Conditions: Cardiomyopathy, Hypertrophic
Keywords: non-obstructive hypertrophic cardiomyopathy genetic cardiomyopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine if LCZ696 can improve functional capacity (via improved peak VO2) in non-obstructive hypertrophic cardiomyopathy (HCM) patient population over the course of 50 weeks of treatment.

Detailed description:
This was a multi-center, placebo-controlled, patient and investigator-blinded study in non-obstructive HCM patients.

The study comprised a ≤ 35-day screening/baseline period, a 4-week single-blind treatment run-in period, followed by a 46-week double-blind placebo-controlled treatment period (total treatment period of 50 weeks), and a follow-up period approximately 30 days after the last dose.

The treatment run-in period was planned to ensure that as large a proportion as possible of patients:

1. had stable symptoms and could comply with study visits, and
2. could tolerate at least low dose LCZ696. During the run-in period, all patients received oral (p.o.) placebo b.i.d. for 2 weeks followed by 50 mg p.o. of active LCZ696 b.i.d. for 2 weeks. Patients who were unable to tolerate either placebo or the 50 mg p.o. b.i.d. dose level, were considered treatment run-in failures and were neither randomized into the double-blind, placebo-controlled study, nor included in the efficacy analysis.

In the double-blind treatment period, participants were randomized 1:1 to placebo or LCZ696. In the LCZ696 arm, participants started at a LCZ696 100 mg p.o. b.i.d dose. After approximately 14 days, patients who tolerated the 100 mg p.o. b.i.d. dose were up-titrated to 200 mg p.o. b.i.d. dose, whereas those who did not meet the safety criteria were titrated back down to the 50 mg b.i.d. dose.

Arms:
arm 1: Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d. arm 2: Placebo to LCZ696

Interventions: intervention 1: LCZ696 intervention 2: Placebo
Intervention descriptions: intervention 1: LCZ696 orally twice daily intervention 2: placebo

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
LCZ696 
Clinical Trial Protocol CLCZ696I12201 / NCT04164732
A multi-center, randomized, placebo-controlled patient and 
investigator-blinded study to explore the efficacy of oral 
sacubitril/valsartan in adult patients with non-obstructive 
hypertrophic cardiomyopathy (nHCM) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2019-003098-24 
Version number: 
v02 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
08-Apr-2022


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Site Operations Manual (SOM) 
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report. 


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Table of contents 
Site Operations Manual (SOM) ........................................................................................... 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 2 (April 2022) ............................................................................................... 11 
Amendment 1 (February 2020) ......................................................................................... 12 
Protocol summary .............................................................................................................. 14 
1 
Introduction ....................................................................................................................... 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose .................................................................................................................. 18 
2 
Objectives and endpoints ................................................................................................... 18 
3 
Study design ...................................................................................................................... 19 
4 
Rationale ............................................................................................................................ 22 
4.1 
Rationale for study design ..................................................................................... 22 
4.2 
Rationale for selection of patient population ......................................................... 22 
4.3 
Rationale for dose/regimen and duration of treatment .......................................... 23 
4.4 
Rationale for choice of control drugs (placebo) .................................................... 23 
4.5 
Rationale for choice of background therapy .......................................................... 23 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 23 
4.7 
Risks and benefits .................................................................................................. 24 
4.7.1 
Potential risks of cardiopulmonary exercise testing.............................. 24 
 
 25 
4.7.3 
Blood sample volume ............................................................................ 25 
5 
Population .......................................................................................................................... 25 
5.1 
Inclusion criteria .................................................................................................... 25 
5.2 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 28 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational and control drugs .......................................................... 29 
6.1.2 
Additional study treatments .................................................................. 29 
6.1.3 
Treatment arms/group ........................................................................... 29 
6.2 
Other treatment(s) .................................................................................................. 30 
6.2.1 
Concomitant therapy ............................................................................. 30 


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6.2.2 
Prohibited medication ........................................................................... 31 
6.2.3 
Rescue medication ................................................................................ 31 
6.2.4 
Restriction for study subjects ................................................................ 31 
6.3 
Subject numbering, treatment assignment, randomization .................................... 32 
6.3.1 
Subject numbering ................................................................................ 32 
6.3.2 
Treatment assignment, randomization .................................................. 32 
6.4 
Treatment blinding ................................................................................................. 32 
6.5 
Dose escalation and dose modification .................................................................. 33 
6.6 
Additional treatment guidance ............................................................................... 35 
6.6.1 
Treatment compliance ........................................................................... 35 
6.6.2 
Recommended treatment of adverse events .......................................... 35 
6.6.3 
Emergency breaking of assigned treatment code .................................. 36 
6.7 
Preparation and dispensation ................................................................................. 36 
7 
Informed consent procedures ............................................................................................ 36 
8 
Visit schedule and assessments ......................................................................................... 38 
8.1 
Screening ............................................................................................................... 41 
8.1.1 
Eligibility screening .............................................................................. 41 
8.1.2 
Information to be collected on screening failures ................................. 41 
8.2 
Subject demographics/other baseline characteristics ............................................. 41 
8.3 
Efficacy .................................................................................................................. 41 
8.3.1 
Cardiopulmonary Exercise Test (CPET) .............................................. 41 
 
 42 
8.3.3 
Appropriateness of efficacy assessments .............................................. 42 
8.4 
Safety and Tolerability .......................................................................................... 42 
8.4.1 
Physical Examination ............................................................................ 42 
8.4.2 
Vital signs.............................................................................................. 43 
8.4.3 
Height and weight ................................................................................. 43 
8.4.4 
Laboratory evaluations .......................................................................... 43 
8.4.5 
Electrocardiogram (ECG) ..................................................................... 43 
8.4.6 
Pregnancy and assessments of fertility ................................................. 44 
8.4.7 
Appropriateness of safety measurements .............................................. 44 
 
 44 
 
 44 
 
 45 
9 
Study discontinuation and completion .............................................................................. 46 
9.1 
Discontinuation ...................................................................................................... 46 


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9.1.1 
Discontinuation of study treatment ....................................................... 46 
9.1.2 
Withdrawal of informed consent ........................................................... 47 
9.1.3 
Lost to follow-up ................................................................................... 48 
9.1.4 
Study stopping rules .............................................................................. 48 
9.1.5 
Early study termination by the sponsor ................................................. 48 
9.2 
Study completion and post-study treatment .......................................................... 49 
10 Safety monitoring and reporting ........................................................................................ 49 
10.1 
Definition of adverse events and reporting requirements ...................................... 49 
10.1.1 
Adverse events ...................................................................................... 49 
10.1.2 
Serious adverse events .......................................................................... 50 
10.1.3 
SAE reporting........................................................................................ 51 
10.1.4 
Pregnancy reporting .............................................................................. 52 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 53 
10.2 
Additional Safety Monitoring ................................................................................ 53 
10.2.1 
Liver safety monitoring ......................................................................... 53 
10.2.2 
Renal safety monitoring ........................................................................ 54 
11 Data Collection and Database management ...................................................................... 54 
11.1 
Data collection ....................................................................................................... 54 
11.2 
Database management and quality control ............................................................ 55 
11.3 
Site monitoring ...................................................................................................... 55 
12 Data analysis and statistical methods ................................................................................ 56 
12.1 
Analysis sets .......................................................................................................... 56 
12.2 
Subject demographics and other baseline characteristics ...................................... 56 
12.3 
Treatments ............................................................................................................. 57 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 57 
12.4.1 
Definition of primary endpoint(s) ......................................................... 57 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 57 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 57 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 57 
12.5 
Analysis of secondary endpoints ........................................................................... 57 
12.5.1 
Safety endpoints .................................................................................... 57 
 
 58 
12.7 
Interim analyses ..................................................................................................... 59 
12.8 
Sample size calculation .......................................................................................... 59 
12.8.1 
Primary endpoint(s) ............................................................................... 59 
13 Ethical considerations and administrative procedures ...................................................... 60 


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13.1 
Regulatory and ethical compliance ........................................................................ 60 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 60 
13.3 
Publication of study protocol and results............................................................... 60 
13.4 
Quality Control and Quality Assurance ................................................................. 61 
14 Protocol adherence ............................................................................................................ 61 
14.1 
Protocol amendments ............................................................................................. 61 
15 References ......................................................................................................................... 62 
16 Appendices ........................................................................................................................ 64 
16.1 
Appendix 1: Clinically notable laboratory values ................................................. 64 
16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ......................................................................................................... 65 
16.3 
Appendix 3: Guidelines for the management of renal dysfunction ....................... 69 
16.4 
Appendix 4: Treatment guidelines for hyperkalemia (serum potassium greater 
than or equal to 5.3 mmol/L [mEq/L] .................................................................... 70 
16.5 
Appendix 5: Guidelines for the management of blood pressure ........................... 72 
16.6 
Appendix 6: Screening flow chart for asymptomatic patients ............................... 73 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 18 
Table 3-1 
Safety monitoring criteria that must be met for initial treatment and 
throughout all treatment periods ........................................................... 21 
Table 4-1 
Rationale for study design ..................................................................... 22 
Table 6-1 
Investigational and control drug ............................................................ 29 
Table 6-2 
Prohibited medication ........................................................................... 31 
Table 6-3 
Blinding levels ...................................................................................... 33 
Table 8-1 
Assessment Schedule ............................................................................ 38 
 
 45 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 53 
Table 16-1 
Liver event and laboratory trigger definitions ...................................... 65 
Table 16-2 
Follow up requirements for liver events and laboratory triggers .......... 66 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 21 
Figure 16-1 
Screening flow chart for asymptomatic patients ................................... 73 
 


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List of abbreviations 
ACEI 
Angiotensin-converting-enzyme inhibitor (ACE inhibitor) 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANP 
Atrial natriuretic peptide 
ARB 
Angiotensin receptor blocker 
ARNI 
Angiotensin receptor neprilysin inhibitor 
AST 
aspartate aminotransferase 
AT1 
Angiotensin II type 1 
b.i.d. 
twice a day 
BMI 
Body Mass Index 
BNP 
Brain-type natriuretic peptide 
BP 
Blood pressure 
BUN 
blood urea nitrogen 
cGMP 
cyclic guanosine monophosphate 
CMO&PS 
Chief Medical Office & Patient Safety 
CNP 
C-type natriuretic peptide 
CPET 
Cardiopulmonary exercise testing 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated Glomerular Filtration Rate 
ELISA 
Enzyme-linked immunosorbent assay 
EOS 
End of study 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
human Chorionic Gonadotropin 
HCM 
Hypertrophic cardiomyopathy 
HCV 
Hepatitis C virus 
HFpEF 
Heart failure with preserved ejection fraction 
HFrEF 
Heart failure with reduced ejection fraction 
HIV 
human immunodeficiency virus 
i.v. 
intravenous 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 


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ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
 
 
LFT 
Liver function test 
LLOQ 
lower limit of quantification 
LV 
Left ventricle (heart) 
 
 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MRA 
Mineralocorticoid receptor antagonist 
NEPi 
Neprilysin inhibitor 
nHCM 
non-obstructive hypertrophic cardiomyopathy 
NPR 
Natriuretic peptide receptor 
NYHA 
New York Heart Association 
p.o. 
oral 
PD 
pharmacodynamic(s) 
PDE-5 
Phosphodiesterase-5 
 
  
PPS 
Per protocol set 
 
 
PT 
prothrombin time 
 
 
QTcF 
QT interval corrected by Fridericia’s formula 
RAS 
Randomized analysis set 
RBC 
red blood cell(s) 
SAE 
serious adverse event 
SBP 
Systolic Blood Pressure 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
sMDRD 
simplified Modification of Diet in Renal Disease 
SMQ 
Standardized MedDRA Query 
SOM 
Site Operations Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
ULN 
upper limit of normal 


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VO2 
Volume of Oxygen 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study patient 
Dosage 
Dose of the study treatment given to the subject 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. 
Investigational 
drug/treatment 
The drug whose properties are being tested in the study 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Randomization 
number 
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment 
Run in Failure 
A patient who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to patient’s medications or other 
intervention) 
Screen Failure 
A patient who is screened but is not treated or randomized 
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 treatment 
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy 
Study treatment 
discontinuation 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Subject 
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient. 
Subject number 
A unique number assigned to each patient upon signing the informed 
consent. This number is the definitive, unique identifier for the patient and 
should be used to identify the patient throughout the study for all data 
collected, sample labels, etc. 
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 occurs only when a patient does not 
want to participate in the study any longer and does not allow any further 
collection of personal data  


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Amendment 2 (April 2022) 
Amendment rationale 
In addition, text has been added to existing sections of the protocol for 1) clarification on the 
Informed Consent process prior to all assessments performed as well as 2) the investigator SAE 
reporting timelines. 
Changes to the protocol 
 
  
 
 
 
• Section 5.1 Inclusion criteria  
• Added additional text to emphasize to sites that Informed Consent must be signed 
prior to discontinuation of ACE-I/ARB during the >36 hour washout period, if 
applicable. 
 
 
 
 
 
 
 
 
 
• Section 10.1.3 SAE reporting 
Added additional text for clarification on investigator reporting timelines for SAEs 
 


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Amendment 1 (February 2020) 
Amendment rationale  
The purpose of this amendment is to address concerns raised by several Health Authorities and 
Ethics Committees during their review of the protocol.  First, the Health Authorities requested 
greater clarification on the use of a 250 pg/ml cutoff of NT-proBNP as a criterion for screening 
asymptomatic patients.  A justification for this value has now been added into Section 4.2 of 
the protocol.   Second, clarification of the risk of fetal harm was requested in Section 4.7 of the 
protocol.  Third, further clarification of the scope of the interim analysis was also requested and 
has now been added to Section 12.7.  Finally, a number of typographical errors in the inclusion 
and exclusion criteria listed in the Protocol Summary were corrected to be consistent with the 
inclusion and exclusion criteria listed in Section 5. Additional minor clarifications and 
typographical errors throughout the protocol have also been corrected. 
Changes to the protocol 
• Protocol summary 
• Key inclusion and exclusion criteria were corrected to reflect the criteria listed in 
Section 5 of the protocol. 
• Section 3 Study design 
• Clarified the use of safety criteria to assess tolerability of study medication.  
• Section 4.2 Rationale for selection of patient population 
• Added rationale for the NT-proBNP cutoff required to screen asymptomatic patients. 
• Section 4.7 Risks and benefits 
• Clarified risk of fetal harm by study medication if women of childbearing potential 
become pregnant while on study medication. 
• Section 5.1 Inclusion criteria 
• Inclusion criteria 4 has been updated to allow asymptomatic/NYHA Class I patients 
with peak VO2 of 80% to enroll in the study to harmonize with exclusion criteria 4. 
• Section 5.2 Exclusion criteria 
• Exclusion criteria 3 was clarified to exclude only those patients with a history of atrial 
fibrillation within 6 months of the screening/baseline visit. 
• Section 8 Visit schedule and assessments 
• Corrected a typographical error to make clear the requirement for recording adverse 
events during the screening/baseline period. 
• Section 8.4.4 Laboratory evaluations 
• Added clarification that plasma samples instead of serum samples can be collected for 
local laboratory analysis as per local practice.  
• Section 10.2.1 Liver safety monitoring 
• Correction made to indicate that results of local liver chemistry tests associated with a 
liver event should be recorded in source documents rather than in the CRF. 


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• Section 12.7 Interim Analysis 
• Added clarification that the planned interim analysis will also include review of safety 
data.  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  
 


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Protocol summary 
Protocol number 
CLCZ696I12201 
Full Title 
A multi-center, randomized, placebo-controlled patient and investigator-
blinded study to explore the efficacy of oral sacubitril/valsartan in adult 
patients with non-obstructive hypertrophic cardiomyopathy (nHCM) 
Brief title 
Study of efficacy of oral sacubitril/valsartan in adult patients with non-
obstructive hypertrophic cardiomyopathy 
Sponsor and 
Clinical Phase 
Novartis - Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to determine if LCZ696 is safe, tolerable and 
can improve exercise capacity (via improved peak VO2) in non-obstructive 
HCM patient population over the course of 50 weeks of treatment. 
 
 
 
 
Primary Objective(s)  The primary objective of this study is to evaluate the efficacy of LCZ696 
on cardiopulmonary exercise test (CPET) parameters in patients with non-
obstructive HCM, based on Peak VO2 , after 50 weeks of treatment 
Secondary 
Objectives 
To evaluate the safety and tolerability of LCZ696 in patients with non-
obstructive HCM, based on standard safety assessments (AE, vital signs, 
ECGs, physical examinations and safety labs) 
Study design 
This 
multi-center 
study 
includes 
a 
single-blind 
(i.e., 
patient-
blinded) treatment run-in period aimed to ensure as large a proportion as 
possible of patients tolerate LCZ696 throughout the study, followed by a 
randomized, placebo-controlled, parallel-group, patient and investigator-
blinded study in patients with non-obstructive HCM, over a total of 50 week 
treatment period. The maximum study duration, from initial screening to end 
of study (EOS) for each patient is approximately 58 weeks. 
Population 
Approximately 44 male and female adult (≥ 18 years of age) non-obstructive 
HCM patients will be randomized into the study with the intention of 40 
completing the 50 week treatment period. 
Key Inclusion 
criteria 
• 
Diagnosed with Hypertrophic Cardiomyopathy (hypertrophied and non-
dilated left ventricle in the absence of any systemic cause) with a left 
ventricular wall thickness ≥ 13mm by the echocardiogram obtained 
during the screening/baseline period, based on local evaluation of 
echocardiographic images. 
• 
LVEF ≥ 50% by echocardiogram obtained during the 
screening/baseline period, based on local evaluation of 
echocardiographic images. 
• 
Symptoms consistent with New York Heart Association (NYHA) Class 
II-III heart failure by physician assessment, or asymptomatic/NYHA 
Class I patients with:  
• 
NT-proBNP above 250 pg/ml and 
• 
peak VO2 of ≤80% of predicted based on age and gender. 


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Key Exclusion 
criteria 
• 
Patients with a resting or provokable left ventricular outflow tract 
gradient of ≥30mm Hg, based on local evaluation of echocardiographic 
images obtained during the screening/baseline period. 
• 
Septal reduction procedure within 3 months of the screening/baseline 
visit. 
• 
Patients with a peak VO2 on the screening/baseline cardiopulmonary 
exercise test of > 80% of predicted based on age and gender. 
• 
Patients who require treatment with ACE inhibitors, angiotensin 
receptor blockers (ARBs), or renin inhibitors. Patients who can 
discontinue ACE inhibitors, angiotensin receptor blockers, or renin 
inhibitors can participate if they are off these medicines for at least 36 
hours prior to the screening/baseline assessments. 
• 
Known infiltrative or storage disorder causing cardiac hypertrophy that 
mimics hypertrophic cardiomyopathy, such as Fabry disease, or 
amyloidosis. 
• 
Systolic blood pressure of <100 mmHg or symptomatic hypotension 
during the screening/baseline period or treatment run-in period. 
• 
Contraindication to ARB administration, including hyperkalemia (serum 
K>5.2 mmol/L) or prior history of angioedema. 
Study treatment 
• 
LCZ696 at doses of 50 mg, 100 mg and 200 mg b.i.d. 
• 
Placebo to LCZ696  
Efficacy 
assessments 
Cardiopulmonary exercise testing (CPET) 
Key safety 
assessments 
• 
Adverse event monitoring 
• 
Vital signs 
• 
Physical examinations 
• 
Monitoring of laboratory markers in blood 
• 
ECGs 
Data analysis 
The primary analysis will assess the effect of LCZ696 on the change from 
baseline in peak VO2 at week 50 compared to placebo. A longitudinal mixed 
effects model for the change from baseline will be used. The least-squares 
(LS) mean and associated 90% confidence interval (CI) for the change from 
baseline in peak VO2 for each treatment, and the estimated mean treatment 
difference, the p-value, and the corresponding 2-sided 80% CI will be 
extracted from the model at each time point.  
Key words 
non-obstructive, hypertrophic cardiomyopathy, genetic cardiomyopathy 


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1 
Introduction 
1.1 
Background 
Hypertrophic Cardiomyopathy (HCM) 
Hypertrophic cardiomyopathy (HCM) is a genetic, primary disorder of cardiac myocytes 
characterized by cardiac hypertrophy, unexplained by secondary causes, and a non-dilated left 
ventricle with preserved or increased ejection fraction (Marian and Braunwald 2017). 
Prevalence of HCM has been estimated at 0.16% to 0.29% (≈ 1:625–1:344 individuals) in the 
general adult population, without a distinct geographic, ethnic, or sex pattern of distribution 
(Maron et al 1995). 
Recent genetic discoveries have identified several mutations in genes encoding 
sarcomere-associated proteins causing HCM. MYH7 and MYBPC3, encoding β-myosin heavy 
chain and myosin-binding protein C, respectively, are the two most common genes involved, 
together accounting for ~50% of the HCM families (Richard et al 2003). The penetrance and 
phenotypic expression of the sarcomere mutations are highly variable; therefore, genetic testing, 
although supporting the diagnosis of HCM, is not predictive of severity or prognosis of this 
disease. In addition, in ~ 40% of HCM patients, the causal genes still remain to be identified. 
The clinical diagnosis of HCM is based on detection of cardiac hypertrophy by imaging 
techniques, such as echocardiography or cardiac magnetic resonance imaging. HCM is defined 
by an end-diastolic ventricular septal thickness in adults ≥13 mm, occurring in the absence of 
abnormal loading conditions or other secondary causes, such as hypertension, aortic stenosis, 
the physiological hypertrophy of athletes, or other conditions that mimic the HCM phenotype 
(i.e. Fabry disease, glycogen and lysosomal storage diseases and others). The hypertrophy is 
frequently asymmetrical, and predominantly involves the basal interventricular septum. The left 
ventricle in HCM usually has a normal end-diastolic volume, a high-normal (65% to 70%) or 
elevated (>70%) ejection fraction, and a reduced end-systolic volume. Obstruction of the left 
ventricular outflow tract is present at rest (defined as echocardiographic pressure gradient 
≥30 mmHg due to mitral-septal contact during systole) in about one third of HCM patients and 
can be provoked in another third of patients, while the remaining third have left ventricular 
hypertrophy without obstruction at rest or with provocation. The histopathology features of 
HCM include myocyte disarray and interstitial fibrosis, observed in cardiac tissue samples from 
HCM patients (either from autopsy or biopsy samples). 
The clinical manifestations and related prognosis of HCM are highly variable and mainly 
dependent on the grade of diastolic ventricular dysfunction and left ventricular outflow 
obstruction, imbalance between myocardial oxygen supply and demand (ischemic chest pain) 
and the presence of cardiac arrhythmias (palpitations, presyncope, syncope, sudden cardiac 
death). Therefore, evaluation and monitoring of patients with HCM commonly include a 
complete clinical history, physical examination, cardiac imaging, electrocardiography and 
cardiopulmonary exercise testing (CPET). In non-obstructive, asymptomatic HCM patients, 
CPET is especially useful as a tool for the evaluation of undiagnosed exercise intolerance and 
for the objective determination of functional capacity and impairment (Coats et al 2015). 


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Pharmacological treatments of patients with HCM are currently limited to β-Adrenergic 
receptor blockers, L-type calcium channel blockers, and disopyramide, intended to improve 
cardiac perfusion and symptoms. Septal reduction therapy, either by surgical septal myectomy 
or alcoholic septal ablation, is an invasive treatment in HCM patients with left ventricular 
outflow tract obstruction (systolic pressure gradient ≥30 mm Hg at rest or with provocation) 
who are symptomatic and not responding to pharmacological treatment. Advanced stages of 
heart failure with preserved or reduced ejection fraction who have failed pharmacotherapy and, 
when indicated, septal reduction therapy, may require implantation of a left ventricular device 
or cardiac transplantation. Therefore, there is still an unmet medical need for new therapies for 
HCM. 
Recently more pharmacological agents have been tested in HCM patients targeting different 
aspects in the pathogenesis of this disease. However, several drugs, such as spironolactone as a 
potential antifibrotic agent (Maron et al 2018), perhexiline as a metabolic modulator 
(Abozguiaet al 2010), ranolazine and eleclazine as late sodium current blockers 
(Olivotto et al 2018), did not show clear clinical benefits. Mavacamten, a selective allosteric 
modulator of cardiac myosin ATPase, and valsartan, an angiotensin receptor blocker, are 
currently being evaluated in clinical studies in HCM patients. 
LCZ696 Clinical Profile and Development in HCM 
LCZ696, also known as Entresto® (sacubitril/valsartan), is a first in class angiotensin receptor 
neprilysin inhibitor (ARNI), currently approved in over 100 countries including the United 
States and European Union for the treatment of chronic heart failure with reduced ejection 
fraction. 
Upon oral administration, LCZ696 delivers systemic exposure of valsartan, an angiotensin 
receptor blocker (ARB), and sacubitril (AHU377), a neprilysin inhibitor (NEPi) prodrug 
Angiotensin receptor blockade by valsartan is selective and competitive at the AT1 receptor, 
which mediates the deleterious effects of angiotensin II on the cardiovascular system, including 
pro-fibrotic/pro-hypertrophic mechanisms. 
The NEPi component of LCZ696, sacubitril, is a prodrug that is further metabolized via 
esterases to the active NEPi, sacubitrilat (LBQ657), which inhibits the degradation of natriuretic 
peptides and therefore enhances the effects of their biological activity. 
These effects are mediated by the natriuretic peptide receptor-A (NPR-A or NPR-1), a guanylyl 
cyclase-linked receptor whose activation generates the second messenger cyclic guanosine 
monophosphate (cGMP). This intracellular signal elicits the well-characterized blood pressure 
lowering, diuretic and natriuretic effects of these peptides (Espiner et al 1995). 
There is also evidence for a direct role of the natriuretic peptides in suppressing cardiac 
remodeling, supported by both in vitro and in vivo data. Hypertrophy of cardiac myocytes in 
culture is inhibited by ANP (Horio et al 2000) and all the three members of the natriuretic 
peptide family, ANP, BNP and C-type natriuretic peptide (CNP), inhibit fibroblast proliferation 
(Cao and Gardner 1995). In vivo, the lack of ANP and BNP bioactivities in NPR-1 gene 
knockout (NPR-1−/−) mice leads to both cardiac hypertrophy and fibrosis (Oliver et al 1997). 
Gene delivery of ANP is reported to attenuate hypertension and cardiac hypertrophy in a salt-


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sensitive rat model (Lin et al 1998). Data from patients with hypertension demonstrated a 
greater reduction in left ventricular mass following both 12 and 52 weeks of treatment with 
LCZ696 compared to olmesartan (Schmieder et al 2017). 
Clinically, several LCZ696 pharmacology studies have been completed to date, showing clear 
benefits to patients with cardiovascular disease, including heart failure and hypertension, in 
which vasoconstriction, volume expansion, and target organ damage (i.e., fibrosis, hypertrophy, 
myocardial/vascular stiffness) play a key role in their pathophysiology. 
The PARAMOUNT-HF clinical trial in patients with heart failure and preserved left ejection 
fraction (HFpEF) demonstrated a statistically significantly greater reduction in NT pro-BNP 
from baseline to Week 12 for LCZ696 200 mg twice per day (b.i.d.) compared to valsartan 
160 mg b.i.d., with a difference between groups of 23% (p=0.005) This study was also able to 
demonstrate a reduction in the size of the left atrium and improvement in NYHA functional 
class scores with LCZ696 compared to valsartan (Solomon et al 2012). 
A larger Phase III clinical trial, PARAGON-HF, evaluating the effect of LCZ696 compared to 
valsartan in the reduction of cardiovascular death and rate of HF hospitalizations in patients 
with HFpEF is currently on going (NCT01920711). Of note, patients with a clinical diagnosis 
of HCM were excluded from both the PARAMOUNT and PARAGON clinical studies and, 
thus, a clinical study to directly evaluate the effects of LCZ696 in HCM patients has not been 
conducted to date. 
1.2 
Purpose 
The purpose of this study is to determine if LCZ696 can improve functional capacity (VO2 max) 
in patients with non-obstructive hypertrophic cardiomyopathy over the course of 50 weeks of 
treatment. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the effect of LCZ696 on 
cardiopulmonary exercise test (CPET) 
parameters in patients with non-obstructive 
HCM 
• 
Peak VO2 after 50 weeks of treatment 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the safety and tolerability of 
LCZ696 in patients with non-obstructive HCM 
• 
Adverse events (AEs), vital signs, ECGs, 
physical examinations and safety labs 


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Objective(s) 
Endpoint(s) 
3 
Study design 
This multi-center study of non-obstructive HCM patients includes a single-blind (i.e., patient-
blinded) treatment run-in period aimed to ensure as large a proportion as possible of patients 
(1) have stable symptoms and can comply with study visits during the placebo run-in period, 
and (2) can tolerate at least low dose LCZ696. The treatment run-in period is followed by a 
randomized, placebo-controlled, parallel-group, patient and investigator-blinded treatment 
period. It is estimated that 44 patients will be randomized into the double-blind 
placebo-controlled part of the study in order to have approximately 40 patients complete the 
week 50 CPET assessment. 
The study will be comprised of a ≤ 35 day screening/baseline period, a 4-week single-blind 
treatment run-in period, followed by a 46 week double-blind placebo-controlled treatment 
period (total treatment period of 50 weeks), and a follow-up period approximately 30 days after 
the last dose. The maximum study duration, from initial screening to end of study (EOS) for 
each patient is approximately 58 weeks. More details are provided in the Site Operations 
Manual. 
Screening/baseline period 
Patients who sign informed consent and pass the initial screening/baseline evaluations will then 
have CPET and echocardiogram testing conducted. The 35 day screening/baseline period is 
designed to allow for scheduling and availability of results in order to establish patient's study 


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eligibility and baseline status. All screening/baseline safety evaluation results must be available 
prior to dosing. Patients who enter screening/baseline but are determined not to be eligible to 
enter the treatment run-in period will be considered as screen failures. See protocol Section 8.1 
for permitted re-screening criteria.  
Treatment run-in period 
Patients who qualify for study eligibility will then enter a single-blind treatment run-in period, 
during which all patients will receive oral (p.o.) placebo b.i.d. for 2 weeks followed by 50 mg 
p.o. b.i.d. of active LCZ696 for 2 weeks. Patients who are unable to tolerate either placebo or 
the 50 mg p.o. b.i.d. dose level, (i.e. do not meet safety criteria as specified in Table 3-1), will 
be considered treatment run-in failures and will not be randomized into the double-blind, 
placebo-controlled study, nor included in the efficacy analysis. At the end of the 4-week 
treatment run-in period, patients who meet the safety criteria (Table 3-1) will be eligible for 
randomization.  
Randomized treatment period 
At randomization (week 4 visit), eligible patients will be randomized into the study to receive 
oral (p.o.) doses of LCZ696 or placebo in a 1:1 ratio in a double-blind, placebo-controlled 
treatment period. All randomized patients will be titrated up to the 100 mg p.o. b.i.d. dose. 
All patients will return to the study center approximately 14 days later for assessment of 
tolerability of the 100 mg p.o. b.i.d. dose (i.e. must meet safety criteria as specified in 
Table 3-1). Patients whose assessments demonstrate that they tolerate the 100 mg p.o. b.i.d. 
dose will be up-titrated to 200 mg p.o. b.i.d. dose, whereas those who do not meet the safety 
criteria (Table 3-1) will be titrated back down to the 50 mg b.i.d. dose. Tolerance to the current 
dose (50 mg b.i.d. or 200 mg b.i.d.) will be again assessed ~14 days later, and those patients 
who demonstrate tolerance will remain on this dose throughout the remaining treatment period, 
unless a change in tolerance is noted as defined by the criteria in Section 16.3 - Section 16.5. 
Those patients who do not tolerate the 200 mg p.o. b.i.d. dose will be titrated down to 100 mg 
p.o. b.i.d. as outlined in Section 6.5. 
Tolerability can be assessed at scheduled visits or at any time during an unscheduled visit 
throughout the study as deemed appropriate by the investigator. Investigators are encouraged 
to have patients who report intolerance to study medication shortly after dose titration to return 
to the clinic as soon as possible for re-assessment and dose modification via an unscheduled 
visit. Those patients who do not tolerate higher doses will be adjusted down to the previous 
dose as outlined in Section 6.5. Patients who no longer tolerate the 50 mg p.o. b.i.d. dose will 
be discontinued from study treatment. 


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Table 3-1 
Safety monitoring criteria that must be met for initial treatment and 
throughout all treatment periods 
Parameter 
Screening/baseline Period 
Safety Monitoring during 
treatment run-in and randomized 
treatment periods 
Potassium 
≤ 5.2 mmol/L (mEg/L) 
≤ 5.4 mmol/L (mEg/L) 
eGFR 
≥ 30 mL/min/1.73m2 
≥ 25 mL/min/1.73m2 
Blood Pressure 
SBP ≥ 100 mmHg 
No symptomatic hypotension as 
determined by the investigator and 
SBP ≥ 100 mmHg 
AEs / Med History 
No conditions that preclude 
continuation according to the 
eligibility criteria 
No AEs that preclude continuation 
according to the investigator’s 
judgment 
Note that for abnormalities in potassium and eGFR, laboratory values should be repeated to confirm 
abnormality as outlined in Section 16.3 and Section 16.4. For out-of-range blood pressure readings, 
measurement may be repeated up to two times as detailed in the Site Operations Manual and 
Section 16.5. 
Note that for Screening/baseline Period and the Treatment Run-in Period exclusion criteria 
(Section 5.2) also reflect these safety monitoring criteria. 
Patients will receive study treatment for ~50 weeks, which includes the 4-week treatment run-
in period, with dose tolerability being assessed at each visit as well as at unscheduled visits (as 
necessary) and through feedback that patients may provide between visits. Safety and 
tolerability assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology and blood chemistry), AE and SAE monitoring. At week 
 week 50, patients will have follow-up CPET 
. No further 
treatment will be provided after the week 50 visit, and patients will return to the study center 
~30 days later for final safety and EOS evaluations. 
Refer to the Assessment Schedule (Table 8-1) for full visit schedule. 
Figure 3-1 
Study Design 
 


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4 
Rationale 
4.1 
Rationale for study design 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Overall 
This study has a parallel arm design to reduce treatment assignment 
bias and allow an assessment of placebo and treatment in the same 
setting with a similar patient population. The 4-week treatment run-in 
period prior to randomization is utilized to ensure that only patients who 
have stable symptoms and can tolerate the active treatment will be 
randomized into the double-blind portion of the study.  
Randomization 
This study has a 1:1 randomization scheme with no pre-specified strata. 
The 1:1 randomization ratio was chosen to maximize study power to 
detect differences in the primary endpoint, given the sample size. 
Blinding 
This is a patient- and investigator-blinded study. Blinding is used to 
reduce investigator and patient bias in reporting safety and efficacy 
outcomes. 
Duration of study periods 
A screening/baseline period of 35 days was chosen to provide trial sites 
with flexibility in the scheduling of the CPET and echocardiography 
assessments prior to the start of treatment. The treatment period of 
50 weeks was chosen to allow sufficient time for cardiac remodeling 
based on the observations from the PARAMOUNT trial, in which left 
atrial volume was significantly reduced only after 36 weeks of treatment 
with LCZ696 in patients with HFpEF (Solomon et al 2012). A follow up 
period of 30 days was designed to allow for a final safety after complete 
washout of LCZ696. 
4.2 
Rationale for selection of patient population 
This study will enroll only patients with non-obstructive hypertrophic cardiomyopathy (nHCM) 
who have a reduced exercise capacity as determined by their screening VO2max measurement. 
These patients can include both those who are symptomatic, as well as those who may be 
asymptomatic. The nHCM asymptomatic patients with reduced VO2max may not report 
symptoms despite impaired exercise tolerance because they limit daily their physical activity to 
avoid the onset of symptoms.  
As indicated in Appendix 6 of the protocol, local laboratory assessment of NT-proBNP is 
required for subjects who are asymptomatic (NYHA Class I) in order to assess their eligibility 
for subsequent CPET evaluation to determine their % predicted VO2max. Only asymptomatic 
patients with an NT-proBNP level >250 pg/ml are required to be screened for reduced VO2max 
levels.  Previous work in the field has shown that NT-proBNP levels correlate with VO2max 
measurements in patients with hypertrophic cardiomyopathy and further, a NT-proBNP cutoff 
level of 316 pg/ml had a 78% sensitivity to detect HCM patients with a VO2max of <80% of 
predicted (Thaman et al 2006).  The cutoff of 250 pg/ml of NT-proBNP was chosen to improve 
the sensitivity to detect patients with a peak VO2max of <80% predicted without dramatically 
increasing the screen failure rate. 


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The patient population is selected based on the effects seen with LCZ696 in the Phase II study 
PARAMOUNT-HF, where patients with heart failure and preserved left ejection fraction 
(HFpEF) demonstrated a reduction in the size of the left atrium and resulting improvement in 
NYHA functional class with LCZ696 compared to valsartan alone (Solomon et al 2012). 
In both the PARAMOUNT-HF study and the ongoing Phase III study of LCZ696 in HFpEF 
patients (PARAGON-HF), HCM patients were excluded.  
This study will determine whether the improvement in structural as well as symptomatic effects 
of LCZ696 as seen in PARAMOUNT-HF could translate to the HCM population. 
4.3 
Rationale for dose/regimen and duration of treatment 
The 4-week treatment run-in period, prior to randomization, is utilized to help ensure that only 
patients who can tolerate the active treatment will be randomized into the double-blind portion 
of the study. 
The starting dose for LCZ696 for patients entering into the treatment run-in period of this trial 
is set at 50 mg p.o. administered twice daily (b.i.d.). After 2 weeks of treatment, the dose of 
LCZ696 will be increased to 100 mg p.o. b.i.d. For those patients who tolerate the 100 mg p.o. 
b.i.d. dose, a final dose titration to 200 mg p.o. b.i.d. will be done after another 2 weeks of 
treatment. The 200 mg p.o. b.i.d. dose will be continued for the remainder of the trial as 
tolerated, or titrated back down if not tolerated. The selection of the starting dose, dose titration, 
and maximum dose is based on the approved package insert for sacubitril/valsartan for the 
treatment of patients with reduced ejection fraction heart failure.  
See Section 3 and Section 6.5 for further details regarding dose modification and tolerability. 
4.4 
Rationale for choice of control drugs (placebo) 
LCZ696 will be administered in addition to standard of care for nHCM patients, with placebo 
control used in addition to standard of care for nHCM patients to enable an unbiased comparison 
of safety and pharmacodynamic effects in active-treated patients when compared to placebo-
treated patients. 
4.5 
Rationale for choice of background therapy 
The trial will be done on top of standard of care for non-obstructive hypertrophic 
cardiomyopathy (e.g., β-blockers, verapamil, and/or disopyramide) as per study investigator. 
If necessary during the course of the trial, standard of care therapy may be down-titrated as 
described in Section 6.5. 
4.6 
Purpose and timing of interim analyses/design adaptations 
An interim analysis is planned after approximately 20 patients complete their Week 26 visit. 
 
 
 No other changes to the 
design of the study are anticipated as a result of the analysis. Additional information is presented 
in Section 12.7. 


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4.7 
Risks and benefits 
The benefit for patients participating in this study is unknown, as LCZ696 has never been 
studied in patients with nHCM. 
In patients treated with LCZ696, there is an increased risk of hyperkalemia, especially in cases 
of severe renal impairment, diabetes mellitus, hypoaldosteronism or high potassium diet. 
Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium 
supplements) should be used with caution. In case of hyperkalemia, adequate measures should 
be considered e.g. reduce dietary potassium, adjust the dose of concomitant medications as 
discussed in Section 16.4 (Appendix 4). 
In HFrEF patients treated with LCZ696, symptomatic hypotension, dizziness, and syncope have 
been reported and thus are risks in this trial. Correctable causes of hypotension 
(e.g. hypovolemia) should be treated and drugs known to affect blood pressure such as diuretics, 
calcium channel antagonists should be down-titrated or discontinued as described in 
Section 16.5 (Appendix 5). If required, immediate treatment for symptomatic hypotension may 
include volume replacement. 
LCZ696 is teratogenic in rabbits, and is associated with increased embryo-fetal toxicity, 
including embryo-fetal lethality in rats and rabbits. Both sacubitril and valsartan have been 
associated with fetal-toxicity and embryo-fetal lethality in rabbits. Pre- and post-natal 
development studies in rats with valsartan, but not sacubitril, indicate reductions in pup 
development and survival.  
Sacubitril/valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs 
that act on the renin-angiotensin system during the second and third trimesters of pregnancy 
reduces fetal renal function and increases fetal and neonatal morbidity and death. Most 
epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in 
the first trimester have not distinguished drugs affecting the renin-angiotensin system from 
other antihypertensive agents. Therefore, women of child bearing potential must be informed 
that taking the study treatment can cause harm to the fetus if pregnancy were to occur during 
the study and must agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
patient will not reliably comply, they should not be entered or continue in the study. 
The risk to patients in this trial may be minimized by compliance with the eligibility criteria 
and study procedures and close clinical monitoring, including monitoring for low blood 
pressure and changes in potassium or serum creatinine to down titrate dose or withdrawal 
patient from treatment. 
4.7.1 
Potential risks of cardiopulmonary exercise testing 
CPET is routinely performed in patients with cardiovascular disease. Overall, the incidence of 
adverse events (AEs) secondary to this test is very low when performed under appropriately 
supervised conditions. The major, but rare, complications include myocardial infarction, 
cardiac arrhythmia, syncope, and orthopedic injury. Adherence to the exercise test protocol with 
continuous ECG and hemodynamic monitoring will help to minimize the risk of such 
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4.7.3 
Blood sample volume 
Risks associated with blood collection include pain, swelling and/or bruising at the insertion 
site of the needle. Although rare, localized clot formation, infections and nerve damage may 
occur. Lightheadedness and/or fainting may also occur during or shortly after the blood draw. 
A volume smaller than a typical blood donation is planned to be collected over a period of 
approximately 12 months from each patient as part of the study. Additional samples may be 
required for safety monitoring. The timing of blood sample collections is outlined in the 
Assessment Schedule (Table 8-1). 
5 
Population 
Approximately 44 patients, male and females age 18 and over, with non-obstructive HCM will 
be enrolled into this study and treated with study drug for 50 weeks. 
The Investigator must ensure that all patients being considered for the study meet the following 
eligibility criteria. No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible patients. 
Patient selection is to be established by checking through all eligibility criteria during the 
screening/baseline period. 
Eligibility should be re-discussed with potential study patients, in case of changes to their 
health, at the time of their Day 1 visit prior to the administration of the first dose of study 
medication. A relevant record (e.g. checklist) of the eligibility criteria must be stored with the 
source documentation at the study site. 
Deviation from any entry criterion excludes a patient from enrollment into the study. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Male or female, ≥ 18 years of age at the time of consent 
2. Diagnosed with Hypertrophic Cardiomyopathy (hypertrophied and non-dilated left 
ventricle in the absence of any systemic cause) with a left ventricular wall 
thickness >13mm by the echocardiogram obtained during the screening/baseline period, 
based on local evaluation of echocardiographic images. 


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3. LVEF >50% by echocardiogram obtained during the screening/baseline period, based on 
local evaluation of echocardiographic images. 
4. At the screening/baseline visit symptoms consistent with New York Heart Association 
(NYHA) Class II-III heart failure by physician assessment, or asymptomatic/NYHA Class 
I patients with: 
• NT-proBNP above 250 pg/ml and 
• peak VO2 of ≤80% of predicted based on age and gender. 
Refer to Section 16.6 for further details on screening patients who are 
asymptomatic/NYHA Class I. 
5. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
6. Written informed consent must be obtained before any assessment is performed (including 
discontinuation of prior ACE-I/ARB as part of >36 hour washout period, where 
applicable) 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria during the screening/baseline period are not 
eligible for inclusion in this study. 
1. Patients with a resting or provokable (i.e., exercise or valsalva-induced) left ventricular 
outflow tract gradient of ≥30mm Hg, based on local evaluation of echocardiographic 
images obtained during the screening/baseline period. 
2. Septal reduction procedure within 3 months of the screening/baseline visit. 
3. History of atrial fibrillation within 6 months of the screening/baseline visit, or secondary 
prevention implantable cardioverter-defibrillator device (ICD; primary prevention ICDs 
without a history of appropriate therapy, including shock or anti-tachycardia pacing, are 
allowable), or patients who are pacemaker dependent. 
4. Patients with a peak VO2 on the screening/baseline cardiopulmonary exercise test 
of > 80% of predicted based on age and gender. 
5. Patients who require treatment with ACE inhibitors, angiotensin receptor blockers 
(ARBs), or renin inhibitors. Patients who can discontinue ACE inhibitors, angiotensin 
receptor blockers, or renin inhibitors can participate if they are off these medicines for at 
least 36 hours prior to the screening/baseline assessments and are expected to be able to 
remain off these medicines for the duration of the study treatment period.  
6. Treatment with sacubitril/valsartan within three months prior to screening. 
7. Known infiltrative or storage disorder causing cardiac hypertrophy that mimics 
hypertrophic cardiomyopathy, such as Fabry disease, or amyloidosis. 
8. Acute decompensated heart failure requiring augmented therapy with diuretics within 
30 days of the screening/baseline visit. 
9. Known or suspected symptomatic coronary artery disease or evidence of prior myocardial 
infarction based on symptoms or cardiac imaging history. 
10. More than moderate valvular heart disease or clinically significant congenital heart 
disease. Allowable conditions include systolic anterior motion of the mitral valve (SAM), 
bicuspid aortic valve without clinically significant stenosis or regurgitation; spontaneously 


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closed ventricular septal defects; patent foramen ovale, small (≤ 2 mm) restrictive 
ventricular septal defects with normal ventricular size, and other minor defects following 
consultation with the sponsor's medical lead. 
11. Systolic blood pressure of <100 mmHg or symptomatic hypotension during the 
screening/baseline period or treatment run-in period. 
12. Persistent uncontrolled hypertension, defined as a systolic blood pressure (SBP) 
≥150 mmHg, during the screening/baseline period, or a history of uncontrolled 
hypertension that could have led to cardiac hypertrophy. 
13. Presence of known, functionally significant, bilateral renal artery stenosis. 
14. Contraindication to ARB administration, including hyperkalemia (serum 
potassium >5.2 mmol/L during screening/baseline period) or prior history of angioedema. 
15. Concomitant medical conditions that would preclude performance of exercise testing 
(e.g., lung disease, orthopedic/rheumatologic conditions,). 
16. Impaired renal function, defined as an estimated glomerular filtration rate (eGFR), during 
the screening/baseline period and prior to entering treatment at day 1, < 
30 mL/min/1.73 m2, calculated using the simplified Modification of Diet in Renal Disease 
(sMDRD) equation. 
17. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or 
SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin >1.5 mg/dl 
during the screening/baseline period. 
18. History of malignancy of any organ system (other than localized basal or squamous cell 
carcinoma of the skin or localized prostate cancer), treated or untreated, within 5 years of 
the screening/baseline visit, regardless of whether there is evidence of local recurrence or 
metastases. 
19. History of immunodeficiency diseases, including a positive HIV (ELISA and Western 
blot) test result. 
20. History of hypersensitivity to any constituent of the study drugs or to drugs of similar 
chemical classes. 
21. Patients with prior major organ transplant or intent to transplant (i.e. on transplant list). 
22. Use of other investigational drugs during the screening/baseline period, or within 30 days 
or 5 half- lives of entering the screening/baseline period, whichever is longer. 
23. History of non-compliance to medical regimens and patients who are considered 
potentially unreliable. 
24. History of drug abuse or unhealthy alcohol use within the 12 months prior to dosing, 
where unhealthy alcohol use is defined as (1) Five or more drinks for men or 4 or more 
drinks for women on the same occasion on each of 5 or more days in the past 30 days or 
(2) an average of > 14 drinks per week for men or > 7 drinks per week for women. 
25. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, 
excludes a patient. Patients with a positive HCV antibody test should have HCV RNA 
levels measured. Patients with positive (detectable) HCV RNA should be excluded. 
26. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive serum 


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human chorionic gonadotropin (hCG) laboratory test at screening/baseline or a positive 
urine pregnancy test (to be confirmed by serum hCG testing) at the day 1 visit. 
27. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for ≥7 days after stopping study drug. Highly effective contraception 
methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up follicle stimulating hormone (FSH) level assessment. 
• Sterilization of the sole male partner of a female study participant (at least 6 months 
prior to completing the screening/baseline period).  
• Combination of any two of the following (a+b or a+c, or b+c), according to country 
approvals and availability:  
a. use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 
b. placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
• In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks ago. In the case of reported post-menopausal status or oophorectomy alone 
(e.g. without hysterectomy), only when the reproductive status of the woman has been 
confirmed by follow up FSH hormone level assessment is she considered not of child 
bearing potential. 
28. 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. 
6 
Treatment 
Patients will be instructed to take their study medication in accordance to the guidance outlined 
in the Site Operations Manual.  


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All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosing Log CRF. All kits of investigational treatment assigned by the IRT 
will be recorded/databased in the IRT. 
The patient should be instructed to contact the investigator if he/she is unable for any reason to 
take the study drug as prescribed. 
6.1 
Study treatment 
The study treatment is LCZ696 and placebo to LCZ696 in dosages of 50 mg, 100 mg, and 200 
mg administered as an oral tablet (p.o.), twice per day (b.i.d.). All study drug will be dispensed 
through IRT as double-blind labeled supply.  
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for patient numbering, prescribing/dispensing, and taking study treatment are 
outlined in the Site Operations Manual. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
LCZ696 50 mg 
or matching 
placebo 
Tablet 
Oral use 
Double Blind 
supply 
Sponsor (global) 
LCZ696 100 mg 
or matching 
placebo 
Tablet 
Oral use 
Double Blind 
supply 
Sponsor (global) 
LCZ696 200 mg 
or matching 
placebo 
Tablet 
Oral use 
Double Blind 
supply 
Sponsor (global) 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and placebo are included in this trial. 
6.1.3 
Treatment arms/group 
Treatment run-in period 
During the treatment run-in period, all patients will be assigned to receive placebo and 50 mg 
doses of LCZ696 in a single-blind manner, although the study medication will be packed and 
labeled according to double-blind requirements. 
Randomized treatment period 
During the double-blind, placebo-controlled randomized treatment period, patients will be 
assigned at the day 29 visit to one of the following 2 treatment arms in a ratio of 1:1: 


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• LCZ696  
• Placebo to LCZ696 
Patients will be randomized to one of the 2 treatment arms, but the dose in each treatment arm 
(50 mg, 100 mg or 200 mg) will depend on individual tolerability. See Section 3 and Section 6.5 
for further details regarding dose modification and tolerability. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
In general, the use of any concomitant medication/therapy deemed necessary for the care of the 
patient is permitted except when specifically prohibited (see Section 6.2.2). All medications, 
procedures, and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient was enrolled into the study must be recorded on the 
appropriate CRFs. 
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. If the patient is already 
enrolled, contact Novartis to determine if the patient should continue participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Medications known to raise potassium levels 
Potassium-sparing diuretics, potassium supplements, mineralocorticoid receptor antagonist 
(MRAs) and any other medications known to raise serum potassium levels should be used with 
caution while the patient is receiving the study drug due to the increased possibility of 
occurrence of hyperkalemia. The investigator is encouraged to assess patients’ serum potassium 
levels regularly, especially in those who are receiving these medications. 
Phosphodiesterase-5 (PDE-5) inhibitors 
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of the occurrence of hypotension. 
Neseritide and intravenous (i.v.) nitrates 
The concomitant administration of LCZ696 with neseritide and i.v. nitrates has not been 
studied. In the event a study patient requires the concomitant administration of neseritide and/or 
i.v. nitrates with the study medications, the investigator should consider starting them at a lower 
dose or a slower infusion rate while monitoring the patient’s blood pressure (BP) carefully. 
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 
In elderly patients, volume depleted patients (including those on diuretic therapy), or patients 
with compromised renal function, concomitant use of LCZ696 and NSAIDs may lead to an 
increased risk of worsening of renal function. Therefore, monitoring of renal function is 


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recommended when initiating or modifying treatment in patients on LCZ696 who are taking 
NSAIDs concomitantly. 
Lithium 
Increases in serum lithium concentrations and lithium toxicity have been reported during 
concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum 
lithium levels during concomitant use with LCZ696. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table are NOT allowed after the start of study drug 
due to safety reasons, unless the actions specified are taken. 
Table 6-2 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Any ACE Inhibitor 
Treatment period 
Discontinue study treatment. The ACEI must 
be stopped for ≥36 hours prior to re-initiation of 
study drug. 
Any Angiotensin Receptor 
Blocker (ARB) 
Treatment period 
Discontinue study treatment. The ARB must be 
stopped prior to re-initiation of study drug. 
Any renin inhibitor 
Treatment period 
Discontinue study treatment. The 
renin inhibitor must be stopped prior to re-
initiation of study drug 
ACEIs, ARBs and renin inhibitors 
The concomitant use of ACEIs, ARBs or a renin inhibitor is strictly prohibited while the patient 
is receiving study drug. If the addition of an ACEI, ARB or renin inhibitor is necessary, then 
study drug must be temporarily discontinued. If the patient is to be started on an ACEI, the 
study drug must be stopped ≥36 hours prior to initiating ACEI. If study drug is to start, the 
ACEI must be stopped ≥36 hours prior to re-initiating study drug. ARBs or a renin inhibitor 
should be stopped prior to resuming study drug. 
6.2.3 
Rescue medication 
Guidance on handling renal dysfunction, hyperkalemia and hypotension are provided to 
investigators in Section 16.3 (Appendix 3), Section 16.4 (Appendix 4) and Section 16.5 
(Appendix 5), respectively. Patients may receive ACEIs, ARBs or a renin inhibitor during the 
study ONLY if the study drug has been temporarily or permanently discontinued (Table 6-2). 
Use of rescue medication must be recorded on the Concomitant medications/Significant 
nondrug therapies CRF. 
6.2.4 
Restriction for study subjects 
6.2.4.1 
Dietary restrictions and smoking 
There are no specific dietary or smoking restrictions for the duration of this study. 


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6.2.4.2 
Other restrictions 
There are no specific restrictions for the duration of this study. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
The "subject number" assigned to a patient at screening/baseline remains the unique identifier 
for the patient throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the Site Operations Manual. 
6.3.2 
Treatment assignment, randomization 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of "subject 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 Novartis Global Clinical Supply (GCS) using a 
validated system that automates the random assignment of medication numbers to packs 
containing the study treatment. 
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office. 
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of patients. 
6.4 
Treatment blinding 
Prior to randomization, this study will include a single-blinded treatment run-in period, where 
the investigator will be aware that all patients who sign informed consent and pass the 
screening/baseline period will be treated with placebo p.o. b.i.d. for 2 weeks, followed by 
treatment with 50 mg p.o. b.i.d. of active LCZ696. Investigative staff will be aware of the order 
of study drug administration during the treatment run-in period. Investigative staff will not 
inform patients of the order of the treatments in the run-in period to minimize risk of patient 
bias. After randomization the study will be conducted as a patient and investigator-blinded 
study. Patients and investigators will remain blinded to study treatment throughout the rest of 
the study, except where indicated below. The identity of the treatments will be concealed by the 
use of study drugs that are all identical in packaging, labeling, appearance, and schedule of 
administration. 
Site staff 
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the double-blind, placebo-controlled portion of the study. Unblinding a single 


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patient at site for safety reasons (necessary for patient management) will occur via the IRT 
system. 
Sponsor staff 
 
 
 
 
The study statistician, programmers, and other personnel involved in data analyses 
 will be able to access treatment assignment information at any time 
throughout the study. For interim analyses, they will be allowed to share unblinded information 
(unblinded individual data and/or unblinded summaries) with the rest of the clinical trial team 
for internal decision making purposes. The clinical trial team is allowed to share unblinded 
results with other sponsor staff (e.g., decision boards) as required for internal decision making 
on the study or the project at the time of interim analyses while the study is ongoing. 
Following final database lock all roles may be considered unblinded. 
Refer to Table 6-3 for detailed blinding rules for this patient and investigator-blinded study. 
Table 6-3 
Blinding levels 
Role 
Time or Event 
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single subject 
unblinded) 
Interim 
Analysis & 
dose escalation 
Subjects/Patients 
B 
B 
B 
B 
Site staff 
B 
B 
UI 
B 
Drug Supply and 
Randomization Office 
UI 
UI 
UI 
UI 
Statistician/statistical 
programmer/data analysts 
UI 
UI 
UI 
UI 
All other sponsor staff not 
identified above 
B 
B 
UI 
UI 
B Remains blinded 
UI Allowed to be unblinded on individual patient level 
6.5 
Dose escalation and dose modification 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose level 
adjustments and interruptions of study treatment are permitted in order to keep the patient on 
study drug. The following guidelines should be followed: 
Every attempt should be made to maintain patients at the target study drug dose level (200 mg 
b.i.d.) throughout the trial. If the patient does not tolerate the target study drug dose level, the 
investigator can adjust or stop concomitant background medications for co-morbid conditions 
to rectify the situation, before considering to down titrate to the next lower study drug dose 
level. For hypotension or dizziness, consideration should be given to reduce the dose or to stop 


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concomitant antihypertensive agents and non-antihypertensive agents that lower BP, or the dose 
of diuretic can be reduced. 
Adjustment of study drug dose level 
If, despite adjustment of concomitant medications per the guidance provided, the situation is 
not rectified the investigator may consider down titrating the study drug dose level according 
to the following instructions: 
During the treatment period, down titration of the study drug at any time based on the judgment 
of the investigator will be allowed according to the safety and tolerability criteria defined in 
Section 16.3 (Appendix 3), Section 16.4 (Appendix 4) and Section 16.5 (Appendix 5). If down 
titration is necessary, the patient should be down titrated to the next lower study drug dose level 
(Table 6-1). The patient may continue receiving the lower dose level for a recommended period 
of 1 to 2 weeks before being re-challenged at the next higher dose level. For example, a patient 
who encounters tolerability problems at the target study drug dose level (200 mg b.i.d.), should 
receive the study drug at 100 mg b.i.d. for 1 to 2 weeks at the discretion of the investigator. 
Then, he/she should be re-challenged with up-titration back to 200 mg b.i.d. of study drug. 
If the tolerability issues are not alleviated despite down titration by one dose level, the 
investigator may down titrate further to the next lower study drug dose level for 1 to 2 weeks, 
up to temporary discontinuation of the study drug. Again, once stable, the patient should be re-
challenged with up titration to the next higher dose level every 1 to 2 weeks in an attempt to 
bring back the patient gradually to the target study drug dose level (200 mg b.i.d.). The 
investigator may choose the next dose level for down- or up-titration according to his or her 
judgment (Table 6-1). 
The IRT system should be contacted to register any changes in the patient’s study drug dose 
level, including in cases of temporary and permanent discontinuation of the study drug, and to 
obtain the medication numbers of the study drug supplies required for the new study drug dose 
level. 
In some instances, according to the safety and tolerability criteria and the investigator’s 
judgment, dose level 1 (50 mg b.i.d.) or 2 (100 mg b.i.d.) could be maintained if he/she considers 
that the patient’s condition would not allow any further up titration to the target dose level of 
study drug (200 mg b.i.d.). In this case, it would be acceptable to maintain the patient at dose 
level 1 or level 2, whichever is the higher and tolerated dose level by the patient. 
Study drug restart after temporary treatment interruption 
Study drug should be reintroduced in those patients who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator. Once the investigator considers the 
patient’s condition appropriate for receiving the study drug, the investigator should re-start the 
patient on the study drug at the most appropriate and allowable dose level (Table 6-1) per his/her 
medical judgment. If tolerated, the patient should be up-titrated a dose level every 2 weeks to 
the target dose (200 mg b.i.d.), as per the investigator’s judgment. Should the patient not tolerate 
the re-start study drug dose level, he/she may be down titrated again (if appropriate) or 
temporarily discontinue the study medication again and a new attempt to up titrate or 


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reintroduce the study drug could be considered by the investigator as soon as medically justified 
in his/her judgment. 
The use of an ACEI, ARB or a renin inhibitor is prohibited while the patient is taking study 
drug. However, if for any reason a patient off study drug has started treatment with an ACEI it 
must be discontinued ≥36 hours prior to restarting study drug. For patients off study drug treated 
with an ARB or a renin inhibitor it must be discontinued prior to re-initiation of study drug 
(Table 6-2). 
These changes must be recorded on the Dosing Log CRF. 
More dosing guidance can be found in the Site Operations Manual. 
In case of pregnancy, the patient will be discontinued from study treatment immediately, and 
encouraged to return for safety follow-up/EoS visit assessments approximately 30 days after 
the last dose of study medication. See Section 10.1.4 for further details on pregnancies and 
reporting guidelines. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed. Compliance will be assessed by 
the investigator and/or study personnel at each visit using pill counts (if applicable) and 
information provided by the patient. This information should be captured in the source 
document at each visit. 
The investigator and/or study personnel should counsel the patient if compliance is below 80% 
at any time during the study. Study drug accountability will be determined by the site monitor 
while performing routine site visits and at the completion of the study. 
All study treatment dispensed and returned must be recorded in the Drug Accountability Log. 
6.6.2 
Recommended treatment of adverse events 
Treatment guidelines for renal dysfunction, hyperkalemia, and management of blood pressure 
are provided in Section 16.3 (Appendix 3), Section 16.4 (Appendix 4) and Section 16.5 
(Appendix 5), respectively. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 


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6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide the 
requested patient identifying information and confirm the necessity to break the treatment code 
for the patient. The investigator will then receive details of the investigational drug treatment 
for the specified patient and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• name 
• subject number 
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Patients for whom an emergency unblinding occurs will be discontinued from further study 
treatment. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section. 
LCZ696 or placebo will be self-administered by the patient on an outpatient basis twice daily 
via oral route of administration. 
See the Site Operations Manual for further details. 
7 
Informed consent procedures 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. 


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Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's 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 investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification (IN) 
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the patient. 
Women of child bearing potential must be informed that taking the study treatment involves 
risks to the fetus if pregnancy were to occur during the study, and agree that in order to 
participate in the study, they must adhere to the contraception requirements. 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
Refer to the Site Operations Manual for a complete list of informed consent forms (ICFs) 
included in this study. 


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8 
Visit schedule and assessments 
The Assessment schedule (Table 8-1) lists all of the assessments in this study and when they are performed. All data obtained from these 
assessments must be supported in the patient’s source documentation. 
Patients should be seen for all visits/assessments as outlined in the assessment schedule (Table 8-1) or as close to the designated day/time as 
possible. Missed or rescheduled visits should not lead to automatic discontinuation. Visit windows are outlined in the Site Operations Manual. 
Patients who prematurely discontinue the study for any reason, including during the treatment run-in period, should be scheduled for an EOS 
visit approximately 30 days after their last dose of study drug, at which time all of the assessments listed for the final EOS visit, as well as 
safety labs if labs were not collected at the time of discontinuation, will be performed. At the EOS visit, all dispensed investigational product 
should be reconciled, and any adverse event(s) and concomitant medication(s) recorded in the CRF. 
Table 8-1 
Assessment Schedule 
Period 
Screening 
Treatment run-in1 
Randomized Treatment 
Safety F/U 
Visit Name 
Screening/Baseline 
Week 0 
Week 2 
Week 
4 
Week 
6 
Week 
8 
Week 
14 - 
Phone 
Call 
Week 
26 
Week 
38 - 
Phone 
Call 
Week 
50 
UNSCH2 
EOS Visit3 
Days 
-35 to -1 
1 
15 
29 
43 
57 
99 
183 
267 
351 
 
381 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
Physical Examination 
S 
S 
S4 
S4 
S4 
S4 
  
S 
  
S 
S4 
S 
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
X 
X 
  
  
  
X 
  
X 
  
X 
X 
X 


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Period 
Screening 
Treatment run-in1 
Randomized Treatment 
Safety F/U 
Visit Name 
Screening/Baseline 
Week 0 
Week 2 
Week 
4 
Week 
6 
Week 
8 
Week 
14 - 
Phone 
Call 
Week 
26 
Week 
38 - 
Phone 
Call 
Week 
50 
UNSCH2 
EOS Visit3 
Days 
-35 to -1 
1 
15 
29 
43 
57 
99 
183 
267 
351 
 
381 
Vital Signs 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
X 
Electrocardiogram 
(ECG) 
X 
X 
  
  
  
X 
  
X 
  
X 
X 
  
Hepatitis and HIV 
screen 
S 
  
  
  
  
  
  
  
  
  
  
  
Follicle stimulating 
hormone (FSH)5 
X 
  
  
  
  
  
  
  
  
  
  
  
Serum Pregnancy 
Test6 
X 
  
  
  
  
  
  
  
  
  
  
X 
Urine Pregnancy Test6 
  
S 
  
S 
  
S 
Monthly home testing 
S 
  
Hematology 
X 
X 
  
  
  
X 
  
X 
  
X 
X 
  
Clinical Chemistry 
X 
X 
  
  
  
X 
  
X 
  
X 
X 
  
Local Potassium and 
Serum Creatinine 
  
X 
X 
X 
X 
X 
  
  
  
  
X 
  
Cardiopulmonary 
Exercise Test (CPET) 
X9 
  
  
  
  
  
  
X 
  
X 
  
  
Randomization 
  
  
  
X 
  
  
  
  
  
  
  
  


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Period 
Screening 
Treatment run-in1 
Randomized Treatment 
Safety F/U 
Visit Name 
Screening/Baseline 
Week 0 
Week 2 
Week 
4 
Week 
6 
Week 
8 
Week 
14 - 
Phone 
Call 
Week 
26 
Week 
38 - 
Phone 
Call 
Week 
50 
UNSCH2 
EOS Visit3 
Days 
-35 to -1 
1 
15 
29 
43 
57 
99 
183 
267 
351 
 
381 
Drug dispensation 
  
X 
X 
X 
X 
X 
  
X 
  
  
X 
  
Adverse Events 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications and 
Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
information 
  
  
  
  
  
  
  
  
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 All assessments should be completed prior to dispensing study medication to establish pre-dose baseline. 
2 These Unscheduled Visit assessments are optional procedures that may be performed at investigator's discretion. 
3 Patients who prematurely discontinue from the study, but do not withdraw consent will be asked to return to the clinic approximately 30 days after their last dose of 
study drug for an end of study visit. All scheduled EOS assessments should be collected at this visit. In addition, if no safety labs were collected at the date of study drug 
discontinuation, safety labs should also be collected at the EOS visit. 
4 Abbreviated physical exam; Details of physical exams are provided in the Site Operations Manual. 
5 Only from women who have had oophorectomy without hysterectomy, and from women who are reported to be post-menopausal. 
6 All female patients will have serum pregnancy test at screening/baseline. Women whose FSH results demonstrate that they are not capable of becoming pregnant will 
not have further pregnancy assessments. Women who are still considered to be of child-bearing potential will have a urine pregnancy test on a monthly basis throughout 
the study as per the assessment table and an EOS serum test. The results of the urine test must be available prior to dispensing any/additional study medication.  
 
  
 
 
 
 
 
 


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8.1 
Screening 
It is permissible to re-screen a patient if s/he fails the initial screening/baseline, based on visit 
windows or eligibility criteria; however, each case must be discussed and agreed with the 
sponsor on a case-by-case basis. 
In the case where a safety laboratory assessment at screening/baseline is more than 10% outside 
of the range specified in the exclusion criteria, the assessment may be repeated once prior to 
randomization. If the repeat value remains outside of the specified ranges, the patient must be 
excluded from the study. 
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual. 
8.1.1 
Eligibility screening 
All patients will be screened for HIV and Hepatitis B and C. See Site Operations Manual for 
details. 
8.1.2 
Information to be collected on screening failures 
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual. 
8.2 
Subject demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the CRF. Patient demographic and baseline 
characteristic data to be collected on all patients which will include (at least): year of birth, age, 
sex, race, ethnicity, a detailed medical history (including cardiac and other conditions relevant 
to the study population to be enrolled) and current medical conditions present before the signing 
of informed consent. 
Investigators will have the discretion to record abnormal test findings on the appropriate CRF 
whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. Details are outlined in the Site Operations Manual. 
8.3 
Efficacy 
Pharmacodynamic measurements will be assessed at the timepoints defined in the Assessment 
Schedule (Table 8-1). Detailed instructions on these assessments are outlined in the Site 
Operations Manual. 
Pharmacodynamic (PD) assessments will be conducted in all patients at all dose levels, 
including the placebo group. 
8.3.1 
Cardiopulmonary Exercise Test (CPET) 
Cardiopulmonary exercise testing (CPET) is a non-invasive method used to assess the 
performance of the heart and lungs at rest and during exercise. The primary efficacy endpoint 
in this study is peak VO2, as determined by CPET. 


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CPET assessments will take place at visits specified in the Assessment Schedule (Table 8-1). 
Please refer to the Site Operations Manual for more details on the procedure. 
8.3.2 
Echocardiography 
 
 
  
The screening/baseline echocardiographic assessment will include evaluation of any resting left 
ventricular outflow tract (LVOT) gradient as well as any exercise-induced LVOT gradient. 
Qualified investigator staff will review the screening/baseline echocardiography results as they 
relate to study eligibility. Additionally, echocardiographic images will be evaluated by a central 
reader for all randomized patients as detailed in the Imaging Charter. 
 
 
 
Refer to the Site Operations Manual and Imaging Charter for more details on the methods for 
assessment and recording.  
8.3.3 
Appropriateness of efficacy assessments 
Cardiopulmonary exercise testing is a well-established assessment technique that combines 
standard exercise testing and measurement of ventilator gas exchanges for an objective 
determination of functional capacity and impairment in patients with hypertrophic 
cardiomyopathy. 
Echocardiography is a commonly used technique to measure cardiac structure and functional 
parameters. 
8.4 
Safety and Tolerability 
Safety and tolerability assessments are specified below with the Assessment Schedule 
(Table 8-1) detailing when each assessment is to be performed. The methods, assessment, 
specification, and data recording for each assessment will be detailed in the Site Operations 
Manual. 
Novartis may request additional information on specific AEs or laboratory events of interest 
and may make requests to perform additional diagnostic tests to further assess the safety profile 
of the study drugs. Such information may include diagnostic procedure reports, discharge 
summaries, autopsy reports, and other relevant information that may help in assessing the 
reported AE. For details on AE collection and reporting, refer to AE section. 
8.4.1 
Physical Examination 
Qualified site staff will conduct complete or abbreviated physical examinations at times 
indicated in the Assessment Schedule (Table 8-1). Details of system classes examined during 
the complete and the abbreviated physical examinations are provided in the Site Operations 
Manual. 


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Information about all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to informed consent are included 
in the appropriate page of the CRF. Significant findings observed after informed consent 
signature which meet the definition of an AE must be appropriately recorded on the Adverse 
Event CRF. 
8.4.2 
Vital signs 
Vital signs will be collected at visits outlined in the Assessment Schedule (Table 8-1) and will 
include measurements of oral body temperature, blood pressure and pulse rate. Refer to the Site 
Operations Manual for details. 
8.4.3 
Height and weight 
Height and weight will be collected at visits outlined in the Assessment Schedule (Table 8-1). 
Body Mass Index (BMI) will be calculated. Refer to the Site Operations Manual for details. 
8.4.4 
Laboratory evaluations 
A central laboratory will be used for analysis or specimen management of most specimens 
collected. Details on the collection, shipment of samples, and reporting of results by the central 
laboratory are provided to investigators in the laboratory manual. The list of safety related 
laboratory tests that will be analyzed in this study are specified in the Site Operations Manual. 
At visits specified in the Assessment Schedule (Table 8-1), sites will collect a sample for local 
analysis of serum potassium and serum creatinine levels. There are countries where plasma 
potassium and creatinine are used instead of serum potassium for routine clinical care. Plasma 
samples can be used instead of serum samples in this study. Serum potassium thresholds in the 
study protocol, including those values cited in Appendix 4, can be converted to plasma 
potassium thresholds for the study by subtracting 0.4 mmol/L from the serum potassium 
threshold (Hartland and Neary 1999). No conversion is required for plasma creatinine.   
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions, or as AEs as appropriate. 
All abnormal lab results must be evaluated for criteria defining an AE and reported as such if 
the criteria are met. For those lab adverse events, repeated evaluations are mandatory until 
normalization of the result(s) or until the result is no longer considered to be clinically 
significant. 
8.4.5 
Electrocardiogram (ECG) 
Electrocardiogram (ECG) assessments will be conducted at visits specified in the Assessment 
Schedule (Table 8-1). Full details of all procedures relating to the ECG collection and reporting 
are contained in the Site Operations Manual. 
Sites will record in the CRF the following parameters: PR interval, QRS duration, heart rate, 
RR interval, QT interval, and Fridericia QT correction (QTcF). As applicable, QTcF may be 
calculated in-house unless auto-calculated by the ECG machine. 
Clinically significant abnormalities must be reported as adverse events. 


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8.4.6 
Pregnancy and assessments of fertility 
All women will have serum pregnancy testing at screening/baseline. Those women who are 
noted to have history of oophorectomy without hysterectomy, and those who are reported to be 
post-menopausal - based on reported 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile - will have hormone levels (FSH) assessed at screening/baseline. 
After the screening/baseline period, all women of child bearing potential will continue to have 
urine and serum pregnancy testing throughout the study as per the Assessment Schedule 
(Table 8-1). Additional pregnancy testing may be performed as per local requirements. The 
results of the local urine pregnancy testing must be available prior to dispensing any/additional 
study medication. A positive pregnancy test requires immediate interruption of study drug until 
serum β-hCG is performed and found to be negative.  
Medical documentation of oophorectomy, hysterectomy or tubal ligation must be retained as 
source documents and documented as medical history in the CRF. 
8.4.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 


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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, he/she believes that 
continuation would negatively impact the patient's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Patient/guardian decision 
• An episode of sustained ventricular tachycardia 
• New onset of persistent atrial fibrillation 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the patient 
• Following emergency unblinding 
• Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator 


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• Any adverse events or laboratory abnormalities that in the judgment of the investigator, 
taking into consideration the patient’s overall status, prevents the patient from continuing 
participation in the study  
• If a liver, renal, hyperkalemic, or hypotensive event occurs, follow guidelines outlined in 
Section 16.2 , Section 16.3, Section 16.4 or Section 16.5 regarding discontinuation of 
study treatment. 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the patient’s premature discontinuation of study treatment 
and record this information. 
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the EOS assessments indicated in the Assessment Schedule (Table 8-1) 
approximately 30 days after their last dose of study medication. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the patient/pre-designated contact as specified in the lost to follow-up section. 
This contact should preferably be done according to the study visit schedule. 
If any patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, if a patient cannot or is unwilling to come to the clinic 
for the EOS visit, at a minimum, the following data should be collected via telephone/email 
contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent 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. 


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Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a patient’s samples until the time of withdrawal) according to applicable law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and "Rest of World": All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements. 
9.1.3 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the patient's scheduled EOS visit would have occurred. 
9.1.4 
Study stopping rules 
Enrollment in the study will be placed on hold if any of the following occurs: 
• After any patient experiences sudden cardiac death 
• The Sponsor considers that the number and/or severity of AEs, abnormal safety 
monitoring tests or abnormal laboratory findings justify putting the study on hold. 
• The Sponsor unilaterally requests it. 
The study may resume following the safety review, if the Lead Investigator(s) and Sponsor 
agree it is safe to proceed. 
9.1.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should early termination be 
necessary, patients must be seen as soon as possible, study medication should be 
discontinued, and patients 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 investigator or sponsor 
depending on the local regulation will be responsible for informing IRBs/IECs of the early 
termination of the trial. 


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9.2 
Study completion and post-study treatment 
Study completion is defined as when the last patient finishes their EOS/Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign, including abnormal laboratory findings, symptom or disease) in a patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual patient and 
identifying AEs. 
Novartis' qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade  
1. mild: usually transient in nature and generally not interfering with normal activities 
2. moderate: sufficiently discomforting to interfere with normal activities 
3. severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient. 
3. Its duration (start and end dates). If the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2for definition of SAE) and which 
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5. Action taken regarding with study treatment. All AEs must be treated appropriately. 
Treatment may include one or more of the following:  
1. Dose not changed 
2. Dose Reduced/increased 
3. Drug interrupted/discontinued 
6. Its outcome (not recovered/not resolved; recovered/resolved; 
recovering/resolving, recovered/resolved with sequelae; fatal; or unknown) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Novartis may request additional information on specific AEs of interest and may make requests 
to perform additional diagnostic tests to further assess the safety profile of the study drugs. 
Such information may include diagnostic procedure reports, discharge summaries, autopsy 
reports, and other relevant information that may help in assessing the reported AE. 
All additional information will be de-identified prior to collection by Novartis or its agents. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease. Clinically notable lab ranges are included in Section 16.1 (Appendix 1). 
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for screening failures. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
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• fatal 
• life-threatening 
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 the ICH-E2D Guidelines). 
• 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 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 


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regarding the submission process and requirements are to be found in the investigator folder 
provided to each site. 
The following timelines should be noted for SAE reporting period: 
1. Screen failures (e.g. a patient who is screened but does not enter the treatment run-in 
period/never receives study treatment): SAEs occurring after the patient has provided 
informed consent until the time the patient is deemed a Screen Failure must be reported to 
Novartis. 
2. Treatment run-in failures (e.g. a patient who is screened and treated in the treatment run-in 
period but not randomized): SAEs collected between time patient signs ICF until 30 days 
after the patient has discontinued or stopped study treatment. 
3. Randomized patients (e.g. a patient who completes the treatment run-in period and is 
randomized into the double-blind, placebo-controlled portion of the study): SAEs 
collected between time patient signs ICF until 30 days after the patient has discontinued or 
stopped 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 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS 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. 
Any SAEs experienced after the 30 day reporting period should only be reported to 
Novartis Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications at the time of birth. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 


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form and should include an assessment of the possible relationship to the study treatment for 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
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 recorded on 
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 within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 
Please refer to Table 16-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 


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Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e. ALT, AST, TBL, 
PT/INR, ALP and G-GT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the patient. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded in source documents. 
• If the initial elevation is confirmed, close observation of the patient will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the patient if appropriate 
• Causality assessment of the liver event 
• Other investigations can include, based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
Refer to Appendix 2 (Section 16.2) and the SOM for additional details. 
10.2.2 
Renal safety monitoring 
The serum creatinine will be used to monitor for renal injury. A serum creatinine increase 
≥ 25% compared to baseline during normal hydration status is considered a renal event and 
should be followed up by the investigator or designated personnel at the trial site as summarized 
in Section 16.3 (Appendix 3). Abnormal renal event findings must be confirmed ≥ 24 hours but 
≤ 5 days after first assessment. 
Refer to Section 16.3 (Appendix 3) and the Site Operations Manual for additional details. 
11 
Data Collection and Database management 
11.1 
Data collection 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
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check for data discrepancies in the eCRFs and allow modification and/or verification of the 
entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site. 
11.2 
Database management and quality control 
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 are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Select laboratory samples will be processed centrally and the results will be sent electronically 
to Novartis (or a designated CRO). 
For echocardiograms, a dedicated imaging CRO will collect all randomized patient echo data 
from sites and provide analysis by a central reader. The analysis results will be sent 
electronically to Novartis (or a designated CRO). 
Randomization codes and data about all study treatment (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) at specific timelines. 
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. 
Once all the necessary 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 to be accessed by independent programmer and statistician. 
Any changes to the database after that time can only be made after written agreement by 
Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative or designated CRO 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 


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quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of patient records, the accuracy of data capture / data entry, the adherence to the protocol and 
to 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 or designated CRO staff. 
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 will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
For all analysis sets, patients will be analyzed according to the study treatment(s) received. 
The safety analysis set will include all patients that received any study drug. The randomized 
analysis set (RAS) will consist of all randomized patients. The per-protocol set (PPS) will be a 
subset of the RAS that will consist of all randomized patients who have no major protocol 
deviations with relevant impact on PD/efficacy data and whom are at least 80% compliant with 
study drug administration. PD/efficacy variables will be analyzed based on the PPS. 
12.2 
Subject demographics and other baseline characteristics 
Baseline will be defined as the last non-missing assessment prior to the first dose of study drug, 
unless specified otherwise. 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the RAS. Categorical data will be presented 
as frequencies and percentages. For continuous data, mean, standard deviation, median, 
minimum, and maximum will be presented. Relevant medical histories and current medical 


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conditions at baseline will be summarized by system organ class and preferred term, by 
treatment group. 
12.3 
Treatments 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system by treatment for the RAS. 
12.4 
Analysis of the primary endpoint(s) 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint will be the change from baseline in peak VO2 (ml/kg/min) at week 50, 
where baseline peak VO2 will come from the screening/baseline CPET.  
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will assess the effect of LCZ696 on the change from baseline in peak VO2 
at week 50 compared to placebo. A longitudinal mixed effects model for the change from 
baseline will be used. The model will include treatment, time (as a categorical variable), and 
the treatment-by-time interaction as fixed effects, patient as a random effect, and baseline peak 
VO2 as a covariate. The least-squares (LS) mean and associated 90% confidence interval (CI) 
for the change from baseline in peak VO2 for each treatment, and the estimated mean treatment 
difference, the p-value, and the corresponding 2-sided 80% CI will be extracted from the model 
at each time point. 
12.4.3 
Handling of missing values/censoring/discontinuations 
There will be no imputation of missing data. The primary model implicitly imputes missing 
measurements under a missing at random assumption. 
12.4.4 
Sensitivity and Supportive analyses 
Three supportive analyses will be performed to further assess the effect of LCZ696 on changes 
in peak VO2: 
(1)  An analysis of the change from baseline in % of predicted peak VO2. The same model as 
described for the primary endpoint will be used. 
(2)  An analysis of the ratio to baseline in peak VO2. A similar model as described for the 
primary analysis will be used, but with ratio to baseline as the response, and all peak VO2 
measurements will be log transformed prior to analysis. 
(3) The primary analysis performed on the RAS. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Safety endpoints 
All safety analyses will be presented separately for the run-in period and the double-blind period 
using the safety set. All listings and tables will be presented by treatment.  


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Adverse events 
All information obtained on AEs will be displayed by treatment and patient. The number (and 
percentage) of patients with treatment emergent AEs (events started after the first dose of study 
medication or events present prior to start of double-blind treatment but increased in severity 
based on preferred term) will be summarized in the following ways: 
• by treatment, primary system organ class, and preferred term. 
• by treatment, primary system organ class, preferred term, and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ), and preferred term. 
A patient with multiple adverse events within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment, patient, and visit/time and if ranges are available, 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time. 
12-lead ECG 
All ECG data will be listed by treatment, patient, and visit/time, and abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. Shift tables using the low/normal/high classification will be used to compare baseline 
to the worst on-treatment value. 
 
 


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12.7 
Interim analyses 
An interim analysis for safety and efficacy will be performed when approximately 20 patients 
have completed the Week 26 CPET assessment. The same analysis described for the primary 
analysis will be performed using all the available CPET data at the time of the interim database 
freeze. Unblinded results will be reviewed by the clinical team. The clinical team may 
communicate the results (e.g., evaluation of PoC criteria or information needed for 
planning/modifying another study) to relevant Novartis teams for information, consulting, 
and/or decision purposes. Additional interim analyses may be conducted to support decision 
making concerning the current clinical study, the sponsor’s clinical development projects in 
general, or in case of any safety concerns.  
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Approximately forty-four (44) patients will be enrolled in the study with the anticipation that at 
least 40 patients complete the study. With 40 completers, there will be 80% power to achieve 


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an efficacy criteria of at least 50% confidence that LCZ696 increases peak VO2 by at least 
3 ml/kg/min over placebo, provided that the true effect of LCZ696 is at least a 4.15 ml/kg/min 
increase over placebo and the standard deviation of the change from baseline is 4.25 ml/kg/min 
(Olivotto et al 2018). If LCZ696 is not different from placebo, there will be a 1.5% chance of 
achieving the efficacy criteria (i.e., the false positive rate will be 1.5%). For the interim analysis, 
with week 26 data from at least 20 patients, there will be 70% power to meet the efficacy criteria 
under the same assumptions, and a 6% false positive rate if there is no increase over placebo. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient recruitment procedures (e.g. 
advertisements) and any other written information to be provided to patients. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Abozguia K, Elliott P, McKenna W, et al (2010) Metabolic modulator perhexiline corrects 
energy deficiency and improves exercise capacity in symptomatic hypertrophic 
cardiomyopathy. Circulation p. 1562-9. 
Cao L, Gardner DG (1995) Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. 
Hypertension p. 227-34. 
Coats CJ, Rantell K, Bartnik A, et al (2015) Cardiopulmonary Exercise Testing and Prognosis 
in Hypertrophic Cardiomyopathy. Circ Heart Fail p. 1022-31. 
Espiner EA, Richards AM, Yandle TG, et al (1995) Natriuretic hormones. Endocrinol. Metab. 
Clin. North Am. p. 481-509. 
Hartland AJ, Neary RH (1999) Serum potassium is unreliable as an estimate of in vivo plasma 
potassium. Clin Chem; 45:1091-1092. 
Horio T, Nishikimi T, Yoshihara F, et al (2000) Inhibitory regulation of hypertrophy by 
endogenous atrial natriuretic peptide in cultured cardiac myocytes. Hypertension p. 19-24. 
Lin KF, Chao J, Chao L (1998) Atrial natriuretic peptide gene delivery attenuates 
hypertension, cardiac hypertrophy, and renal injury in salt-sensitive rats. Hum. Gene Ther. p. 
1429-38. 
Marian AJ, Braunwald E (2017) Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, 
Clinical Manifestations, Diagnosis, and Therapy. Circ. Res. p. 749-770. 
Maron BJ, Gardin JM, Flack JM, et al (1995) Prevalence of hypertrophic cardiomyopathy in a 
general population of young adults. Echocardiographic analysis of 4111 subjects in the 
CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation p. 785-9. 
Maron MS, Chan RH, Kapur NK, et al (2018) Effect of Spironolactone on Myocardial 
Fibrosis and Other Clinical Variables in Patients with Hypertrophic Cardiomyopathy. Am. J. 
Med. p. 837-841. 
Oliver PM, Fox JE, Kim R, et al (1997) Hypertension, cardiac hypertrophy, and sudden death 
in mice lacking natriuretic peptide receptor A. Proc. Natl. Acad. Sci. U.S.A. p. 14730-5. 
Olivotto I, Camici PG, Merlini PA, et al (2018) Efficacy of Ranolazine in Patients With 
Symptomatic Hypertrophic Cardiomyopathy: The RESTYLE-HCM Randomized, Double-
Blind, Placebo-Controlled Study. Circ Heart Fail p. e004124. 
Richard P, Charron P, Carrier L, et al (2003) Hypertrophic cardiomyopathy: distribution of 
disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. 
Circulation p. 2227-32. 
Schmieder RE, Wagner F, Mayr M, et al (2017) The effect of sacubitril/valsartan compared to 
olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results 
of a randomized, double-blind, active-controlled study. Eur. Heart J. p. 3308-3317. 


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Solomon SD, Zile M, Pieske B, et al (2012) The angiotensin receptor neprilysin inhibitor 
LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised 
controlled trial. Lancet p. 1387-95. 
Thaman R, Esteban MT, Barnes S, et al (2006) Usefulness of N-terminal pro-B-type 
natriuretic peptide levels to predict exercise capacity in hypertrophic cardiomyopathy.  Am. J. 
Cardiol. p. 515-19. 
 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values 
Clinically notable laboratory abnormalities for selected tests based on a percent change from 
baseline: 
Hematology 
• Hematocrit >50% increase, >20% decrease 
• Hemoglobin >50% increase, >20% decrease 
• Platelet count >75% increase, >50% decrease 
• RBC Count  >50% increase, >20% decrease 
• WBC count  >50% increase, >50% decrease 
Blood Chemistry 
• Alkaline phosphatase >100% increase 
• ALT (SGPT) >150% increase 
• AST (SGOT)  >150% increase 
• BUN >50% increase 
• Calcium  >10% increase, >10% decrease 
• Chloride  >10% increase, >10% decrease 
• Creatinine >50% increase 
• Potassium >20% increase, >20% decrease 
• Total bilirubin  >100% increase 
• Uric acid  >50% increase 


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16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-1 
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 


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Table 16-2 
Follow up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 1.5 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
continue follow-up 
monitoring 
• 
If elevation persists for 
more than 2 weeks, 
discontinue the study drug 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 


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Criteria 
Actions required 
Follow-up monitoring 
Jaundice 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
*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 
 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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16.3 
Appendix 3: 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 study drug. 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 start of study treatment, eGFR decreases by ≥25% from the 
screening/baseline visit (or if serum creatinine concentration increase to 2.5 mg/dL [221 
μmol/L]), the investigator will repeat the laboratory evaluation. If the eGFR on repeat 
evaluation is still decreased by ≥25%, 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 creatinine 
• Volume decrease, including that resulting from excessive dosing of diuretics 
• Urinary infection 
• Urinary tract obstruction 
• Study drug 
Action situation 
If a patient’s eGFR decreases by ≥40% from the screening/baseline visit (or if serum creatinine 
concentration rises above 3 mg/dL (265μmol/L), the investigator will check for potentially 
reversible causes of renal dysfunction (see above). 
The investigator may consider down-titration of study drug. If the investigator judges that study 
drug 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 drug was stopped, every effort will be done to 
restart it again, according to clinical conditions. 


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16.4 
Appendix 4: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.3 mmol/L [mEq/L] 
General principles 
Elevation of serum (or equivalent plasma) potassium levels above the predefined values should 
be repeated and confirmed before any action is taken. 
Any patient with a serum potassium > 5.3 mmol/L (mEq/L) at any time after initiation of study 
treatment requires the Investigator to confirm the potassium concentration in a non-hemolyzed 
sample via an immediate repeat lab sample to both the clinic local lab and the study central lab. 
Regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) 
should continue 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 [mEq/L]) or potential danger (≥ 6.0 mmol/L 
[mEq/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 5.3 and less than or equal to 5.5 mmol/L (mEq/L) 
• Confirm potassium concentration in a non-hemolyzed sample. 
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, tomatoes, dried fruits, potatoes, low-salt substitutes, 
coffee, etc.). 
• Correct metabolic acidosis if necessary. 
• Review medical regimen (including dietary supplements and over-the-counter 
medications) for agents known to cause hyperkalemia. Consider reduction in dose or 
discontinuation of these agents:  
• MRAs (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 substitute 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors 
• Trimethoprim and trimethoprim-containing combination products, such as Bactrim® 
and Septra® (trimethoprim/sulfamethoxazole fixed combination) 
• Herbal Supplements:  
• For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum 
officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily 
of the valley, Siberian ginseng, hawthorn berries. 


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• Assess patient for dehydration or any condition that could lead to dehydration (e.g., 
diarrhea, vomiting) and/or hypovolemia and initiate appropriate corrective measures of 
rehydration. 
• Repeat serum potassium measurement within 3 to 5 days 
• If serum potassium remains > 5.3 and ≤ 5.5 mmol/L (mEq/L), regularly monitor serum 
potassium levels to ensure stability (suggested once monthly) 
• Consider down-titration of study drug, according to investigator’s medical judgment. 
Serum potassium greater than 5.5 and less than 6.0 mmol/L (mEq/L) 
• Confirm potassium concentration in a non-hemolyzed sample. 
• Consider down-titration or temporarily discontinue study drug according to investigator 
medical judgment. 
• Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L 
• Repeat serum potassium measurement after 2-3 days 
• If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with 
repeat potassium within 5 days. 
Serum potassium greater than or equal to 6.0 mmol/L (mEq/L) 
• Immediately discontinue study drug 
• Confirm potassium concentration in a non-hemolyzed sample 
• Urgently evaluate patient and treat hyperkalemia as clinically indicated 
• Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L (mEq/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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16.5 
Appendix 5: Guidelines for the management of blood pressure 
Guidelines 
1. Investigator should monitor BP closely 
2. If symptomatic hypotension occurs:  
a. Correct any treatable cause, e.g. hypovolemia. 
b. If hypotension persists, any antihypertensive drug such as diuretics, calcium channel 
blockers (CCBs), nitrates, beta blockers, aldosterone antagonists and α-blockers, 
should be down-titrated or stopped first before down-titration of the study drug is 
considered. Any non-antihypertensive drug (such as nitrates) should be considered for 
down-titration prior to study drug as determined by the best judgment of the 
investigator. 
c. If hypotension persists, the study drug should be down-titrated or even temporarily 
discontinued. The dose re-challenge and medications adjust guidelines described 
in Section 6.5 should be adhered to as much as possible. 


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Protocol No. CLCZ696I12201 
 
16.6 
Appendix 6: Screening flow chart for asymptomatic patients 
Figure 16-1 
Screening flow chart for asymptomatic patients 
 

SAP_001.pdf: 
Biostatistics & Statistical Programming /  
Novartis Institutes for BioMedical Research 
LCZ696 
CLCZ696I12201 / NCT04164732
A multi-center, randomized, placebo-controlled patient and 
investigator-blinded study to explore the efficacy of oral 
sacubitril/valsartan in adult patients with non-obstructive 
hypertrophic cardiomyopathy (nHCM) 
Statistical Analysis Plan (SAP) 
Author(s): 
, Trial Statistician 
Document type: 
SAP Documentation – NIBR  
Document status: 
Amendment 1 Final 
Release date: 
10-Oct-2023
Number of pages: 
30 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
10-Jun-2020 
Prior to DB 
lock 
Creation of initial 
version 
N/A - First version 
NA 
29-Sep-2023 
Prior to DB 
lock 
Updated to reflect the 
impact of the protocol 
amendment v02 (PA02) 
on the statistical 
aspects of the study 
and to 
add/clarify/update other 
points. 
Information about the 
latest study reference 
documentation was 
updated. 
Sections 1.2 & 9 
 
 
 
 
 
 
 
 
 
 
 
 
 
The wording for the 
completed Interim 
Analysis 1 was updated 
to past tense for clarity. 
Section 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol deviation with 
code=’TRT02’ was 
added in table 4-1 and 
leads to exclusion from 
all analysis sets 
Section 4 
 
 
 
In addition to boxplots, 
arithmetic mean and 
spaghetti plots were 
added for vital signs. An 
additional spaghetti plot 
was also added for 
biochemistry lab 
parameters. 
Section 7.3 


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Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
It was clarified that 
deaths will be listed, if 
any death occurs. 
Section 7.2 
 
 
 
Spaghetti plots for the 
primary efficacy 
endpoint were removed. 
Section 6.1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
It was clarified that 
baseline will be 
presented in any change 
from baseline and ratio 
to baseline plots. 
Section 6.1.4.2, 
6.1.5.2, 7 & 8 
 
 
 
Bar charts used for 
model-based graphs 
were replaced by line 
plots.  
Section 6.1.4.2 & 
6.1.5.2. 
 
 
 
The analysis of the time 
weighted average daily 
dose was added. 
Section 7.2 
 
 
 
‘Subject’ was replaced 
with ‘Patient’ in line with 
the general document 
wording. 
Section 7.2 
 
 
 
An additional sensitivity 
model analysis was 
added for the primary 
endpoint. 
Section 6.1.5 
 
 
 
 
 
 
 
 
 
 
 
NYHA class was added 
in the background and 
demographic summary 
table. 
Section 7.2 


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Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
It was clarified that any 
compliance 
values>100% will be set 
to and used as 100% in 
the corresponding 
summary statistics. 
Section 7.2 
 
 
 
 
 
  
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Scope of document .................................................................................................. 7 
1.2 
Study reference documentation ............................................................................... 7 
1.3 
Study objectives ....................................................................................................... 7 
1.3.1 
Primary objective(s) ................................................................................ 7 
1.3.2 
Secondary objective(s) ............................................................................ 7 
 
 7 
1.4 
Study design and treatment ...................................................................................... 8 
2 
First interpretable results (FIR) ......................................................................................... 10 
3 
Interim analyses ................................................................................................................. 10 
4 
Statistical methods: Analysis sets ...................................................................................... 11 
5 
Statistical methods for Pharmacokinetic (PK) parameters ................................................ 13 
6 
Statistical methods for Pharmacodynamic (PD)/Efficacy parameters .............................. 14 
6.1 
Primary efficacy objective ..................................................................................... 14 
6.1.1 
Variable ................................................................................................. 14 
6.1.2 
Descriptive analyses .............................................................................. 14 
6.1.3 
Graphical presentation .......................................................................... 14 
6.1.4 
Statistical model, assumptions and hypotheses ..................................... 14 
6.1.5 
Sensitivity and supportive analyses ...................................................... 15 
6.2 
Secondary efficacy objectives ............................................................................... 16 
 
 16 
 
 16 
 
 22 
 
 23 
 
 23 
7 
Statistical methods for safety and tolerability data ............................................................ 24 
7.1 
Variables ................................................................................................................ 24 
7.2 
Descriptive analyses .............................................................................................. 24 
7.3 
Graphical presentation ........................................................................................... 27 
 
 27 
 
 29 
10 Reference list ..................................................................................................................... 30 
 


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List of tables 
Table 1-1 
Safety monitoring criteria that must be met for initial treatment and 
throughout all treatment periods ............................................................. 9 
Table 4-1 
Protocol deviation codes and analysis sets............................................ 11 
Table 6-1 
NYHA functional class ......................................................................... 18 
 
 27 
                    
 30 
List of figures 
Figure 1-1 
 
Study Design………………………………………………….………10 


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1 
Introduction  
1.1 
Scope of document 
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLCZ696I12201”. 
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol. 
Tables, Figures, Listings (TFL) detail the presentation of the data, including shells of summary 
tables, figures and listings, and Programming Datasets Specification (PDS) contains 
programming specifications e.g. for derived variables and derived datasets, to support the 
creation of CSR outputs. 
1.2 
Study reference documentation 
Final study protocol, version v02, 08 Apr 2022 and final SOM, version v06, 26 Jan 2022 are 
available at the time of finalization of Statistical Analysis Plan. 
1.3 
Study objectives 
1.3.1 
Primary objective(s) 
Primary objective(s) 
Endpoints related to primary objectives 
• To evaluate the effect of LCZ696 on 
cardiopulmonary exercise test (CPET) 
parameters 
in 
patients 
with 
non-
obstructive HCM. 
• Peak VO2 after 50 weeks of treatment. 
 
1.3.2 
Secondary objective(s) 
Secondary objective(s) 
Endpoints related to secondary objectives 
• To evaluate the safety and tolerability of 
LCZ696 in patients with non-obstructive 
HCM. 
• Adverse events (AEs), vital signs, 
ECGs, physical examinations and safety 
labs. 


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1.4 
Study design and treatment 
This multi-center study of non-obstructive HCM patients includes a single-blind (i.e., patient-
blinded) treatment run-in period aimed to ensure as large a proportion as possible of patients 
(1) have stable symptoms and can comply with study visits during the placebo run-in period, 
and (2) can tolerate at least low dose LCZ696. The treatment run-in period is followed by a 
randomized, placebo-controlled, parallel-group, patient and investigator-blinded treatment 
period. It is estimated that 44 patients will be randomized into the double-blind placebo-
controlled part of the study in order to have approximately 40 patients complete the week 50 
CPET assessment. 
The study will be comprised of a ≤ 35 day screening/baseline period, a 4-week single-blind 
treatment run-in period, followed by a 46-week double-blind placebo-controlled treatment 
period (total treatment period of 50 weeks), and a follow-up period of approximately 30 days 
after the last dose. The maximum study duration, from initial screening to end of study (EOS) 
for each patient is approximately 58 weeks. More details are provided in the Site Operations 
Manual. 
Screening/baseline period 
Patients who sign informed consent and pass the initial screening/baseline evaluations will then 
have CPET and echocardiogram testing conducted. The 35 day screening/baseline period is 
designed to allow for scheduling and availability of results in order to establish patient's study 
eligibility and baseline status. All screening/baseline safety evaluation results must be available 
prior to dosing. Patients who enter screening/baseline but are determined not to be eligible to 
enter the treatment run-in period will be considered  screen failures. See protocol Section 8.1 
for permitted re-screening criteria.  
Treatment run-in period 
Patients who qualify for study eligibility will then enter a single-blind treatment run-in period, 
during which all patients will receive oral (p.o.) placebo b.i.d. for 2 weeks followed by 50 mg 
p.o. b.i.d. of active LCZ696 for 2 weeks. Patients who are unable to tolerate either placebo or 


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the 50 mg p.o. b.i.d. dose level (i.e. do not meet safety criteria as specified in Table 1-1), will 
be considered treatment run-in failures and will not be randomized into the double-blind, 
placebo-controlled study, nor included in the efficacy analysis. At the end of the 4-week 
treatment run-in period, patients who meet the safety criteria (Table 1-1) will be eligible for 
randomization.  
Randomized treatment period 
At randomization (week 4 visit), eligible patients will be randomized into the study to receive 
oral (p.o.) doses of LCZ696 or placebo in a 1:1 ratio in a double-blind, placebo-controlled 
treatment period. All randomized patients will be titrated up to the 100 mg p.o. b.i.d. dose. 
All patients will return to the study center approximately 14 days later for assessment of 
tolerability of the 100 mg p.o. b.i.d. dose (i.e. must meet safety criteria as specified in Table 1-
1). Patients whose assessments demonstrate that they tolerate the 100 mg p.o. b.i.d. dose will 
be up-titrated to 200 mg p.o. b.i.d. dose, whereas those who do not meet the safety criteria 
(Table 1-1) will be titrated back down to the 50 mg b.i.d. dose. Tolerance to the current dose 
(50 mg b.i.d. or 200 mg b.i.d.) will again be assessed ~14 days later, and those patients who 
demonstrate tolerance will remain on this dose throughout the remaining treatment period, 
unless a change in tolerance is noted as defined by the criteria in protocol Section 16.3 - Section 
16.5. Those patients who do not tolerate the 200 mg p.o. b.i.d. dose will be titrated down to 100 
mg p.o. b.i.d. as outlined in protocol Section 6.5. 
Tolerability can be assessed at scheduled visits or at any time during an unscheduled visit 
throughout the study as deemed appropriate by the investigator. Investigators are encouraged 
to request patients who report intolerance to study medication shortly after dose titration, to 
return to the clinic as soon as possible for re-assessment and dose modification via an 
unscheduled visit. Those patients who do not tolerate higher doses will be adjusted down to the 
previous dose as outlined in protocol Section 6.5. Patients who no longer tolerate the 50 mg p.o. 
b.i.d. dose will be discontinued from study treatment. 
Table 1-1 
Safety monitoring criteria that must be met for initial treatment and 
throughout all treatment periods 
Parameter 
Screening/baseline Period 
Safety Monitoring during 
treatment run-in and randomized 
treatment periods 
Potassium 
≤ 5.2 mmol/L (mEg/L) 
≤ 5.4 mmol/L (mEg/L) 
eGFR 
≥ 30 mL/min/1.73m2 
≥ 25 mL/min/1.73m2 
Blood Pressure 
SBP ≥ 100 mmHg 
No symptomatic hypotension as 
determined by the investigator and 
SBP ≥ 100 mmHg 
AEs / Med History 
No conditions that preclude 
continuation according to the 
eligibility criteria 
No AEs that preclude continuation 
according to the investigator’s 
judgment 
Note that for abnormalities in potassium and eGFR, laboratory values should be repeated to confirm 
abnormality as outlined in protocol Section 16.3 and Section 16.4. For out-of-range blood pressure 
readings, measurement may be repeated up to two times as detailed in the Site Operations Manual and 
protocol Section 16.5. 


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Patients will receive study treatment for ~50 weeks, which includes the 4-week treatment run-
in period, with dose tolerability being assessed at each visit as well as at unscheduled visits (as 
necessary) and through feedback that patients may provide between visits. Safety and 
tolerability assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology and blood chemistry), AE and SAE monitoring. At week 
26 and week 50, patients will have follow-up CPET 
. No further 
treatment will be provided after the week 50 visit, and patients will return to the study center 
~30 days later for final safety and EOS evaluations. 
Figure 1-1  
Study design  
 
2 
First interpretable results (FIR) 
First interpretable results (FIR) will be provided for this trial at the IA and at the end of study 
(CSR). 
The study FIR template (mock slides) can be found in SubWay in the study Statistics folder. 
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list. 
3 
Interim analyses  
An interim analysis for safety and efficacy was performed when approximately 20 patients had 
completed the Week 26
. 
 
 
 
 
Unblinded results were reviewed by the clinical team. The clinical team may 
communicate the results (e.g., evaluation of PoC criteria or information needed for 


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planning/modifying another study) to relevant Novartis teams for information, consulting, 
and/or decision purposes. If early efficacy is demonstrated, enrollment of the study may be 
stopped. No other changes to the design of the study are anticipated as a result of the analysis. 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general, or in case of any 
safety concerns. 
4 
Statistical methods: Analysis sets 
For all analysis sets, patients will be analyzed according to the study treatment(s) received. 
Throughout this document, ‘treatment’ refers to one of the two randomized treatment arms 
assigned to each patient at the Day 29/Week 4 visit, i.e., LCZ696 or Placebo. For the safety 
analyses that will be presented separately for the treatment run-in period, ‘treatment’ refers to 
the corresponding treatments given during the treatment run-in period, i.e. placebo b.i.d. for 2 
weeks followed by 50 mg p.o. b.i.d. of active LCZ696 for 2 weeks. 
Unless specified otherwise, baseline will be defined as the last non-missing assessment prior to 
the first dose of study drug administered at the Day 1 visit. 
The safety analysis set will include all patients that received any study drug. 
The randomized analysis set (RAS) will consist of all randomized patients. 
The per-protocol analysis set (PPS) will be a subset of the RAS that will consist of all 
randomized patients who have no major protocol deviations with relevant impact on 
PD/efficacy data and who are at least 80% compliant with the overall study drug administration. 
The definition for the overall compliance to the study drug administration is provided in Section 
7.2. 
The analysis sets and protocol deviation codes are related as follows: 
Table 4-1 
Protocol deviation codes and analysis sets 
Category    
   Deviation code 
Text description of deviation 
Data exclusion 
Patients are excluded from safety analysis in case of these PDs:  
Exclude patient from 
safety analysis set  
 
 
Patients are excluded from RAS analysis in case of these PDs:  
Exclude patient from 
randomized analysis set  
 
 
Patients are excluded from PD/efficacy analysis in case of these PDs: 
Exclude patient from 
per-protocol analysis set 


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Category    
   Deviation code 
Text description of deviation 
Data exclusion 
INCL02 
Diagnosed 
with 
Hypertrophic 
Cardiomyopathy 
(hypertrophied and non-dilated left ventricle in the 
absence of any systemic cause) with a left ventricular 
wall thickness >13mm by the echocardiogram 
obtained during the screening/baseline period, based 
on local evaluation of echocardiographic images. 
 
INCL03 
LVEF >50% by echocardiogram obtained during the 
screening/baseline period, based on local evaluation 
of echocardiographic images. 
 
INCL04 
At the screening/baseline visit symptoms consistent 
with New York Heart Association (NYHA) Class II-III 
heart 
failure 
by 
physician 
assessment, 
or 
asymptomatic/NYHA Class I patients with: 
• NT-proBNP above 250 pg/ml and 
• peak VO2 of ≤80% of predicted based on age and 
gender. 
Refer to Protocol Section 16.6 for further details on 
screening patients who are asymptomatic/NYHA 
Class I. 
 
INCL06 
Written informed consent must be obtained before any 
assessment is performed. 
 
EXCL01 
Patients with a resting or provokable (i.e., exercise or 
valsalva-induced) left ventricular outflow tract gradient 
of ≥30mm Hg, based on local evaluation of 
echocardiographic 
images 
obtained 
during 
the 
screening/baseline period. 
 
EXCL02 
Septal reduction procedure within 3 months of the 
screening/baseline visit. 
 
EXCL03 
History of atrial fibrillation within 6 months of the 
screening/baseline visit, or secondary prevention 
implantable cardioverter-defibrillator device (ICD; 
primary prevention ICDs without a history of 
appropriate 
therapy, 
including 
shock 
or 
anti-
tachycardia pacing, are allowable), or patients who are 
pacemaker dependent. 
 
EXCL04 
Patients with a peak VO2 on the screening/baseline 
cardiopulmonary exercise test of > 80% of predicted 
based on age and gender. 
 
EXCL06 
Treatment with sacubitril/valsartan within three months 
prior to screening. 
 
EXCL07 
Known infiltrative or storage disorder causing cardiac 
hypertrophy that mimics hypertrophic cardiomyopathy, 
such as Fabry disease, or amyloidosis. 
 
EXCL08 
Acute 
decompensated 
heart 
failure 
requiring 
augmented therapy with diuretics within 30 days of the 
screening/baseline visit. 
 


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Category    
   Deviation code 
Text description of deviation 
Data exclusion 
EXCL09 
Known or suspected symptomatic coronary artery 
disease or evidence of prior myocardial infarction 
based on symptoms or cardiac imaging history. 
 
EXCL10 
More than moderate valvular heart disease or clinically 
significant 
congenital 
heart 
disease. 
Allowable 
conditions include systolic anterior motion of the mitral 
valve (SAM), bicuspid aortic valve without clinically 
significant stenosis or regurgitation; spontaneously 
closed ventricular septal defects; patent foramen 
ovale, small (≤ 2 mm) restrictive ventricular septal 
defects with normal ventricular size, and other minor 
defects following consultation with the sponsor's 
medical lead. 
 
EXCL11 
Systolic blood pressure of <100 mmHg or symptomatic 
hypotension during the screening/baseline period or 
treatment run-in period. 
 
EXCL12 
Persistent uncontrolled hypertension, defined as a 
systolic blood pressure (SBP) ≥150 mmHg, during the 
screening/baseline period, or a history of uncontrolled 
hypertension 
that 
could 
have 
led 
to 
cardiac 
hypertrophy. 
 
EXCL14 
Contraindication to ARB administration, including 
hyperkalemia (serum potassium >5.2 mmol/L during 
screening/baseline 
period) 
or 
prior 
history 
of 
angioedema. 
 
EXCL15 
Concomitant medical conditions that would preclude 
performance of exercise testing (e.g., lung disease, 
orthopedic/rheumatologic conditions). 
 
TRT02* 
Mis-randomized patient given study drug. 
 
 
 
 
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL. 
*NOTE: TRT02 PD was raised for patients that were randomized and given study drug even 
though they should have been screen failures. 
5 
Statistical methods for Pharmacokinetic (PK) parameters 
No PK endpoints will be analyzed in this study. 
 


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6 
Statistical methods for Pharmacodynamic (PD)/Efficacy 
parameters 
Unless specified otherwise, all patients within the per-protocol analysis set will be included in 
the PD/efficacy data analysis. 
Note: If a patient experiences an episode of atrial fibrillation immediately before or during the 
CPET, as indicated on the CPET CRF page, the readings from that particular CPET will be 
excluded from all CPET summaries/analyses, but the patient will remain in all analysis sets.      
6.1 
Primary efficacy objective 
To evaluate the effect of LCZ696 on cardiopulmonary exercise test (CPET) parameters in 
patients with non-obstructive HCM. 
6.1.1 
Variable  
The primary efficacy variable/endpoint is the change from baseline in peak VO2 (ml/kg/min) at 
Week 50. 
6.1.2 
Descriptive analyses 
The raw peak VO2 measurements, the change from baseline in peak VO2 measurements and the 
ratio to baseline in peak VO2 measurements will be listed by treatment, patient and visit/time. 
Descriptive statistics will be provided for the raw peak VO2 measurements, the change from 
baseline in peak VO2 measurements and the ratio to baseline in peak VO2 measurements by 
treatment and visit/time and will include sample size, mean (arithmetic), SD, median, minimum 
and maximum. 
6.1.3 
Graphical presentation 
N/A. 
6.1.4 
Statistical model, assumptions and hypotheses 
The effect of LCZ696 on the change from baseline in peak VO2 over time (with Week 50 being 
of primary interest) will be analyzed using a longitudinal mixed effects model with change from 
baseline in peak VO2 as the dependent variable. The model will include treatment, time (as a 
categorical variable relative to start of study treatment, i.e., Week 26 and Week 50), and the 
treatment-by-time interaction as fixed effects, patient as a random effect, and baseline peak VO2 
and the baseline-by-time interaction as covariates. Kenward-Roger method will be used for 
approximating the denominator degrees of freedom. The least-squares (LS) mean and 
associated 2-sided 90% confidence interval (CI) of the change from baseline in peak VO2 for 
each treatment, and the estimated mean treatment difference, the p-value, and the corresponding 
2-sided 80% CI will be extracted from the model at each time point. 
6.1.4.1 
Handling of missing data 
There will be no imputation of missing data. The primary model implicitly imputes missing 
measurements under a missing at random assumption. 


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6.1.4.2 
Graphical presentation of results 
The least-squares (LS) arithmetic mean treatment estimates (+/- 90% CI) will be plotted over 
time and by treatment using line plots (all treatments in the same graph). Baseline will also be 
presented as 0 in this model-based plot for better visualization of the changes from baseline 
over time. 
6.1.5 
Sensitivity and supportive analyses 
The following two supportive analyses will be performed to further assess the effect of LCZ696 
on changes in peak VO2: 
(1)  
An analysis of the ratio to baseline in peak VO2. A similar model to that described in 
Section 6.1.4 for the primary analysis will be used, but with ratio to baseline as the response, 
and all peak VO2 measurements will be log transformed prior to analysis. In particular, ratio to 
baseline in peak VO2 over time (with Week 50 being of primary interest) will be analyzed using 
a longitudinal mixed effects model with log-transformed ratio to baseline in peak VO2 as the 
dependent variable. The model will include treatment, time (as a categorical variable relative to 
start of study treatment, i.e., Week 26 and Week 50), and the treatment-by-time interaction as 
fixed effects, patient as a random effect, and the log-transformed baseline peak VO2 and the 
log-transformed baseline-by-time interaction as covariates. Kenward-Roger method will be 
used for approximating the denominator degrees of freedom. The LS mean and associated 2-
sided 90% CI of the ratio to baseline in peak VO2 for each treatment, on the log scale, will be 
extracted from the model at each time point, along with the estimated mean treatment 
difference, the p-value, and the corresponding 2-sided 80% CI. The means and CIs will be back 
transformed and reported as geometric mean ratios or ratios of geometric mean ratios on the 
original scale. 
(2) 
The same model as described in Section 6.1.4 for the primary endpoint will be used, but 
it will be performed on the RAS. 
(3)       The same model as described in Section 6.1.4 for the primary endpoint will be used, but 
only patients who have RER > 0.95 at baseline, Week 26 and Week 50 time points will be  
analysed. 
6.1.5.1 
Handling of missing data 
It is described in Section 6.1.4.1. 
6.1.5.2 
Graphical presentation of results 
For the change from baseline model, i.e., supportive model (2), the model-based graphs are 
described in Section 6.1.4.2. 
For the log-transformed ratio to baseline model, i.e., supportive model (1), the least-squares 
(LS) geometric mean treatment estimates (+/- 90% CI) will be plotted over time and by 
treatment using line plots (all treatments in the same graph). Baseline will also be presented as 
1 in this model-based plot for better visualization of the ratios to baseline over time. 


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6.2 
Secondary efficacy objectives 
There are no secondary efficacy objectives for this study. 
The secondary objectives of this study are related to the safety and tolerability of LCZ696 and 
are described in Section 7. 
 
 


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7 
Statistical methods for safety and tolerability data 
Unless specified otherwise, all safety analyses will be presented separately for the treatment 
run-in period and the double-blind placebo-controlled randomized treatment period, using the 
safety analysis set. 
7.1 
Variables 
Adverse events, body height, body weight, BMI, vital signs (blood pressure, pulse rate and oral 
body temperature), ECG intervals (PR interval, QRS duration, heart rate, RR interval, QT 
interval and QTcF), laboratory measurements, as well as patient demographics, baseline 
characteristics, and treatment information. 
7.2 
Descriptive analyses 
Patient demographics and other baseline characteristics 
All data for background and demographic variables including disease characteristics (age, 
gender, race, ethnicity, height, weight, BMI, systolic blood pressure, diastolic blood pressure, 
NT-proBNP, peak VO2, % of predicted peak VO2 and NYHA class) will be listed by treatment 
and patient. Summary statistics will be provided by treatment for the RAS. Categorical data 
will be presented as frequencies and percentages. For continuous data, sample size, mean 
(arithmetic), SD, median, minimum and maximum will be presented. The same summary table 
will be created to compare the treatment run-in failure patients vs. the randomized patients for 
the safety analysis set. 
Relevant medical history, current medical conditions, results of laboratory screens and any 
other relevant information will be listed by treatment and patient. Relevant medical histories 
and current medical conditions at baseline will be summarized by system organ class (SOC) 
and preferred term (PT), by treatment for the RAS. A patient with multiple relevant medical 
histories/current medical conditions within a system organ class (SOC) is only counted once 
towards the total of this system organ class (SOC). 
Treatment 
Data for study drug administration (rescue medication) as well as concomitant medications and 
significant non-drug therapies prior to and after the start of the study treatment will be listed by 
treatment and patient. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by Anatomical Therapeutic Chemical (ATC) class and 
treatment for the RAS. A patient with multiple concomitant medications/significant non-drug 
therapies within an Anatomical Therapeutic Chemical (ATC) class is only counted once 
towards the total of this Anatomical Therapeutic Chemical (ATC) class. 
Overall compliance to the study drug administration 
Overall compliance to the study drug administration* will be listed by treatment and patient and 
summarized by treatment for the RAS. 
Note: Any compliance values >100% will be set to and used as 100% in summary statistics. 


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*For each patient, the overall compliance to study drug (%) will be calculated using the 
following formula: 
 
100 ∗[
∑
(𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 𝑎𝑡 𝑉𝑖−1 −𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑 𝑎𝑡 𝑉𝑖)
𝑛
𝑖=1
∑
( (𝑆𝑡𝑢𝑑𝑦 𝑑𝑎𝑦 𝑎𝑡 𝑉𝑖−𝑆𝑡𝑢𝑑𝑦 𝑑𝑎𝑦 𝑎𝑡 𝑉𝑖−1)
𝑛
𝑖=1
∗2 𝑝𝑖𝑙𝑙𝑠 𝑝𝑒𝑟 𝑑𝑎𝑦 )
] 
 
𝑤ℎ𝑒𝑟𝑒, 
 
𝑉0 = 𝑓𝑖𝑟𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛, 
𝑉1 = 𝑠𝑒𝑐𝑜𝑛𝑑 𝑣𝑖𝑠𝑖𝑡 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛,  
  . 
  . 
  . 
𝑉𝑛−1 = 𝑠𝑒𝑐𝑜𝑛𝑑−𝑡𝑜−𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛, 𝑎𝑛𝑑 
 𝑉𝑛= 𝑙𝑎𝑠𝑡 𝑣𝑖𝑠𝑖𝑡 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛. 
Time weighted average daily dose 
Time weighted average daily dose* will be listed by treatment and patient for the RAS and 
summarized by treatment for both the RAS and the PPS separately. Only patients randomized 
to the LCZ696 treatment will be included in this analysis. 
*For each patient, the time weighted average daily dose will be calculated over the 
randomization period using the following formula: 
[
∑
(𝑑𝑎𝑦𝑠 𝑜𝑓 𝑑𝑜𝑠𝑖𝑛𝑔𝑖
𝑎
𝑛
𝑖=1
∗𝑐𝑜𝑟𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒𝑖(𝑖𝑛 𝑚𝑔) ∗2)
𝑑𝑎𝑦𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛 𝑝𝑒𝑟𝑖𝑜𝑑𝑏
] 
𝑤ℎ𝑒𝑟𝑒, 
 
 
 
𝑎= 𝐿𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑎𝑦 𝑜𝑓 𝑑𝑜𝑠𝑒𝑖− 𝑓𝑖𝑟𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑎𝑦 𝑜𝑓 𝑑𝑜𝑠𝑒𝑖+ 1 
Note: During the transition from the previous dose to the next dose, we consider that the next dose starts one day 
after the end study day of the previous dose, i.e., if the previous dose ended on study day x, then the next dose is 
considered to start on study day x+1 even if the next dose started on study day x as per the data. 
 
𝑏= 𝐿𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑑𝑎𝑦 𝑜𝑓 𝑡ℎ𝑒 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛 𝑝𝑒𝑟𝑖𝑜𝑑− 𝑓𝑖𝑟𝑠𝑡 𝑑𝑎𝑦 𝑜𝑓 𝑡ℎ𝑒 𝑟𝑎𝑛𝑑𝑜𝑚𝑖𝑧𝑎𝑡𝑖𝑜𝑛 𝑝𝑒𝑟𝑖𝑜𝑑+ 1  
Vital signs 
All vital signs data will be listed by treatment, patient, and visit/time and if ranges are available, 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time and will include sample size, mean (arithmetic), SD, 
median, minimum and maximum. 


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ECG evaluations 
All ECG data will be listed by treatment, patient, and visit/time, and abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time and will include 
sample size, mean (arithmetic), SD, median, minimum and maximum. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing will be provided presenting all 
parameters in a patient with any abnormal values. Summary statistics will be provided by 
treatment and visit/time and will include sample size, mean (arithmetic), SD, median, minimum 
and maximum. Shift tables using the low/normal/high classification will be used to compare 
baseline to the worst on-treatment value. 
Adverse events 
All information obtained on adverse events will be listed by treatment and patient. If any death 
occurs, then all deaths will be listed by treatment and patient 
The treatment emergent AEs are defined as follows for this study: 
• For the treatment run-in period: Treatment emergent AEs will be the events that 
started at or after the first dose of study medication and before the start of the double-
blind treatment period or events present prior to first dose of study medication but 
increased in severity during the treatment run-in period based on preferred term. 
• For the randomized treatment period: Treatment emergent AEs will be the events that 
started at or after the start of the double-blind treatment period or events present prior 
to the start of double-blind treatment period but increased in severity based on preferred 
term. 
The number and percentage of patients with treatment emergent AEs will be summarized in the 
following ways: 
• by treatment, primary system organ class (SOC), and preferred term (PT). 
• by treatment, primary system organ class (SOC), preferred term (PT), and maximum 
severity. 
• by treatment, Standardized MedDRA Query (SMQ), and preferred term (PT). 
Separate summaries will be provided for study related adverse events, serious adverse events 
and adverse events leading to drug discontinuation. 
A patient with multiple adverse events within a primary system organ class (SOC) is only 
counted once towards the total of the primary system organ class (SOC). 
ClinicalTrials.gov and EudraCT 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than 5% and on <on-treatment/treatment emergent> serious adverse events 


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and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE. 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.  
7.3 
Graphical presentation  
A boxplot of the raw vital signs data (sitting pulse rate, sitting systolic blood pressure and sitting 
diastolic blood pressure) and an arithmetic mean (SE) plot of changes from baseline in vital 
signs data (sitting pulse rate, sitting systolic blood pressure and sitting diastolic blood pressure) 
to visualize trends in longitudinal safety data will be created by treatment and over time. 
Baseline will also be presented as 0 in the arithmetic mean (SE) plot for better visualization of 
the changes from baseline over time. 
In addition, spaghetti plots of vital signs of interest (i.e., sitting systolic blood pressure and 
sitting diastolic blood pressure) and biochemistry lab parameters of interest (i.e., creatinine, 
eGFR, potassium and urea nitrogen) will be created by treatment. Note: Only the patients with 
at least one unscheduled assessment related to AE will be included in the spaghetti plots and all 
the measurements (scheduled, repeated & unscheduled) of these patients will be presented. 
 
 


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Reference list 
1. Clinical Trial Protocol, CLCZ696I12201, Protocol Version 02, dated 08 Apr 2022. 
2. Site Operations Manual for Protocol No. CLCZ696I12201, Version 06, dated 26 Jan 2022.