) and at 3 months (Visit 5) and all categories will be evaluated 
separately: erectile function (questions 1-5; 15), orgasmic function (questions 9-
10), sexual desire (questions 11-12), intercourse satisfaction (questions 6-8) and 
overall satisfaction (questions 13-14). 
6.4.2
Patient-reported frequency of sexual activity 
Since the quantitative amount of sexual activity is not covered in the IIEF-15, patients will keep 
a diary to log any sexual activity during the whole study period starting with an initial 
assessment at Visit 2 covering sexual activity the week before Visit 2. This self-assessment will 
be completed by the patients on an electronic device (tablet). Patients are asked to complete the 
diary once per week until end of the study (Visit 5). The diary consists of seven items assessing 
the patients’ sexual activity of the previous 7 days.
 
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6.5
Safety 
The Sponsor may request additional information on specific adverse events 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 additional information will be de-identified prior to 
collection by Novartis or its agents.Physical examination
6.5.2
Vital signs 
Vital signs include BP and pulse measurements. BP will be measured by using a standard 
sphygmomanometer with an appropriate size cuff and the non-dominant arm in the sitting 
position after 5 minutes of rest.
Guidelines for the management of BP are provided in Appendix 5.Height and weight 
6.5.4
Laboratory evaluations
The investigator or his/her designee should review the central laboratory results as soon as they 
become available to decide on whether any adjustments in the patient’s study drug or non-study 
drug regimen are needed. Therefore, unscheduled visits are possible based on investigator’s 
discretion. 
All central laboratory results will be communicated to the investigators and the sponsor. Details 
on the collection, shipment of samples and reporting of results by the central laboratory will be 
provided to investigators in the laboratory manual.
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator in the Comments screen of the patient's eCRF and additional 
laboratory evaluations should be performed, as judged appropriate by the investigator. If the 
laboratory abnormality induces clinical signs or symptoms, or requires therapeutic intervention, 
then the diagnosis or medical condition must be entered on the AEs screen of the patient's eCRF. 
If the laboratory abnormality is the primary reason for an unforeseen hospitalization or 
otherwise fulfills the seriousness category of an AE, then the procedure for rapid notification 
of SAEs must be followed. Likewise, if the laboratory abnormality leads to discontinuation 
from the study drug (temporarily or permanently), the patient must be followed until the 
abnormality resolves or until it is judged to be permanent.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be measured at Visits 1, 2, 4, 5 and in case of study treatment 
discontinuation (TD) or premature subject/patient discontinuation (PSD).Clinical chemistry
Glucose, blood urea nitrogen (BUN), Blood urea, creatinine, creatinine kinase, total bilirubin, 
AST, ALT, alkaline phosphatase, INR, GFR, HbA1c absolute, HbA1c relative, sodium, 
potassium, chloride, calcium, total protein, albumin, HDL, LDL, triglycerides, and uric acid 
will be measured at visits 1, 2, 4, 5 and in case of TD or PSD.
 
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BUN, creatinine, GFR, potassium and urea will be obtained from patients at every visit when a 
complete laboratory test is not done (i.e., Visit 3, 4 and 4B, please see Table 6-1 for details).
The latter is true for all unscheduled visits done with up-titration intention.Urine analysis
6.5.5
Electrocardiogram (ECG) 
6.5.6
Pregnancy and assessments of fertility 
6.5.7
Angioedema
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes 
and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, 
including the genitalia and intestines. Severe cases may be associated with airway compromise. 
Although the mechanism is not fully understood, bradykinin has been implicated as the putative 
mediator. Therefore, medications that raise the levels of endogenous bradykinin by inhibiting 
the enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and NEP, may 
result in this potentially dangerous side effect. 
It is important that the investigator pays special attention to any swelling or edema that may 
resemble angioedema or angioedema-like events that may be reported by patients. If such an 
event occurs, the investigator will complete an Adjudication Questionnaire for an Angioedema-
like Event form (provided by Novartis) to summarize the event, its treatment, and its ultimate 
outcome. This report along with the requisite medical documentation must be submitted to 
Novartis as soon as possible. Follow-up reports must be communicated to Novartis as soon as 
new information regarding the event becomes available. All hospital records related to the event 
must be communicated to Novartis. The investigator may be also be contacted by Novartis 
regarding AEs that may resemble an angioedema-like event. A list of terms that are considered 
“angioedema-like” (e.g., periorbital swelling) will be provided to sites in a manual. The 
investigator or his/her delegated staff must complete the required forms and provide the 
required medical records for all such events, regardless of whether the investigator views the 
event in question as angioedema or not. 
All angioedema reports will be forwarded to an Angioedema Adjudication Committee by 
Novartis for assessment. Information regarding this committee is outlined in Section 8.5. 
Details on the procedures for reporting angioedema events will be provided to investigators in 
a manual.
6.5.8
Cognitive Impairment
Angiotensin receptor blockade has been suggested to improve cognitive function, as might 
overall improvement in cardiac and vascular function. Thus, improvements in cardiac function 
and cerebral blood flow by LCZ696 are hypothesized to potentially improve vascular effects 
and, thereby, cognition. However, neprilysin is one of multiple enzymes involved in the 
breakdown of amyloid β, a peptide linked to cognitive impairment. Thus, cognitive function 
resulting from combined angiotensin receptor blockade and neprilysin inhibition with LCZ696 
is subject to standardized follow-up. 
It is important that the investigator pays attention to any events of cognitive impairment or 
related events that may be reported by patients. If such an event occurs that meets criteria for 
serious adverse event, the investigator will complete a separate questionnaire for a Dementia-
related Event form (provided by Novartis) to summarize the event, its further diagnostic tests 
 
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performed, and its related information. A list of terms that are considered “dementia-like” (e.g., 
presenile dementia, memory impairment) will be provided to sites in a manual.
6.5.9
Statin-related Events
Statin-related events are subject to additional safety assessments and thus are followed with a 
standardized questionnaire. A list of terms that are considered “statin-related” (e.g., 
rhabdomyolysis, acute pancreatitis, myalgia and muscle spasm) will be provided to sites in a 
manual. 
If such an event occurs that meets criteria for serious adverse event, the investigator will 
complete a separate questionnaire for a Hepatotoxicity and Statin-related Event form (provided 
by Novartis) to summarize the event, its further diagnostic tests performed, and its related 
information.
6.5.10
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.Other 
assessments
6.6.1
Patient Reported Outcomes (PRO)
6.6.2
Pharmacokinetics 
6.6.3
Other biomarkers 
7.
Safety monitoring 
7.1
Adverse events 
 
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7.2
Serious adverse events 
7.2.1
Definition of SAE
7.2.2
SAE reporting 
7.3
Liver safety monitoring 
7.4
Renal safety monitoring 
7.5
Reporting of study treatment errors including misuse/abuse
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
7.6
Pregnancy reporting 
7.7
Prospective suicidality assessment 
8.
Data review and database management 
8.1
Site monitoring 
8.2
Data collection 
8.3
Database management and quality control 
8.4
Data Monitoring Committee 
8.5
Angioedema Adjudication Committee
9.
Data analysis 
9.1
Analysis sets 
9.2
Patient demographics and other baseline characteristics 
The FAS will be the patient population for the above analyses.Treatments 
The FAS will be used for the above analyses.Analysis of the primary variable(s)
9.4.1
Primary Variable(s)
The primary endpoint is the Erectile function score IIEF-15 at 3 months. The trial aims to 
estimate the effect of the treatment policy, irrespective of intercurrent events such as dose 
changes or adherence to randomized treatment. The following estimand will be used:

Population – Full Analysis Set (FAS)
 
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
Variable of Interest – Erectile function score IIEF-15 at 3 months

Intervention effect – effect between sacubitril/valsartan versus enalapril at 3 months
regardless of adherence to randomized treatment.

Summary measure –difference in means
For patients who permanently discontinue study treatment, values collected after study drug 
discontinuation will generally be included in the analysis.
9.4.2
Statistical model, hypothesis, and method of analysis
The primary variable will be analyzed using a mixed model for repeated measures (MMRM), 
The response variable will be the Erectile function score IIEF-15. Treatment 
(sacubitril/valsartan versus enalapril), visit and treatment-by-visit interaction will be included 
as fixed-effect factors; baseline IIEF-15 will be included as a covariate; the within-patient 
covariance will be modeled using an unstructured covariance matrix (a common matrix for the 
two treatment groups). The analysis will include all (two) scheduled post-baseline visits and 
will be performed based on the likelihood method with an assumption of missing at random 
(MAR) for missing data.
The null-hypothesis to be rejected is that there is no difference in mean IIEF-15 scores at 3 
months between the two treatment arms, in mathematical terms: H0: μ1 = μ2 vs. Ha: μ1 ≠μ
2, where μ 1 and μ 2 are mean IIEF-15 scores at 3 months for the treatment groups of 
sacubitril/valsartan versus enalapril, respectively.
The statistical test will be performed at the two-sided significance level of 0.05 based on the 
MMRM model. The estimates and the corresponding 95% confidence intervals will be provided 
for the difference in adjusted means at month 3 between the two treatment groups based on the 
MMRM model. Although this test is defined as two-sided, superiority of sacubitril/valsartan 
versus enalapril will be claimed only, if the difference is in favor of sacubitril/valsartan.
The FAS will be used for the above primary analyses.
9.4.3
Handling of missing values/censoring/discontinuations
Patients will be followed up and all scheduled visits should be performed, even if study drug is 
discontinued for that respective patient prematurely. Therefore, missing values should only 
occur in case of death, withdrawal of informed consent or loss to follow up. In these cases, 
patients will be included with their available values into the statistical MMRM model.
9.4.4
Sensitivity analyses 
The following estimand will be used:

Population – Full Analysis Set (FAS)

Variable of Interest – Erectile function score IIEF-15 at last observed visit

Intervention effect – effect between sacubitril/valsartan versus enalapril at last observed
visit regardless of adherence to randomized treatment.
 
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
Summary measure – difference in means
For patients for whom an IIEF-15 at month 3 is available, this value will be used, regardless of 
adherence to treatment. Analysis will be performed using an Analysis of Covariance model for 
IIEF-15 at last observed visit with factor treatment group and covariate baseline IIEF-15.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
9.5.2
Safety variables
Safety assessments will be based mainly on the frequency of adverse events. Adverse events 
will be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). An adverse event related to study drug is 
defined as one considered by the investigator to have a suspected relationship with the study 
drug. The adverse events will be summarized by the number and percentage of patients in each 
primary system organ class and preferred term. For summaries by severity of event, the most 
severe occurrence for a particular preferred term will be used for a given patient. Summary 
tables of adverse events by treatment and severity will be provided.
Multiple occurrences of the same AE or SAE in the same patient will be counted only once, 
using the worst severity and drug relationship.
In the data listings of adverse events, the severity of an AE, whether or not an AE is study drug 
related, and whether or not it is a serious AE, will be indicated.
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values (means, medians, standard deviations, ranges) and by presenting number 
and percentage of patients with notable laboratory abnormalities according to Appendix 1. 
Data from other tests (vital signs) will be listed, notable values will be flagged, and any other 
information collected will be listed as appropriate.
9.5.3
Resource utilization 
9.5.4
Pharmacokinetics 
9.5.5
DNA 
9.5.6
Biomarkers 
9.5.7
PK/PD 
 
 
 Interim analyses
 
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Not applicable, no interim analysis will be performed.
9.8
Sample size calculation
For the IIEF-15 domain “erectile function”, the treatment effect and SD of sacubitril/valsartan 
compared to enalapril was estimated based on the previous VALED study, which demonstrated 
that valsartan showed a highly significant increase in erectile function from 16.54±8.27 to 
23.14±6.49 IIEF units in hypertensive males (Dusing, 2003). VALED was an open-label  study 
comparing 6 months treatment with valsartan to baseline. CONFIDENCE on the other hand is 
a double-blind randomized trial and the beneficial effect of sacubitril/valsartan will likely be 
driven not by valsartan but by the neprilysin inhibition introduced by sacubitril. For sample size 
calculation the shorter study period, differing patient population (heart failure versus 
hypertension) as well as the use of bisoprolol/metoprolol have to be taken into account. Beta-
blocker have differing effects on erectile function. While propranolol and atenolol are well-
known to reduce sexual function, nebivolol has vasodilating effects, which may even be 
beneficial in erectile dysfuntion (Baumhakel et al., 2011). Bisoprolol/metoprolol have been 
suggested to have a neutral effect on erectile dysfunction (Baumhakel et al., 2011) and were
thus chosen as the allowed concomitant beta-blockers within the study. 
Therefore, a treatment effect of sacubitril/valsartan compared to enalapril of 3.5 IIED units was 
estimated. Assuming a standard deviation of 7 IIEF units and a two-sided alpha of 0.05, 86 
patients per arm would confer a 90% power to detect a conservative treatment difference of 3.5 
IIEF units. This is in accordance with the minimal clinically important difference of the erectile 
function domain of IIEF-15 of 2 and 5 IIEF units in patients with mild and moderate erectile 
dysfunction, respectively (Rosen et al., 2011).
To compensate for some drop-out and other protocol deviations, 100 patients/arm (200 in total) 
should be randomized into this trial. There will be no additional recruitment in case some 
patients will not be able to achieve the target dose since based on PARADIGM-HF and a shorter 
trial duration, no substantial influence on the power of the trial is expected.
 
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10.
Ethical considerations 
10.1
Regulatory and ethical compliance 
10.2
Informed consent procedures 
10.3
Responsibilities of the investigator and IRB/IEC
10.4
Publication of study protocol and results
10.5
Quality Control and Quality Assurance
11.
Protocol adherence 
11.1
Protocol amendments 
12.
References
ALBERTI, L., TORLASCO, C., LAURETTA, L., LOFFI, M., MARANTA, F., SALONIA, A., 
MARGONATO, A., MONTORSI, F. & FRAGASSO, G. 2013. Erectile dysfunction in 
heart failure patients: a critical reappraisal. Andrology, 1, 177-91.
BAUMHAKEL, M. & BOHM, M. 2007. Erectile dysfunction correlates with left ventricular 
function and precedes cardiovascular events in cardiovascular high-risk patients. Int J 
Clin Pract, 61, 361-6.
BECKER, A. J., UCKERT, S., STIEF, C. G., SCHELLER, F., KNAPP, W. H., HARTMANN, 
U. & JONAS, U. 2001. Plasma levels of angiotensin II during different penile conditions 
in the cavernous and systemic blood of healthy men and patients with erectile
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CHANDRA, A., LEWIS, E. F., CLAGGETT, B. L., DESAI, A. S., PACKER, M., ZILE, M. 
R., SWEDBERG, K., ROULEAU, J. L., SHI, V. C., LEFKOWITZ, M. P., KATOVA, 
T., MCMURRAY, J. J. V. & SOLOMON, S. D. 2018. Effects of Sacubitril/Valsartan 
on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary 
Analysis of the PARADIGM-HF Trial. JAMA Cardiol.
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suicidality in a VA primary care setting: 2 items are better than 1 item. American Journal 
of Managed Care, 10, 839-845.
DUSING, R. 2003. Effect of the angiotensin II antagonist valsartan on sexual function in 
hypertensive men. Blood Press Suppl, 2, 29-34.
FRAGA-SILVA, R. A., MONTECUCCO,
F., MACH, F., SANTOS, R. A. & 
STERGIOPULOS, N. 2013. Pathophysiological role of the renin-angiotensin system on 
erectile dysfunction. Eur J Clin Invest, 43, 978-85.
GROUP, C. T. S. 1987. Effects of enalapril on mortality in severe congestive heart failure. 
Results of the Cooperative North Scandinavian Enalapril Survival Study 
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INVESTIGATORS, S. 1991. Effect of enalapril on survival in patients with reduced left 
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N. 1992. Effect of enalapril on mortality and the development of heart failure in 
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hyperpolarizes and relaxes human penile resistance arteries. J Sex Med, 5, 1114-1125.
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STIEF, C. G., FORSSMANN, W. G. & MAGERT, H. J. 2003. Expression of guanylyl 
cyclase B in the human corpus cavernosum penis and the possible involvement of its 
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LEVINE, G. N., STEINKE, E. E., BAKAEEN, F. G., BOZKURT, B., CHEITLIN, M. D., 
CONTI, J. B., FOSTER, E., JAARSMA, T., KLONER, R. A., LANGE, R. A., LINDAU, 
S. T., MARON, B. J., MOSER, D. K., OHMAN, E. M., SEFTEL, A. D., STEWART, 
W. J., AMERICAN HEART ASSOCIATION COUNCIL ON CLINICAL, C., 
COUNCIL ON CARDIOVASCULAR, N., COUNCIL ON CARDIOVASCULAR, S., 
ANESTHESIA, COUNCIL ON QUALITY OF, C. & OUTCOMES, R. 2012. Sexual 
activity and cardiovascular disease: a scientific statement from the American Heart 
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LUE, T. F. 2000. Erectile dysfunction. N Engl J Med, 342, 1802-13.
MCCABE, M. P. 1997. Intimacy and quality of life among sexually dysfunctional men and 
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A. R., ROULEAU, J. L., SHI, V. C., SOLOMON, S. D., SWEDBERG, K., ZILE, M. 
R., INVESTIGATORS, P.-H. & COMMITTEES 2014. Angiotensin-neprilysin 
inhibition versus enalapril in heart failure. N Engl J Med, 371, 993-1004.
PACKER, M., MCMURRAY, J. J., DESAI, A. S., GONG, J., LEFKOWITZ, M. P., RIZKALA, 
A. R., ROULEAU, J. L., SHI, V. C., SOLOMON, S. D., SWEDBERG, K., ZILE, M., 
ANDERSEN, K., ARANGO, J. L., ARNOLD, J. M., BELOHLAVEK, J., BOHM, M., 
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A., DUARTE, Y. C., ERGLIS, A., FU, M., GOMEZ, E., GONZALEZ-MEDINA, A., 
HAGEGE, A. A., HUANG, J., KATOVA, T., KIATCHOOSAKUN, S., KIM, K. S., 
KOZAN, O., LLAMAS, E. B., MARTINEZ, F., MERKELY, B., MENDOZA, I., 
MOSTERD, A., NEGRUSZ-KAWECKA, M., PEUHKURINEN, K., RAMIRES, F. J., 
REFSGAARD, J., ROSENTHAL, A., SENNI, M., SIBULO, A. S., JR., SILVA-
CARDOSO, J., SQUIRE, I. B., STARLING, R. C., TEERLINK, J. R., VANHAECKE, 
J., VINEREANU, D., WONG, R. C., INVESTIGATORS, P.-H. & COORDINATORS 
2015. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of 
clinical progression in surviving patients with heart failure. Circulation, 131, 54-61.
PONIKOWSKI, P., VOORS, A. A., ANKER, S. D., BUENO, H., CLELAND, J. G., COATS, 
A. J., FALK, V., GONZALEZ-JUANATEY, J. R., HARJOLA, V. P., JANKOWSKA, 
 
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E. A., JESSUP, M., LINDE, C., NIHOYANNOPOULOS, P., PARISSIS, J. T., PIESKE, 
B., RILEY, J. P., ROSANO, G. M., RUILOPE, L. M., RUSCHITZKA, F., RUTTEN, 
F. H. & VAN DER MEER, P. 2016. 2016 ESC Guidelines for the diagnosis and 
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treatment of acute and chronic heart failure of the European Society of Cardiology 
(ESC). Developed with the special contribution of the Heart Failure Association (HFA) 
of the ESC. Eur J Heart Fail.
RASTOGI, S., RODRIGUEZ, J. J., KAPUR, V. & SCHWARZ, E. R. 2005. Why do patients 
with heart failure suffer from erectile dysfunction? A critical review and suggestions on 
how to approach this problem. Int J Impot Res, 17 Suppl 1, S25-36.
ROSEN, R. C., RILEY, A., WAGNER, G., OSTERLOH, I. H., KIRKPATRICK, J. & 
MISHRA, A. 1997. The international index of erectile function (IIEF): a 
multidimensional scale for assessment of erectile dysfunction. Urology, 49, 822-30.
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MAJERCAK, I., ANDREKA, P., SHEHOVA-YANKOVA, N., ANAND, I., YILMAZ, 
M. B., GOGIA, H., MARTINEZ-SELLES, M., FISCHER, S., ZILAHI, Z., COSMI, F., 
GELEV, V., GALVE, E., GOMEZ-DOBLAS, J. J., NOCIAR, J., RADOMSKA, M., 
SOKOLOVA, B., VOLTERRANI, M., SARKAR, A., REIMUND, B., CHEN, F. & 
CHARNEY, A. 2016. Initiating sacubitril/valsartan (LCZ696) in heart failure: results 
of TITRATION, a double-blind, randomized comparison of two uptitration regimens. 
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K., BAOU, K., BRATSAS, A., LAZAROS, G. & STEFANADIS, C. 2010. Amino-
terminal pro-C-type natriuretic peptide is associated with arterial stiffness, endothelial 
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WILTINK, J., HAUCK, E. W., PHADAYANON, M., WEIDNER, W. & BEUTEL, M. E. 2003. 
Validation of the German version of the International Index of Erectile Function (IIEF) 
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ROULEAU, J. L., SWEDBERG, K., DESAI, A. S., GONG, J., SHI, V. C. & 
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13.
Appendix 1: Clinically notable laboratory values 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
RBC count 
>50% increase, >20% decrease 
Hemoglobin 
>50% increase, >20% decrease 
Hematocrit 
>50% increase, >20% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
Blood Chemistry 
ALT (SGPT) 
>150% increase 
AST (SGOT) 
>150% increase 
BUN 
>50% increase 
Creatinine
>50% increase 
Total bilirubin 
>100% increase 
CPK 
>300% increase 
Alkaline phosphatase
>100% increase 
Potassium
>20% increase, >20% decrease 
Chloride 
>10% increase, >10% decrease 
Calcium 
>10% increase, >10% decrease 
Uric acid 
>50% increase
 
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14.
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
 
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15.
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
16.
Appendix 4: Treatment guidelines for hyperkalemia (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)

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
 
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
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.

If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with
repeat potassium within 3-5 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.
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
 
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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 increases 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
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 
 
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medication was stopped, every effort will be done to restart it again, according to clinical
conditions.
 
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20.
Appendix 8: IIEF-5
INTERNATIONAL INDEX FOR ERECTILE DYSFUNCTION (IIEF-5)
Over the past 4 weeks:
1.
How do you rate your 
confidence that you could get 
and keep an erection?
1
Very low
2
Low
3
Moderate
4
High
5
Very high
 
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2.
When you had erections with 
sexual stimulation, how often 
were your erections hard 
enough for penetration?
1
Almost 
never/never
2
A few times 
(much less 
than half 
the time)
3
Sometimes
(about half
the time)
4
Most times
(much more 
than half 
the time)
5
Almost 
always/always
3.
During sexual intercourse, 
how often were you able to 
maintain your erection after you 
had penetrated (entered) 
your partner?
1
Almost 
never/never
2
A few times 
(much less 
than half 
the time)
3
Sometimes
(about half
the time)
4
Most times
(much more 
than half 
the time)
5
Almost 
always/always
4.
During sexual intercourse, 
how difficult was it to maintain 
your erection to completion 
of intercourse?
1
Extremely 
difficult
2
Very 
difficult
3
Difficult
4
Slightly 
difficult
5
Not difficult
5.
When you attempted sexual 
intercourse, how often was it 
satisfactory for you?
1
Almost 
never/never
2
A few times 
(much less 
than half 
the time)
3
Sometimes
(about half
the time)
4
Most times
(much more 
than half 
the time)
5
Almost 
always/always
aThe IIEF-5 score is the sum of the ordinal responses to the five items; thus, the score can range from 5 to 25.
21.
Appendix 9: IIEF-15
INTERNATIONAL INDEX FOR ERECTILE DYSFUNCTION (IIEF-15)
These questions ask about the effect your erection problems have had on your sex 
life over the past 4 weeks. Please answer these questions as honestly and as clearly 
as possible.  Please answer every question by checking the appropriate box []. If 
you are unsure about how to answer, please give the most accurate answer you can.
In answering these questions, the following 
definitions apply:
 
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* 
Sexual intercourse
Is defined as vaginal penetration (entry) of the partner.
** 
Sexual Activity
Includes sexual intercourse, caressing, foreplay and masturbation.
*** 
Ejaculate
Is defined as the ejection of semen from the penis (or the sensation of this).
**** Sexual stimulation
Includes situations such as loveplay with a partner, looking at erotic pictures, etc.
1.
Over the past 4 weeks how often were you able to get an erection during sexual activity**?
Please check one box only.
No sexual activity..............................................................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time)........................................................
A few times (much less than half the time).......................................
Almost never or never .......................................................................
2.
Over the past 4 weeks when you had erections with sexual stimulation****, how often were 
your erections hard enough for penetration?
Please check one box only.
No sexual stimulation........................................................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time)........................................................
A few times (much less than half the time).......................................
Almost never or never .......................................................................
The next 3 questions will ask about the erections you may have had during sexual 
intercourse*.
 
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3.
Over the past 4 weeks when you attempted sexual intercourse* how often were you able to 
penetrate (enter) your partner? 
Please check one box only.
Did not attempt to initiate sexual intercourse....................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time) .......................................................
A few times (much less than half the time).......................................
Almost never or never.......................................................................
4.
Over the past 4 weeks during sexual intercourse* how often were you able to maintain your 
erection after you had penetrated (entered) your partner? 
Please check one box only.
Did not attempt to initiate sexual intercourse....................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time) .......................................................
A few times (much less than half the time).......................................
Almost never or never.......................................................................
5.
Over the past 4 weeks during sexual intercourse* how difficult was it to maintain your 
erection to completion of intercourse? 
Please check one box only.
Did not attempt to initiate sexual intercourse....................................
Extremely difficult ............................................................................
Very difficult.....................................................................................
Difficult .............................................................................................
Slightly difficult ................................................................................
Not difficult.......................................................................................
* 
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner  
** 
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation  
*** 
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)  
**** 
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc
 
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6.
Over the past 4 weeks how many times have you attempted sexual intercourse*? 
Please check one box only.
No attempts .......................................................................................
1-2 attempts.......................................................................................
3-4 attempts.......................................................................................
5-6 attempts.......................................................................................
7-10 attempts.....................................................................................
11 and more attempts ........................................................................
7.
Over the past 4 weeks when you attempted sexual intercourse* how often was it 
satisfactory for you? 
Please check one box only.
Did not attempt to initiate sexual intercourse....................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time) .......................................................
A few times (much less than half the time).......................................
Almost never or never.......................................................................
8.
Over the past 4 weeks how much have you enjoyed sexual intercourse*? 
Please check one box only.
No sexual intercourse........................................................................
Very highly enjoyable .......................................................................
Highly enjoyable ...............................................................................
Fairly enjoyable.................................................................................
Not very enjoyable ............................................................................
Not enjoyable ....................................................................................
* 
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner  
** 
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation  
*** 
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)  
**** 
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc
 
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9.
Over the past 4 weeks when you had sexual stimulation**** or had sexual intercourse* how 
often did you ejaculate***?
Please check one box only.
No sexual stimulation or intercourse.................................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time) .......................................................
A few times (much less than half the time).......................................
Almost never or never.......................................................................
10. Over the past 4 weeks when you had sexual stimulation**** or had sexual intercourse* how 
often did you have the feeling of orgasm with or without ejaculation***?
Please check one box only.
No sexual stimulation or intercourse.................................................
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time) .......................................................
A few times (much less than half the time).......................................
Almost never or never.......................................................................
* 
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner  
** 
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation  
*** 
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)  
**** 
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc
The next 2 questions ask about sexual desire.  Let's define sexual desire as a feeling 
that may include wanting to have a sexual experience (e.g. masturbation or 
intercourse*), thinking about sex, or feeling frustrated due to lack of sex.
11. Over the past 4 weeks how often have you felt sexual desire?
Please check one box only.
Almost always or always...................................................................
Most times (much more than half the time) ......................................
Sometimes (about half the time) .......................................................
A few times (much less than half the time).......................................
Almost never or never.......................................................................
 
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12. Over the past 4 weeks how would you assess your level of sexual desire?
Please check one box only.
Very high...........................................................................................
High...................................................................................................
Moderate............................................................................................
Low....................................................................................................
Very low or none at all......................................................................
* 
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner  
** 
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation  
*** 
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)  
**** 
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc
13. Over the past 4 weeks how satisfied on average have you been with your sex life?
Please check one box only.
Very satisfied.....................................................................................
Moderately satisfied ..........................................................................
About equally satisfied and dissatisfied............................................
Moderately dissatisfied .....................................................................
Very dissatisfied................................................................................
14. Over the past 4 weeks how satisfied have you been with your sexual relationship with a 
partner?
Please check one box only.
Very satisfied.....................................................................................
Moderately satisfied ..........................................................................
About equally satisfied and dissatisfied............................................
Moderately dissatisfied .....................................................................
Very dissatisfied................................................................................
15. Over the past 4 weeks how would you rate your confidence that you could get and keep 
an erection?
Please check one box only.
Very high...........................................................................................
High...................................................................................................
Moderate............................................................................................
Low....................................................................................................
Very low............................................................................................
 
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* 
Sexual intercourse: Is defined as vaginal penetration (entry) of the partner  
** 
Sexual activity: Includes sexual intercourse, caressing, foreplay and masturbation  
*** 
Ejaculate: Is defined as the ejection of semen from the penis (or the sensation of this)  
**** 
Sexual stimulation: Includes situations such as loveplay with a partner, looking at erotic pictures, etc
22.
Appendix 10: Sexual activity diary
1. Within the past 7 days, how often did you try to have sexual intercourse (attempted vaginal 
penetration) with your partner?
□
not at all (no attempted sexual intercourse within the past 7 days)
□
once
□
twice
□
three times
□
> three times
2. Within the past 7 days, how often have you tried to masturbate?
□
not at all (no attempt to masturbate within the past 7 days)
□
once
□
twice
□
three times
□
> three times
3. Within the past 7 days, how often did you have an erection at night or in the morning (if both 
apply, please only count once)?
□
not at all (no erection at night or in the morning)
 
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□
once
□
2-3 times
□
4-5 times
□
> 5 times
4. Within the past 7 days, how often have you had intimate physical activity with your partner 
other than having vaginal intercourse (exchange of affection, foreplay, petting, oral 
intercourse)?
□
not at all (no other sexual activity)
□
once
□
2-3 times
□
4-5 times
□
> 5 times
5. Within the past 7 days, did you avoid physical intimacy with your partner because of your 
diminished erectile capability? 
□
yes
□
no
6. Within the past 7 days, how would you rate your affection/emotions towards your partner?
□
non existent 
□
little
□
satisfactory
□
strong 
□
very strong
7. Within the past 7 days, to which extent did your sexual desire influence your mood?
□
very negatively affected
□
negative affected
□
not affected
□
positive affected 
□
very positive affected
 
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SAP_001.pdf: 
Official Title: 
NCT Number: 
Document Date: 
A Randomized, Double-blind, Active-controlled Study to Assess the Effect of 
Sacubitril/Valsartan Compared With Enalapril to Improve Erectile Function in 
Patients With Heart Failure With Reduced Ejection Fraction and Erectile Dysfunction
NCT03917459
Statistical Analysis Plan Amendment 02: 06 October 2021






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CLCZ696BDE03 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
efficacy 
objectives (s) 
 
 
 
 
Patient reported sexual activity updated. 
Added summary of CFB for SAD and 
NT-proBNP. 
Section 2.7.2 
Statistical 
hypothesis, 
model, 
and 
method 
of 
analysis 
 
 
 
Laboratory data for HbA1c absolute 
removed 
Section 
2.8.3 
Laboratory data 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
Figure 1.1-1  Study design ....................................................................................... 8 
1.2 
Study objectives and endpoints ............................................................................... 8 
Table 1.2-1   Study objectives and related endpoints .............................................. 8 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 11 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 11 
2.3.1 
Patient disposition ................................................................................. 11 
2.3.2 
Patient demographics and other baseline characteristics ...................... 11 
2.3.3 
Medical history...................................................................................... 12 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 12 
2.4.1 
Study treatment / compliance ................................................................ 12 
2.4.2 
Prior, concomitant and post therapies ................................................... 12 
2.5 
Analysis of the primary objective .......................................................................... 13 
2.5.1 
Primary endpoint ................................................................................... 13 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 13 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.5.4 
Sensitivity analyses ............................................................................... 14 
2.6 
Analysis of the key secondary objective ............................................................... 14 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 14 
2.7.1 
Secondary endpoints ............................................................................. 16 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 16 
2.8 
Safety analyses....................................................................................................... 16 
2.8.1 
Adverse events (AEs) ............................................................................ 16 
2.8.2 
Deaths .................................................................................................... 17 
2.8.3 
Laboratory data ..................................................................................... 17 
2.8.4 
Other safety data ................................................................................... 19 
2.9 
Pharmacokinetic endpoints .................................................................................... 19 


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2.10 
PD and PK/PD analyses ........................................................................................ 19 
2.11 
Patient-reported outcomes ..................................................................................... 19 
2.11.1 
IIEF-5 .................................................................................................... 19 
2.11.2 
IIEF-15 .................................................................................................. 20 
 
 21 
2.11.4 
Patient-reported sexual activity ............................................................. 21 
 
 21 
 
 21 
2.14 
Interim analysis ...................................................................................................... 22 
3 
Sample size calculation ..................................................................................................... 22 
4 
Change to protocol specified analyses .............................................................................. 23 
5 
Appendix ........................................................................................................................... 23 
5.1 
Imputation rules ..................................................................................................... 23 
5.1.1 
Study drug ............................................................................................. 23 
5.1.2 
AE date imputation ............................................................................... 23 
5.1.3 
Concomitant medication date imputation ............................................. 25 
5.2 
AEs coding/grading ............................................................................................... 28 
5.3 
Laboratory parameters derivations ........................................................................ 28 
5.4 
Statistical models ................................................................................................... 28 
5.4.1 
Primary analysis .................................................................................... 28 
5.4.2 
STRATA.Key secondary analysis ........................................................ 29 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 29 
6 
Reference ........................................................................................................................... 29 


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List of abbreviations 
AE 
ACE  
ACEI  
Adverse event 
Angiotensin-converting-enzyme  
Angiotensin-converting-enzyme inhibitor  
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
CHF 
bis in diem/twice a day 
Chronic heart failure 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
ED 
Data Monitoring Committee  
Erectile dysfunction  
FAS 
Full Analysis Set 
eCRF 
HF 
HFrEF  
Electronic Case Report Form 
Heart Failure 
Heart failure with reduced ejection fraction  
IVR 
Interactive Voice Response 
IWR 
IRB 
IRT 
LFT  
LVEF  
Interactive Web Response 
Institutional Review Board  
Interactive Response Technology  
Liver function test  
Left ventricular ejection fraction 
MedDRA 
mmHg 
Medical Dictionary for Drug Regulatory Affairs 
Millimeter mercury  
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
SAE  
Response Evaluation Criteria in Solid Tumors  
Serious Adverse Event  
SAP 
SBP  
SmPC  
SUSAR 
Statistical Analysis Plan 
Systolic blood pressure  
Summary of product characteristics  
Suspected Unexpected Serious Adverse Reactions  
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This SAP module describes the planned statistical methods for all safety and efficacy analyses. 
Any changes made to the statistical plan and methodology after the clinical database lock will 
be documented as an addendum. 
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in clinical study 
report. 
Data will be analyzed by Novartis according to the data analysis section 9 of the clinical study 
protocol. That statistical methodology is described below and any deviations from the protocol 
are documented. Additional detailed information regarding the analysis methodology is 
contained in the Appendix section. 
1.1 
Study design 
This is a randomized, double-blind, double-dummy, multi-center, active-controlled, 
interventional study to compare sacubitril/valsartan to enalapril in improving erectile function 
in male patients with chronic heart failure (NYHA II) with reduced ejection fraction (HFrEF) 
and erectile dysfunction (ED). 
The study comprises five obligatory and one optional visit over a period of approximately 14 
weeks. Once patients’ eligibility has been ascertained at Visit 1 (Screening), patients will be 
randomized at Visit 2 (Randomization) to receive either sacubitril/valsartan or enalapril in a 1:1 
allocation during the double-blind period. At Visit 2, all efficacy assessments will be collected 
and used as baseline values. Double-blind treatment will be initiated with 5 mg bid enalapril or 
49 mg/51 mg bid sacubitril/valsartan and up-titrated after 2 weeks to the final dose of 10mg bid 
enalapril or 97 mg/103 mg bid sacubitril/valsartan. According to the sacubitril/valsartan SmPC, 
initiation of treatment is recommended with the 24 mg/26 mg bid sacubitril/valsartan or 2.5 mg 
bid enalapril dose for certain patients. For these patients, an optional visit 4B after achieving 
the target dose of 97 mg /103 mg bid sacubitril/valsartan or 10 mg bid enalapril is mandatory. 
For the detailed understanding of study design and allowed investigational treatment dose 
adjustments during double-blind period refer Section 3.1 and Section 5.5.4 of the protocol.  
The study design is shown in the below figure. 


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Figure 1.1-1  Study design 
 
 
There are 200 patients planned to be randomized in 1:1 allocation to receive either 
sacubitril/valsartan or enalapril. 
There will be no stratification at randomization in this study. The primary analysis will be done 
based on the erectile function score of the questionnaire International Index of Erectile Function 
(IIEF-15) at the end of the study i.e. at visit 5 (Week 12). 
There is no interim analysis planned for this study. 
1.2 
Study objectives and endpoints 
Table 1.2-1   Study objectives and related endpoints 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
To 
demonstrate 
the 
superiority 
of 
sacubitril/valsartan compared to enalapril 
regarding improvement in erectile function 
and ability in male patients with chronic heart 
failure and erectile dysfunction using the 
questionnaire International Index of Erectile 
Function (IIEF-15) at the end of the study  
 
Erectile function score using IIEF-15  at 
Week 12. 
Secondary objective(s) 
Endpoint(s) for Secondary objective(s) 
To assess the early-onset effect as well as the 
effect at the end of the study of 
sacubitril/valsartan 
versus 
enalapril 
regarding improvement in sexual activity 
Self-reported sexual activity per week at 
week 4 and week 12 
 
 


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assessed using patient’s self-reported sexual 
activity per week  
 
To assess the early-onset effect as well as the 
effect at the end of the study of 
sacubitril/valsartan 
versus 
enalapril 
regarding NT-proBNP levels  
 
 
 
 
NT-proBNP levels at week 4 and week 12 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The data analysis will be conducted by Novartis on all patient data after database lock for the 
respective trial periods. Analysis datasets and statistical outputs will be produced using the most 
recent SAS® Version 9.4 or higher (SAS Institute Inc., Cary, NC, USA), and stored in Novartis 
global programming & statistical environment (GPS). 


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Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, lower quartile, median, upper quartile and maximum. Categorical variables will be 
summarized by absolute frequencies. Summary statistics will also be presented graphically 
wherever applicable.  
p-value and 95% confidence interval will be provided wherever applicable. Unless otherwise 
stated, the level of significance will be set to 5% (two-sided, family-wise type-I-error).  
For categorical data, percentages will be rounded up to 1 decimal place. For continuous data, 
mean, median and quartiles will be rounded up to 1 additional decimal place compared to the 
original data. Standard deviation will be rounded up to 2 additional decimal places. Minimum 
and maximum will be displayed with the same accuracy as in the original data. Wherever 
changes from baseline will be used, change will be calculated as “post-baseline value – 
baseline value”. The number of decimal places for the “change from baseline” variables will 
be the same as for the original measurement. 
 
2.1.1 
General definitions  
Study treatment: Study treatment refers to 
Sacubitril/valsartan bid and placebo matching enalapril bid 
Enalapril bid and placebo matching sacubitril/valsartan bid.  
Study treatment start and end date: Study treatment start date is defined as the first date 
when a non-zero dose of study drug is administered and recorded on the Drug Administration 
Record (DAR) CRF page. Similarly, study drug end date is defined as the last date when a non-
zero dose of study drug is administered and recorded on the DAR CRF page of the study. 
Study day: Study day will be calculated as (event date – study drug start date + 1 day) for 
events that occurred on or after study drug start date (e.g., visit, lab samples, AEs). For events 
prior to study drug start date (e.g., time of diagnosis), study day will be negative and calculated 
as (event date – study drug start date). Note that study drug start date is study day 1 and the day 
before study drug start date is study day -1 (i.e. not study day 0). 
Note that, the first dose day is Day 1, and the day before the first dose day is counted as day -1 
(not day 0). 
Baseline and post-baseline: Baseline value is defined as the last non-missing assessment prior 
to the first dose of randomized study medication. A post-baseline value refers to a measurement 
taken after the first dose of study treatment. 
Lost to follow up: Subjects whose status is unclear because they fail to appear for study visits 
without stating an intention to discontinue or withdraw. A patient cannot be considered as lost 
to follow-up until the time point of his planned end of study visit has passed. 
Study completion: A patient will be considered to have completed the study when the patient 
has completed the last visit planned in the protocol. 
 


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2.2 
Analysis sets 
The following analysis sets will be used for the statistical analyses:  
Full Analysis Set (FAS): The full analysis set (FAS) will consist of all randomized patients 
who received at least one dose of study drug. Following the intent-to-treat principle, patients 
will be analyzed according to the treatment which they were assigned to at randomization. 
Efficacy variables will be analyzed based on the FAS.  
Safety Set (SAF): The safety set (SAF) will consist of all randomized patients who received at 
least one dose of study drug. Patients will be analyzed according to the treatment actually 
received. The SAF will be used for the analyses of safety variables. 
 
2.2.1 
Subgroup of interest 
Not applicable. 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number and percentage of patients screened, completed the screening and randomized will 
be presented. In addition, the reasons for screen failures will be provided.  
The number and percentage of patients who completed the study and/or discontinued the study 
prematurely (including the primary reason for discontinuation) will be presented, if appropriate, 
for each treatment group and all randomized patients.  
The number and percentage of patients who took rescue medication will be presented. For each 
protocol deviation (PD), the number and percentage of patients for whom the PD applies will 
be tabulated for all the patients in FAS. 
 
2.3.2 
Patient demographics and other baseline characteristics 
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (<65 years vs. >= 65 years and <= 75 years ), sex, race, 
weight, height, body mass index (BMI), category of prior CHF medication, prior HF 
hospitalization, NYHA class, score of short International Index of Erectile Function (IIEF-5), 
and vital signs.  
BMI will be calculated as weight (kg) / height^2 (m^2) from the collected height and weight at 
Visit 1 (Screening).  
Continuous variables will be summarized using n, mean, standard deviation, median, minimum, 
and maximum. Categorical variables will be summarized using frequency and percentage.  
The full analysis set (FAS) will be used for the above analyses. 


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2.3.3 
Medical history 
Any condition entered on the relevant medical history / current medical conditions CRF will be 
coded using the MedDRA dictionary. They will be summarized by system organ class (SOC) 
and preferred term (PT) of the MedDRA dictionary. Summaries for cardiovascular and heart 
failure medical history will be reported separately. Smoking history (baseline) will be 
summarized and listed. 
Apart from summarizing medical history, Cardiovascular history, and Heart failure history will 
also be listed. Analyses will be based on the full analysis set. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The summaries by treatment will be performed by the actual treatment received as follows: 
• Sacubitril/Valsartan 
• Enalapril 
The analysis of study treatment data will be based on Safety analysis set (SAF). 
Duration of exposure 
The duration of exposure to study treatment will also be summarized by treatment group using 
mean, standard deviation, median, minimum and maximum. In addition, the number and 
percentage of patients with cumulative exposure levels (e.g. any exposure, ≥ 2 weeks, ≥4 weeks, 
≥ 6 weeks, ≥8 weeks, ≥ 12 weeks, etc.) will be presented. 
Duration of exposure for study treatment will be defined as the time from first dose of study 
treatment to the time of treatment end for each treatment. 
The analyses of duration of exposure described above will be done for the entire study 
treatment periods. 
Compliance 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient.  
 
2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medications will be summarized in separate tables by treatment group 
based on safety set. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those, 
which were started pre-baseline and continued into the period where study treatment is 
administered. 


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Concomitant medications and significant non-drug therapies, prior to and after the 
randomization date respectively, will be summarized by therapeutic class, preferred term, and 
treatment group according to the WHO-DRL dictionary.  
The number and percentage of patients on different CHF background medications (β-blockers, 
diuretics) will be tabulated by treatment at baseline and during the treatment period. 
 
2.5 
Analysis of the primary objective 
The primary objective is to demonstrate the superiority of sacubitril/valsartan compared to 
enalapril regarding improvement in erectile function and ability in male patients with chronic 
heart failure and erectile dysfunction using the questionnaire International Index of Erectile 
Function (IIEF-15) at the end of the study. 
2.5.1 
Primary endpoint 
The primary endpoint is the erectile function score IIEF-15 at week 12. The trial aims to 
estimate the effect of the treatment policy, irrespective of intercurrent events such as dose 
changes or adherence to randomized treatment.  
The following estimand will be used: 
Population – Full Analysis Set (FAS)  
Variable of Interest – Erectile function score IIEF-15 at week 12  
Intervention effect – effect between sacubitril/valsartan versus enalapril at week 12 regardless 
of adherence to randomized treatment.  
Summary measure – difference in means. 
For patients who permanently discontinue study treatment, values collected after study drug 
discontinuation will generally be included in the primary analysis. 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary variable will be analyzed using a mixed model for repeated measures (MMRM), 
The response variable will be the Erectile function score IIEF-15 and change from baseline. 
Treatment (sacubitril/valsartan versus enalapril), visit and treatment-by-visit interaction will be 
included as fixed-effect factors; baseline IIEF-15 will be included as a covariate; the within-
patient covariance will be modeled using an unstructured covariance matrix (a common matrix 
for the two treatment groups). The analysis will include all (two) scheduled post-baseline visits 
and will be performed based on the likelihood method with an assumption of missing at random 
(MAR) for missing data. 
The null-hypothesis to be rejected is that there is no difference in mean IIEF-15 erectile function 
score at week 12 between the two treatment arms. 
In mathematical terms: 
                                   H0: μ1 = μ2  


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                                            vs. Ha: μ1 ≠ μ2 
where μ1 and μ2 are mean erectile function IIEF-15 scores at week 12 for the treatment groups 
of sacubitril/valsartan versus enalapril, respectively. 
The statistical test will be performed at the two-sided significance level of 0.05 based on the 
MMRM model. The estimates and the corresponding 95% confidence intervals will be provided 
for the difference in adjusted means at month 3 between the two treatment groups based on the 
MMRM model. Although this test is defined as two-sided, superiority of sacubitril/valsartan 
versus enalapril will be claimed only, if the difference is in favor of sacubitril/ valsartan. 
The FAS will be used for the above primary analyses. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Patients will be followed up and all scheduled visits should be performed, even if study drug is 
discontinued for that respective patient prematurely. Therefore, missing values should only 
occur in case of death, withdrawal of informed consent or loss to follow up. In these cases, patients 
will be included with their available values into the statistical MMRM model. 
2.5.4 
Sensitivity analyses 
A ‘while on treatment’ estimand might be meaningful to explore the effect of drop-outs on the 
primary estimand. This estimand will include drop-outs with their last observed value and will 
not (like the MMRM model of the primary estimand) extrapolate a possible improvent that 
might have been observed if the patient had continued. The following estimand will be used: 
Population – Full Analysis Set (FAS)  
Variable of Interest – Erectile function score IIEF-15 at last observed visit.  
Intervention effect – effect between sacubitril/valsartan versus enalapril at last observed visit 
regardless of adherence to randomized treatment.  
Summary measure – difference in means. 
For patients for whom an IIEF-15 at week 12 is available, this value will be used, regardless of 
adherence to treatment. Analysis will be performed using an Analysis of Covariance model for 
IIEF-15 at last observed visit with factor treatment group and covariate baseline IIEF-15. 
2.6 
Analysis of the key secondary objective 
Not applicable. 
2.7 
Analysis of secondary efficacy objective(s) 
All the secondary efficacy evaluation will be performed on FAS population. 
Following are the secondary objectives need to be assessed in this trial: 
• To assess the early-onset effect as well as the effect at the end of the study of 
sacubitril/valsartan versus enalapril regarding improvement in sexual activity assessed 
using patient’s self-reported  sexual activity per week  
 
 


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Sexual activity diary contains seven questions. Six questions have 5 response options (scored 
from 1 to 5) and one question (Question no. 5) has 2 response options (yes or no). Descriptive 
summary for total score of Self-reported sexual activity (Except question no. 5) will be provided 
per week (i.e at week 4 and week 12). For question no. 5, only frequency distribution for each 
category (yes and no) will be provided at week 4 and week 12. 
 
 
Q1-Q2 
Score 
Not at all (no attempt to masturbate within the past 7 days) 
1 
Not at all (no attempted sexual intercourse within the past 7 
days) 
1 
Once 
2 
Twice 
3 
Three times 
4 
More than three times 
5 
Q3-Q4 
Score 
Not at all (no erection at night or in the morning) 
1 
Not at all (no other sexual activity) 
1 
Once 
2 
2-3 times 
3 
4-5 times 
4 
More than 5 times 
5 
Q6 
Score 
Non existent 
1 
Little 
2 
Satisfactory 
3 
Strong 
4 
Very strong 
5 
Q7 
Score 
Very negatively affected 
1 
Negatively affected 
2 
Not affected 
3 
Positively affected 
4 
Very positively affected 
5 


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• To assess the early-onset effect as well as the effect at the end of the study of 
sacubitril/valsartan versus enalapril regarding NT-proBNP levels  
 
2.7.1 
Secondary endpoints 
The following secondary variables will be analyzed: 
• Self-reported  sexual activity per week at week 4 and week 12 
• NT-proBNP levels at week 4 and week 12 
 
2.7.2 
Statistical hypothesis, model, and method of analysis 
Not applicable 
Patient-reported sexual activity 
Sexual activity diary contains seven questions. Six questions have 5 response options (scored 
from 1 to 5) and one question (Question no. 5) has 2 response options (yes or no). Descriptive 
summary for total score and change from baseline of Self-reported sexual activity (Except 
question no. 5) will be provided per week (i.e at week 4 and week 12). For question no. 5, only 
frequency distribution for each category (yes and no) will be provided at week 4 and week 12. 
NT-proBNP 
Raw & Change from basline NT-proBNP levels at week 4 and week 12 will be summarized 
descriptively using n, mean, standard deviation, median, minimum and maximum. 
NT-proBNP data will remain blinded till data base lock. 
2.7.3 
Handling of missing values/censoring/discontinuations 
No missing data imputation will be used for secondary variables. 
2.8 
Safety analyses 
Safety set will be used for the safety analyses. 
2.8.1 
Adverse events (AEs) 
Adverse events will be coded by primary system organ class and preferred term according to 
the Medical Dictionary for Regulatory Activities (MedDRA). 
The crude incidence of treatment emergent adverse events (i.e. 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 by primary system organ class and 
preferred term. 


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Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having at least one 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 
particular AE ‘severity’ is missing, this variable will be listed as missing and treated as missing 
in summaries. If a subject reported more than one adverse event with the same preferred term, 
the adverse event with the greatest severity and drug relationship 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  
• All adverse events 
• Adverse events suspected to be related to study drug by the investigator 
• Deaths 
• Serious adverse events 
• Adverse events leading to discontinuation 
• Adverse events requiring dose adjustment or study-drug interruption 
In the data listings of adverse events, the severity of an AE, whether or not an AE is study drug 
related, and whether or not it is a serious AE, will be indicated. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
The following event will be considered as adverse event of special interest. 
• Angioedema  
Adverse events of special interest will be coded by primary system organ class and preferred 
term according to the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events 
of special interest will be summarized by presenting, for each treatment group, the number and 
percentage of patients having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term).  
2.8.2 
Deaths 
Separate summaries and listings will be provided for deaths. Death information will be 
summarized based on safety set. 
2.8.3 
Laboratory data 
The laboratory analysis will be carried out on safety set. 
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values (means, medians, standard deviations, ranges) to each visit. The summary 
of laboratory evaluations will be presented for hematology and blood chemistry parameters 
seperately. 


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The following laboratory variables will be presented for all visits: 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count. 
Biochemistry 
Glucose, blood urea nitrogen (BUN), Blood urea, creatinine, creatinine kinase, total bilirubin, 
AST, ALT, alkaline phosphatase, INR, GFR,  HbA1c relative, sodium, potassium, chloride, 
calcium, total protein, albumin, HDL, LDL, triglycerides, and uric acid  The number and 
percentage of subjects with clinically notable laboratory results after baseline will be presented. 
Clinically notable laboratory results, for those parameters where ranges are available, are given 
in Table 2.8.3-1 below. For the calculation the denominator are based on the evaluable post-
baseline subjects who did not have the notable abnormality at baseline.  
For all laboratory evaluation scheduled and unscheduled laboratory measurements will be taken 
into account. 
Table 2.8.3-1 
Clinically notable laboratory values  
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
 
RBC count 
>50% increase, >20% decrease 
Hemoglobin  
>50% increase, >20% decrease 
Hematocrit  
>50% increase, >20% decrease 
WBC count  
>50% increase, >50% decrease 
Platelet count  
>75% increase, >50% decrease 
Blood Chemistry 
 
ALT (SGPT)  
>150% increase 
AST (SGOT) 
>150% increase 
BUN  
>50% increase 
Creatinine  
>50% increase 
Total bilirubin  
>100% increase 
CPK  
>300% increase 
Alkaline phosphatase  
>100% increase 
Potassium 
>20% increase, >20% decrease 
Chloride 
>10% increase, >10% decrease 
Calcium  
>10% increase, >10% decrease 


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Uric acid 
>50% increase 
 
2.8.3.1 
Urine analysis 
Not Applicable 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable. 
2.8.4.2 
Vital signs 
Vital signs include blood pressure and pulse measurements. These parameters will be 
summarized by visit with standard summary statistics (mean, median, standard deviation, and 
ranges), including change from baseline. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values.  
The number and percentage of patients with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2.8.4-1 below. 
2.8.4.3 
Height and weight 
Height and weight collected will be listed based on safety set. 
2.8.4.4 
Physical examination 
Collected physical examination parameters on CRF will be listed based on safety set. 
2.9 
Pharmacokinetic endpoints   
Not applicable.  
2.10 
PD and PK/PD analyses 
Not applicable. 
 
2.11 
Patient-reported outcomes 
The following Patient reported outcomes (PROs) will be analyzed in the study: 
2.11.1 
IIEF-5 
The IIEF-5 score will be used in male patients with heart failure with reduced ejection fraction 
to determine the patients’/subjects’ eligibility for study participation. The IIEF-5 consists of 5 
items. For every item, 5 possible response options are available (score 1-5) adding up to a 
maximum total score of 25. Erectile function will be determined by study personnel by adding 
individual scores to a total score.  


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22-25:   No erectile dysfunction  
17-21:   Mild erectile dysfunction  
12-16:   Mild to moderate erectile dysfunction  
8-11  :   Moderate erectile dysfunction  
5-7    :   Severe erectile dysfunction. 
The number and percentage of patients in each category based on total score will be summarized 
for FAS population. 
2.11.2 
IIEF-15 
The IIEF-15 score will be used in male patients with heart failure with reduced ejection fraction. 
The IIEF-15 is a validated, multi-dimensional, self-administered questionnaire for the 
assessment of erectile function. The questionnaire of 15 items organized in 5 domains. The 
respective domains are:  
• Erectile function  
• Orgasmic function  
• Sexual desire  
• Intercourse satisfaction  
• Overall satisfaction  
For every item 5 possible response options are available (score 1-5) resulting in a maximum 
score of 75. Each domain will be determined by study personnel by adding individual scores to 
a total score based on the following consideration.  
For each question, 0-5 points can be achieved with 5 being the best outcome (Rosen et al., 1997). 
In this study, the IIEF-15 will be completed by patients at baseline (Visit 2), as well as at 2 weeks 
(Visit 3), at 1 month (Visit 4) and at 3 months (Visit 5) and all categories will be evaluated 
separately: erectile function (questions 1-5; 15), orgasmic function (questions 9-10), sexual desire 
(questions 11-12), intercourse satisfaction (questions 6-8) and overall satisfaction (questions 13-
14). Among 15 questions except question 6 all the questions are scored properly. For question 6 
score value (range) will be changed manually based on below  considerations for analysis. 
How many times have you attempted sexual intercourse ?  
Score value 
    No attempt 
0 
One to two attempts 
1 
Three to four attempts 
2 
Five to six attempts 
3 
Seven to ten attempts 
4 
Eleven and more attempts 
5 
 




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2.14 
Interim analysis 
No interim analysis will be performed. 
3 
Sample size calculation 
For the IIEF-15 domain “erectile function”, the treatment effect and SD of sacubitril/valsartan 
compared to enalapril was estimated based on the previous VALED study, which demonstrated 
that valsartan showed a highly significant increase in erectile function from 16.54±8.27 to 
23.14±6.49 IIEF units in hypertensive males (Dusing, 2003). VALED was an open-label study 
comparing 6 months treatment with valsartan to baseline. CONFIDENCE on the other hand is 
a double-blind randomized trial and the beneficial effect of sacubitril/valsartan will likely be 
driven not by valsartan but by the neprilysin inhibition introduced by sacubitril. For sample size 


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calculation the shorter study period, differing patient population (heart failure versus 
hypertension) as well as the use of bisoprolol/metoprolol have to be taken into account. Beta-
blocker have differing effects on erectile function. While propranolol and atenolol are well-
known to reduce sexual function, nebivolol has vasodilating effects, which may even be 
beneficial in erectile dysfuntion (Baumhakel et al., 2011). Bisoprolol/metoprolol have been 
suggested to have a neutral effect on erectile dysfunction (Baumhakel et al., 2011) and were 
thus chosen as the allowed concomitant beta-blockers within the study. 
Therefore, a treatment effect of sacubitril/valsartan compared to enalapril of 3.5 IIEF units was 
estimated. Assuming a standard deviation of 7 IIEF units and a two-sided alpha of 0.05, 86 
patients per arm would confer a 90% power to detect a conservative treatment difference of 3.5 
IIEF units. This is in accordance with the minimal clinically important difference of the erectile 
function domain of IIEF-15 of 2 and 5 IIEF units in patients with mild and moderate erectile 
dysfunction, respectively (Rosen et al., 2011). 
To compensate for some drop-out and other protocol deviations, 100 patients/arm (200 in total) 
should be randomized into this trial. There will be no additional recruitment in case some 
patients will not be able to achieve the target dose since based on PARADIGM-HF and a shorter 
trial duration, no substantial influence on the power of the trial is expected. 
4 
Change to protocol specified analyses 
Not applicable. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Not applicable. 
5.1.2 
AE date imputation 
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the Table 5.1.2-1 below.  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the AE year value is missing, the imputed AE start date is set to  
NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore: 
a. If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY). 
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY). 






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a. If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY). 
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point  
(01MONYYYY). 
4. If the CMD start date year value is equal to the treatment start date year value: 
a. and the CMD month is missing or the CMD month is equal to the treatment start 
month, 
i. If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date.  
ii.   Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date. 
b. Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY). 
Else if the CMD month is greater than the treatment start month, the imputed CMD start date is 
set to the start month point (01MONYYYY). 
Table 5.1.3-1:  CMD date imputation 
 
MON MISSING 
MON < CFM 
MON = CFM 
MON > CFM 
YYYY  
MISSING (F) 
(F) 
(F) 
(F) 
 
Uncertain 
Uncertain 
Uncertain 
Uncertain 
YYYY <  
CFY 
(D)=01JULYYYY 
(C)=15MONYY 
(C)=15MONYY 
(C)=15MONYY 
 
Before Treatment Start 
Before Treatment Start Before Treatment Start 
Before Treatment Start 
YYYY =  
CFY 
(B) 
(C)=15MONYY 
(B) 
(A)=01MONYYYY 
 
Uncertain 
Before Treatment Start Uncertain 
After Treatment Start 
YYYY >  
CFY 
(E)= 01JANYYYY 
(A)=01MONYYYY 
(A)=01MONYYYY 
(A)=01MONYYYY 
 
After Treatment Start 
After Treatment Start 
After Treatment Start 
After Treatment Start 
 
Before Treatment Start  
Partial indicates date prior to Treatment Start Date 
After Treatment Start  
Partial indicates date after Treatment Start Date 
Uncertain 
Partial insufficient to determine relationship to Treatment Start Date 
         LEGEND: 
(A) 
MAX (01MONYYYY,TRTSTD+1) 
(B) 
IF CMDTYP1C IN (1,3) THEN TRTSTD-1 
     ELSE IF CMDTYP1C in (. , 2) THEN TRTSTD+1 


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MON MISSING 
MON < CFM 
MON = CFM 
MON > CFM 
(C) 
15MONYYYY 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
(F) 
IF CMDTYP1C IN (1,3) THEN TRTSTD-1 
    ELSE IF CMDTYP1C in (. , 2) THEN TRTSTD+1 
 
 
 
 


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Concomitant Medication End Date Imputation 
1. 
If the CM end date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end 
date will be set to NULL. 
2. 
Else, if the CM end date month is missing, the imputed end date will be set to the earliest 
of the (Last contact date of subject in study, 31DECYYYY, date of death). 
3. 
If the CM end date day is missing, the imputed end date will be set to the earliest of the 
(Last contact date of subject in study, last day of the month, date of death). 
4. 
If the imputed CM end date is less than the existing CM start date, the CM start date 
will be used as the imputed CM end date. 
 
5.1.3.1 
Prior therapies date imputation 
Not applicable. 
5.1.3.2 
Post therapies date imputation 
Not applicable. 
5.1.3.3 
Other imputations 
5.2 
AEs coding/grading 
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1 and above. 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
SAS code for mixed model: 
proc mixed data=aaa; 
class TRT USUBJID AVISITN; 
model AVAL/CHG=TRT AVISITN BASE TRT*AVISITN  
/  ddfm=kr; lsmeans TRT*AVISITN / diff cl; 
repeated AVISITN / type=un subject=USUBJID; 
Run; 
 


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SAP- Amendment 02 
 
CLCZ696BDE03 
 
In case the MMRM model does not converge the following sequential steps will be used: 
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2. 
2. change type=un to type=cs. If still no convergence, perform step 3. 
3. remove covariates in the following order until convergence: BASE*AVISITN, 
5.4.2 
STRATA.Key secondary analysis 
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
Table 5-1 
Protocol deviations that cause subjects to be excluded 
Deviation ID 
Description of Deviation 
Exclusion in Analyses 
Severity code 
INCL01 
 
Signed informed consent was not obtained 
prior to initiation of any study-related 
procedure. 
 
EXCLUDE FROM FAS 
AND SAF 
3 
 
Table 5-2 
Analysis set exclusions based on population codes 
Analysis set  
Population codes that cause a subject to be 
excluded 
SAF  
3 
FAS  
3 
 
Table 5-3 
Population code text 
Population Code 
Population code text 
 
3 
EXCLUDE FROM FAS AND SAF 
Unless otherwise stated, summary tables, figures and listings will be on all subjects included in 
the analysis set under consideration. 
6 
Reference