Clinical trial NCT02884206
Conditions: Chronic Heart Failure (CHF)
Keywords: heart failure cognition positron emission tomography magnetic resonance imaging LCZ696 valsartan Chronic heart failure CHF
Sponsor: Novartis Pharmaceuticals
Start date: 2016-11-23; Completion date: 2022-05-16
Enrollment: 592 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was a multi-center, randomized, double-blind, parallel group, active comparator trial designed to evaluate the overall effect of LCZ696 compared to valsartan on cognitive function as assessed by the CogState comprehensive cognitive battery in patients with Heart failure and preserved ejection fraction (HFpEF).

Detailed description:
The Screening epoch of approximately 3 weeks was used to assess eligibility. Eligible patients then entered the single-blind treatment run-in epoch (Active Run-In Epoch), which was designed to assess patient's tolerability to study drug and to determine patients who were likely to stay on study drug for the duration of the trial. The treatment run-in consisted of valsartan 40 mg bid (if necessary), followed by valsartan 80 mg bid, and then followed by LCZ696 100 mg bid, over 3 to 8 weeks duration. Patients unable to tolerate either valsartan or LCZ696 at the prescribed doses during the treatment run-in were not eligible for randomization and were discontinued from the study.

At randomization (Visit 199/201), eligible patients were randomized 1:1 to receive either LCZ696 200 mg bid or valsartan 160 mg bid (double-blind period).

Patients who terminated the study early were expected, and were encouraged, to attend all the protocol specified study visits, to perform all measurements as stipulated in the visit schedule and to remain in follow up for the duration of the trial.

Arms: arm 1: Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years arm 2: Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.
Interventions: intervention 1: LCZ696 intervention 2: Valsartan intervention 3: Placebo of LCZ696 intervention 4: Placebo of Valsartan
Intervention descriptions: intervention 1: LCZ696 50, 100, and 200 mg tablets taken orally twice daily with matching placebo for valsartan intervention 2: Valsartan 40, 80, and 160 mg tablets taken orally twice daily with matching placebo for LCZ696 intervention 3: Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets intervention 4: Placebo to match valsartan 40 mg, 80 mg, and 160 mg tablets

Protocol documents:
Prot_000.pdf: 


Novartis
Page 2
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 2 ...........................................................................................................................12
Amendment 1 ...........................................................................................................................12
Protocol summary.....................................................................................................................15
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................21
2
Study objectives and endpoints .........................................................................................22
2.1
Primary objective(s)...............................................................................................22
2.2
Secondary objective(s)...........................................................................................22
2.3
Exploratory objectives...........................................................................................22
2.4
Objectives and related endpoints...........................................................................22
3
Investigational plan ...........................................................................................................24
3.1
Study design...........................................................................................................24
3.2
Rationale for study design .....................................................................................29
3.3
Rationale for dose/regimen, route of administration and duration of treatment....32
3.4
Rationale for choice of comparator .......................................................................33
3.5
Purpose and timing of interim analyses/design adaptations..................................33
3.6
Risks and benefits..................................................................................................33
4
Population..........................................................................................................................35
4.1
Inclusion criteria ....................................................................................................35
4.2
Exclusion criteria...................................................................................................35
5
Treatment...........................................................................................................................38
5.1
Study treatment......................................................................................................38
5.1.1
Investigational and control drugs..........................................................38
5.1.2
Additional treatment..............................................................................39
5.2
Treatment arms ......................................................................................................39
5.3
Treatment assignment and randomization.............................................................39
5.4
Treatment blinding.................................................................................................40
5.5
Treating the patient................................................................................................40
5.5.1
Patient numbering .................................................................................40


Novartis
Page 3
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
5.5.2
Dispensing the study drug.....................................................................40
5.5.3
Handling of study and additional treatment..........................................41
5.5.4
Instructions for prescribing and taking study treatment........................41
5.5.5
Permitted dose adjustments and interruptions of study treatment ........42
5.5.6
Rescue medication ................................................................................44
5.5.7
Concomitant medication .......................................................................44
5.5.8
Prohibited medication ...........................................................................45
5.5.9
Emergency breaking of assigned treatment code..................................46
5.6
Study Completion and Discontinuation.................................................................47
5.6.1
Study completion and post-study treatment..........................................47
5.6.2
Discontinuation of study treatment .......................................................47
5.6.3
Withdrawal of informed consent...........................................................48
5.6.4
Loss to follow-up ..................................................................................49
5.6.5
Early study termination by the sponsor.................................................49
6
Visit schedule and assessments .........................................................................................49
6.1
Information to be collected on screening failures..................................................55
6.2
Patient demographics/other baseline characteristics .............................................55
6.3
Treatment exposure and compliance .....................................................................55
6.4
Efficacy..................................................................................................................55
6.4.1
Cognitive function assessment by CCB................................................55
6.4.2
Individual cognitive domains................................................................57
57
6.4.4
Instrumental activities of daily living as assessed by functional 
activity questionnaire ............................................................................57
6.4.5
Appropriateness of efficacy assessments..............................................57
6.5
Safety.....................................................................................................................59
6.5.1
Brain amyloid PET imaging..................................................................59
60
6.5.3
Plasma beta-amyloid .............................................................................60
6.5.4
Cardiovascular events ...........................................................................60
6.5.5
Physical examination ............................................................................60
61
6.5.7
Height and weight .................................................................................61
61
6.5.9
Pregnancy and assessments of fertility .................................................63
63


Novartis
Page 4
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6.5.11
Appropriateness of safety measurements..............................................64
6.6
Other assessments..................................................................................................64
64
6.6.2
Resource utilization...............................................................................65
6.6.3
Pharmacokinetics ..................................................................................65
65
7
Safety monitoring ..............................................................................................................66
7.1
Adverse events.......................................................................................................66
7.2
Serious adverse events...........................................................................................68
7.2.1
Definition of SAE .................................................................................68
7.2.2
SAE reporting........................................................................................69
7.3
Liver safety monitoring .........................................................................................69
7.4
Renal safety monitoring.........................................................................................70
7.5
Cognition safety monitoring..................................................................................70
7.6
Reporting of study treatment errors including misuse/abuse ................................70
7.7
Pregnancy reporting...............................................................................................71
71
8
Data review and database management.............................................................................72
8.1
Site monitoring ......................................................................................................72
8.2
Data collection.......................................................................................................73
8.3
Database management and quality control............................................................73
8.4
Data Monitoring Committee..................................................................................74
74
9
Data analysis......................................................................................................................74
9.1
Analysis sets ..........................................................................................................75
9.2
Patient demographics and other baseline characteristics.......................................75
9.3
Treatments .............................................................................................................76
9.4
Analysis of the primary variable(s) .......................................................................76
9.4.1
Variable(s).............................................................................................76
9.4.2
Statistical model, hypothesis, and method of analysis..........................77
9.4.3
Handling of missing values/censoring/discontinuations.......................78
9.4.4
Sensitivity analyses ...............................................................................79
9.5
Analysis of secondary variables ............................................................................80
9.5.1
Efficacy variables..................................................................................80
9.5.2
Safety variables .....................................................................................80
9.5.3
Resource utilization...............................................................................82


Novartis
Page 5
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
9.5.4
Pharmacokinetics ..................................................................................82
82
9.5.6
Biomarkers ............................................................................................83
9.5.7
PK/PD ...................................................................................................83
83
83
83
9.7
Interim analyses .....................................................................................................86
9.8
Sample size calculation..........................................................................................86
9.8.1
Sample size calculation for the primary endpoint.................................86
9.8.2
Sample size calculation for the PET imaging substudy........................86
9.8.3
Blinded sample size re-estimation ........................................................87
10 Ethical considerations........................................................................................................87
10.1
Regulatory and ethical compliance........................................................................87
10.2
Informed consent procedures.................................................................................87
10.3
Responsibilities of the investigator and IRB/IEC..................................................88
10.4
Publication of study protocol and results...............................................................88
10.5
Quality control and quality assurance....................................................................88
11 Protocol adherence ............................................................................................................89
11.1
Protocol amendments.............................................................................................89
12 References .........................................................................................................................89
94
14 Appendix 2: Liver event definition and follow-up requirements......................................95
15 Appendix 3: Treatment guidelines for hyperkalemia (serum potassium greater than 
or equal to 5.3 mmol/L [mEq/L])......................................................................................97
16 Appendix 4: Guidelines for the management of blood pressure .......................................99
17 Appendix 5: Guidelines for the management of renal dysfunction.................................100
List of tables
Table 2-1
Objectives and related endpoints ..........................................................22
Table 3-1
Minimum pre-study total daily doses of commonly used ACEis and 
ARBs allowing patients to begin the treatment run-in epoch at Visit 
102 (valsartan 80 mg bid) .....................................................................27
Table 3-2
Safety monitoring criteria that must be met at Visit 1 (screening), 
Visit 103 and Visit 199/201 ..................................................................27
Table 3-3
Study drug dose levels during randomized treatment epoch ................28
Table 5-1
Study drug dispensed for the treatment run-in epoch by study visit.....42


Novartis
Page 6
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Table 5-2
Study drug dispensed during the randomized treatment epoch by 
study visit ..............................................................................................42
Table 5-3
Prohibited treatment..............................................................................45
Table 6-1
Assessment schedule.............................................................................51
62
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................71
85
Table 14-1
Liver event definitions ..........................................................................95
Table 14-2
Follow up requirements for liver events ...............................................95
List of figures
Figure 3-1
Study design..........................................................................................25
Figure 3-2
Treatment run-in epoch overview .........................................................26


Novartis
Page 7
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
List of abbreviations
Aβ
Amyloid beta
ACE(i)
Angiotensin converting enzyme inhibitor
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer’s disease assessment scale-cognitive subscale
ADNI
Alzheimer’s disease neuroimaging initiative
AE
Adverse event
AESI
Adverse event of special interest
Alb
Albumin
ALT 
Alanine aminotransferase
ANCOVA
Analysis of covariance
APOE4
Apolipoprotein E ε4 allele
ARB 
Angiotensin receptor blocker
ARNI
Angiotensin receptor neprilysin inhibitor
AST
Aspartate aminotransferase
AUC
Area under the curve
bid
twice daily dosing
BMI 
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CCB
CogState cognitive battery
CFR
US Code of Federal Regulations 
CI
Confidence interval
Cmax
Concentration maximum
CNS
Central nervous system
COX
Cyclo-oxygenase
CPAL
Continuous paired associate learning
CPO 
Country pharma organization
CQA
Compliance quality assurance
CRF
Case report form
CRO
Contract Research Organization
CSF
Cerebrospinal fluid
C-SSRS
Columbia suicidality severity rating scale
CV
Cardiovascular
DAR
Drug administration record
DBP
Diastolic blood pressure
DET
Detection test
DM
Diabetes mellitus
DMC
Data monitoring committee
 


Novartis
Page 8
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Echo
Echocardiography
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
ENR 
Enrolled set run-in phase
EOS
End of study
EOT
End of treatment
FAS
Full analysis set
FAQ
Functional activities questionnaire
FLAIR
Fluid attenuated inversion recovery
FSH
Follicle stimulating hormone
GCCS
Global cognitive composite score
GCP
Good Clinical Practice
GMLT
Groton maze learning test
γGT
Gamma-glutamyl transferase
HF
Heart failure
HFpEF
Heart failure and preserved ejection fraction
HFrEF
Heart failure and reduced ejection fraction
HIV
Human immunodeficiency virus
HTN
Hypertension
IADL
Instrumental activities of daily living
IB
Investigator brochure
ICF
Informed consent form
ICH
International council for harmonisation
IDT
Identification test
IEC
Independent ethics committee
IN
Investigator notification
IRB
Institutional review board
IRT
Interactive response technology
ISLT-DR
Interactive shopping list test delayed recall
IVRS
Interactive voice response system
LFT
Liver function test 
LRS
LCZ696 run-in set
LV
Left ventricular
LVEF
Left ventricular ejection fraction
MAR 
Missing at random
MBq
Megabecquerel
MCCB
MATRICS cognitive assessment battery
MCHC
Mean corpuscular hemoglobin concentration


Novartis
Page 9
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
MCI
Mild cognitive impairment
MCV
Mean corpuscular volume
MDRD
Modification of diet in renal disease
MedDRA
Medical dictionary for regulatory activities
MI
Myocardial infarction
MID
Minimally important difference
MMSE
Mini mental state examination
MNAR
Missing not at random
MRA
Mineralocorticoid receptor antagonist
MRI 
Magnetic resonance imaging
NEP(i)
Neutral endopeptidase inhibitor
NSAIDS
Non-steroidal anti-inflammatory drugs
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Heart Association
ONB
One back test
PCI
Percutaneous coronary intervention
PDE-5
Phosphodiesterase inhibitor 5
PET
Positron emission tomography
PPS 
Per protocol set
PT
Prothrombin time
QM
Quality management
RAN
Randomized set
RAS 
Renin angiotensin system
RBC
Red blood cell
RDW
Red blood cell distribution width
SAE
Serious adverse event
SAF
Safety set
SBP 
Systolic blood pressure
SCR 
Screened set
SCr
Serum Creatinine
SD
Standard deviation
SIB
Suicidal ideation and behavior
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SMQ
Standard medical query
SNRI
Serotonin norepinephrine reuptake inhibitor
SOP
Standard operating procedure
SSRI 
Selective serotonin reuptake inhibitor
SUSAR
Suspected unexpected serious adverse reaction
SUVr
Standardized uptake value ratio


Novartis
Page 10
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
TBL
Total bilirubin
TD
Study Treatment Discontinuation
TSH
Thyroid stimulating hormone
ULN
Upper limit normal
US CFR
United States code of federal regulations
VRS
Valsartan run-in set
WBC
White blood cell
WoC
Withdrawal of Consent


Novartis
Page 11
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Glossary of terms
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects
with established disease and in those with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material


Novartis
Page 12
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Amendment 2
Amendment rationale
The purpose of this administrative amendment is to correct the typographical error in the 
clean version of the protocol amendment 1 with respect to the numbering of the exclusion 
criteria’s that was starting at ‘2’ instead of ‘1’ (in the Section 4.2 Exclusion criteria). As of 
18-Aug-2017 fifteen patients are randomized into the study.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are non-substantial and do not require 
IRB/IEC approval prior to implementation.
The changes herein do NOT affect the trial specific model ICF.
Amendment 1
The first amendment of protocol CLCZ696B2320 was dated 01-Jun-2017.
Amendment rationale
Recruitment in Study CLCZ696B2320, also known as PERSPECTIVE study, began on 26-
Nov-2016. As of 1-Jun-2017 one patient is randomized into the study.
Although 
CLCZ696B2320 study was designed as an independent study to evaluate cognitive function 
and cerebral amyloid accretion in HFpEF patients, most of the inclusion and exclusion criteria 
were derived from the PARAGON-HF trial (an event-driven trial) where they were thought 
not to impact the objectives of the CLCZ696B2320 study. 
However experience to date suggests that the observed screen failure rate in CLCZ696B2320 
study is considerably higher than originally anticipated. Many of the failures are due to 
patients not being able to meet the magnetic resonance imaging (MRI) cerebrovascular 
criteria. The existing MRI criteria were intended to exclude patients with significant 
cerebrovascular pathology in whom the rate of change in cognitive function over time may be 
different to those without significant background vascular disease. However, based on 
PERSPECTIVE study screening experience as well as available literature, the prevalence of 
cerebrovascular disease appears to be significantly higher than originally anticipated and the 
existing exclusion criteria appear to limit the population to the extent that the study cohort 
might not be truly reflective of the heart failure patients seen in the community. Therefore , in 
the interest of keeping the study population reflective of the HF population seen in the 
community, the amended protocol will no longer exclude cerebrovascular disease as assessed 
on the MRI criteria. Cerebrovascular disease burden will continue to be assessed as per the 
existing criteria, and the baseline value will be used as an additional independent variable in 
the statistical analysis modeling for the primary and relevant secondary endpoints. Patients 


Novartis
Page 13
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
with clinically significant cerebral pathology, for example large cerebral aneurysm, space 
occupying lesion etc. will continued to be excluded from the study. In addition, some of the 
existing criteria taken from PARAGON-HF were originally developed to help identify 
patients at high risk for cardiovascular events which are not relevant for the objectives of 
CLCZ696B2320 study. Therefore this amendment aims to revise some of the study inclusion 
and exclusion criteria to remove unnecessary restrictions and to ensure the study population 
reflects the HFpEF population in the community.  In addition, this amendment also corrects 
inconsistencies between various sections of the protocol, corrects typographical errors, and 
provides clarifications where instructions are less clear. Some of the key changes to the 
protocol are listed below.
None of the changes are expected to have major impact on the objectives or the analysis of the 
study results.
Changes to the protocol
Key updates to Section 4.1 (Inclusion criteria) and Section 4.2 (Exclusion criteria):

NT-proBNP requirement is adjusted to ≥125 pg/mL to be consistent with new 
European Society of Cardiology guidelines.

Prior heart failure hospitalization is removed as an eligibility criterion for inclusion in the 
study as this criterion by itself may not support a diagnosis of heart failure in the absence 
of NT-ProBNP values of ≥ 125 pg/mL.

Removed the requirement to meet MRI criteria for cerebrovascular and white matter 
lesion. Clinically significant cerebral pathology that may impact cognition will remain as 
an exclusion criterion.

Removed the existing exclusion criterion in order to allow participation of patients with a 
history of cardiomyopathies that have an ejection fraction of >40%; as exclusion of these 
patients is not relevant to the study objectives and these patients may benefit from 
treatment with LCZ696.

Significant obstructive valvular disease is added as an exclusionary criterion as these 
patients are less tolerant to vasodilators.

Listed the exclusions and restrictions regarding the use of sedative hypnotics, selective 
serotonin re-uptake inhibitors, serotonin norepinephrine re-uptake inhibitors which are 
described elsewhere in the protocol but are missing from Section 4.1.

Clarification provided regarding the exclusionary criterion for thyroid function tests, 
Vitamin B12 or folate deficiency.
Updated Sections 5.3 and 6.5.1 to indicate that amyloid status results will not be made 
available to investigators.
Updated Section 5.5.4 by adding time window for dose administration instead of just starting 
time.
Assessment scheduled (Table 6-1) was updated to clarify that the plasma beta amyloid will be 
assessed only in patients participating in PET substudy.
Updated Section 6.5.1 to indicate that, the end of study (EOS) imaging procedures will be 
performed only when prior assessments were made more than 12 months ago.


Novartis
Page 14
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Updated Sections 6.5.8.6 and 6.5.9 to clarify that FSH levels will be measured to confirm 
menopausal status in patients who have undergone oophorectomy without hysterectomy.
In Section 9.4, the cerebrovascular disease burden as measured by MRI was added as one of 
the independent variables in the statistical analysis modeling for the primary endpoint and 
relevant secondary endpoints. In Section 9.4.1 minor edit and additional clarification are 
added for the calculation of each composite score for GCCS battery to make the calculations 
more clear.
Additional minor changes were made to correct typographical errors and inconsistencies in 
the protocol.  


Novartis
Page 15
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Protocol summary
Protocol number
CLCZ696B2320
Title
A multicenter, randomized, double-blind, active-controlled study to 
evaluate the effects of LCZ696 compared to valsartan on cognitive 
function in patients with chronic heart failure and preserved ejection 
fraction
Brief title
Study to evaluate the effects of LCZ696 on cognitive function in patients 
with chronic heart failure (HF) and preserved ejection fraction (pEF)
Sponsor and Clinical 
Phase
Novartis, Phase 3 
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to evaluate the effect of LCZ696 compared to 
valsartan on cognitive function in patients with HFpEF.
Primary Objective
To evaluate the effects of LCZ696 compared to valsartan on cognitive 
function over 3 years in patients with HFpEF as assessed by the CogState 
cognitive assessment battery.
Secondary Objectives

To evaluate the effect of LCZ696 compared to valsartan on -amyloid 
deposition in the brain in a subset of patients using amyloid positron 
emission tomography (PET) imaging over 3 years. 

To evaluate the effects of LCZ696 compared to valsartan on individual 
cognitive domains (memory, executive function, and attention) as 
assessed by the individual components of the CogState battery over 3 
years

To compare LCZ696 to valsartan in evaluating changes in instrumental 
activities of daily living (IADL) as assessed with Functional Activity 
Questionnaire (FAQ) over 3 years.
Study design
This study is a multi-center, randomized, double-blind, parallel group, 
active comparator trial designed to evaluate the overall effect of LCZ696 
compared to valsartan on cognitive function as assessed by the CogState
comprehensive cognitive battery in patients with HFpEF. 
Population
The study population will consist of 520 patients ≥60 years of age with 
chronic symptomatic HF (New York Heart Association (NYHA) class II-IV) 
and left ventricular ejection fraction (LVEF) > 40%.
Inclusion criteria
1. Written informed consent including consent for APOE4 gene testing 
must be obtained before any assessment is performed
2. Male or female patients aged ≥60 years of age.
3. Chronic heart failure with current symptom(s) (NYHA class II-IV) at 
Screening visit.
4. LVEF > 40% 
a.
By any method using most recent assessment within 6 months 
prior to screening visit OR
b.
By an echocardiogram performed during the screening visit, if 
previous assessment is not available.
5. NT-proBNP ≥ 125 pg/mL at Screening visit


Novartis
Page 16
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6. Patient with evidence of adequate functioning (e.g.: intellectual, motor, 
visual and auditory) to complete the study assessments and has 
elementary education or 6 years of sustained employment.
Key Exclusion criteria
1. Current acute decompensated HF requiring augmented therapy with 
diuretics, vasodilators and/or inotropic drugs.
2. Acute coronary syndrome (including myocardial infarction (MI)), cardiac 
surgery, other major cardiovascular (CV) surgery, or urgent 
percutaneous coronary intervention (PCI), carotid surgery or carotid 
angioplasty, history of stroke or transient ischemic attack within the 3 
months prior to Screening visit or an elective PCI within 30 days prior 
to Screening visit.  
3. Patients with a history of hereditary or idiopathic angioedema or 
angioedema related to previous angiotensin converting enzyme 
inhibitor (ACEi) or angiotensin receptor blocker (ARB) therapies.
4. Patients who require treatment with 2 or more of the following: an ACEi, 
an ARB or a renin inhibitor.
5. Patients with one of the following:
a.
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 as 
calculated by the Modification of Diet in Renal Disease (MDRD) 
formula at screening visit, or
b.
eGFR <25 mL/min/1.73m2 at Visit 103 or at end of run-in / 
randomization visit, or
c.
eGFR reduction >35% (compared to Visit 1) at Visit 103 or Visit 
199/201
6. MMSE score <24 at Screening visit 
7. Patients with a clinical diagnosis of Alzheimer’s disease or other 
dementia syndromes or any indication for or current treatment with 
cholinesterase inhibitors and/or another prescription Alzheimer’s 
Disease (AD) treatment (e.g., memantine).
8. Any history of medical or neurological condition likely to affect the 
participant’s cognition  (e.g., clinically significant brain trauma with loss 
of consciousness > 3 minutes within 6 months prior to screening, 
Huntington’s disease, Parkinson’s disease, Lyme’s disease, syphilis, 
HIV dementia, uncontrolled seizure disorder) or clinically significant 
abnormalities in thyroid function tests, Vitamin B12 or folate deficiency 
requiring treatment at screening (Patients who are adequately treated 
may be included at investigator discretion).  
9. Inability to perform cognitive battery or other study evaluations based 
on significant motor (e.g. hemiplegia, muscular-skeletal injury) or 
sensory (blindness, decreased or uncorrected visual or auditory 
acuity) skill.
10.Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the 
Columbia suicidality severity rating scale (C-SSRS), if this ideation 
occurred in the past 6 months, or “yes” on any item of the Suicidal 
Behavior section, except for the “Non-Suicidal Self-Injurious Behavior” 
question, if this behavior occurred in the past 2 years.
11.Clinically significant cerebral pathology, for example large cerebral 
aneurysm, space occupying lesion etc. that may impact cognition as 
assessed by MRI central reader.
12.History of hypersensitivity to any of the study drugs or to drugs of 
similar chemical classes.
13.History or presence of any other disease with a life expectancy of <3 






Novartis
Page 19
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
1
Introduction
1.1
Background 
Heart failure (HF) is a major public health problem associated with a high mortality rate, 
frequent hospitalizations, and poor quality of life. Despite existing treatment options, heart 
failure remains a progressive syndrome with a high mortality rate, and an illness with an 
unmet need for new therapies to improve health outcomes (McMurray et al 2012).
LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) for the treatment of patients 
with chronic heart failure and reduced ejection fraction (HFrEF). After ingestion, LCZ696 
delivers systemic exposure to sacubitril (AHU377), a neprilysin inhibitor pro-drug, and 
valsartan, an angiotensin receptor blocker (ARB). Neprilysin (neutral endopeptidase, (NEP)) 
is a naturally occurring membrane-bound enzyme, responsible for the degradation of 
natriuretic peptides and other peptide hormones such as adrenomedullin, bradykinin, 
substance P, angiotensin I and II, β-amyloid, and possibly endothelin-1.  LCZ696, through its 
unique mode of action potentiates beneficial endogenous vasoactive peptides via NEP 
inhibition while inhibiting the Renin Angiotensin System (RAS) via angiotensin II type 1 
receptor blockade; both mechanisms are considered to act in a complementary and additive 
manner to improve outcome in patients with HFrEF.
Consistent with this mechanism of action, the recently completed landmark randomized trial
(PARADIGM-HF, N=8442) demonstrated that LCZ696 was superior to enalapril (current 
standard of care) in reducing cardiovascular (CV) death and heart failure hospitalization in 
patients with HFrEF. The magnitude of these advantages of LCZ696 over an angiotensin 
converting enzyme (ACE) inhibitor was statistically significant and clinically relevant, 
particularly since the drug was compared with current standard of care with an established 
mortality benefit in HF patients (McMurray et al 2014). In this study, compared with enalapril 
(ACEi), LCZ696 demonstrated a 20% risk reduction for HF hospitalization or CV death 
(primary endpoint, p = 0.0000002), 20% risk reduction in CV death alone (p=0.00004), and 
21% risk reduction for first HF hospitalization (p=0.00004). In addition, LCZ696 also 
demonstrated benefit in symptom improvement, total HF hospitalization, all cause 
hospitalization and emergency room visits compared to enalapril.  LCZ696 is currently under 
investigation for patients with heart failure and preserved ejection fraction (HFpEF) in an 
ongoing large randomized clinical trial (PARAGON-HF, 4600 patients with HFpEF), where 
no standard of care is available.
Cognitive impairment has been reported in patients with heart failure in several studies over 
the past three decades.  The prevalence of cognitive impairment observed in these heart failure 
studies (no distinction made between HFrEF or HFpEF) ranged from 25 to 75% (Ampadu and 
Morley 2015, Cannon et al 2015). Changes in cognition as a result of improved cardiac 
function have not been extensively evaluated.  However, studies in heart failure patients 
implanted with a left ventricular assist device showed that cognition, as assessed by a 
comprehensive battery of tests, was improved during follow-up ranging from 6 months to 2 
years (Simoni et al 2014).  


Novartis
Page 20
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Observational epidemiological studies have shown a relationship between cognitive 
impairment and elevated blood pressure (BP).  For example, the Honolulu-Asia Aging Study 
revealed that systolic blood pressure in midlife was associated with cognitive impairment later 
in life (Launer et al 2000).  In another longitudinal study that followed elderly patients in 
Sweden, an association was shown between blood pressure at age 70 and the subsequent 
development of dementia 10 to 15 years later (Skoog et al 1996). Thus, a reasonable 
expectation would be that antihypertensive therapy should slow cognitive decline. However, 
the effect of blood pressure lowering on cognition, although extensively studied, has yielded 
inconsistent findings.  These conflicting results are likely due to the use of different study 
designs, varying baseline blood pressures, inconsistent inclusion criteria, and most 
importantly, inadequate power to detect meaningful responses (Gorelick and Nyenhuis 2012).   
Nevertheless, it is therefore possible that an improvement in cardiac function and blood 
pressure per se, as a result of long-term drug treatment, with LCZ696, may result in beneficial 
effects on cognition.
Cognitive decline is also observed in patients with a history of stroke or vascular disease 
detected by neuroimaging. Cognitive impairment associated with cerebrovascular dysfunction 
is classified as “vascular cognitive impairment” (Gorelick et al 2011).  In contrast, cognitive 
functional changes that are evident in Alzheimer’s Disease (AD) are associated with beta 
amyloid (Aβ) neuritic plaques and neurofibrillary tangles. These two conditions (deposition of 
neuritic plaque and changes in cerebrovascular structure and function) can exist concurrently
in elderly patients and is now being described as one entity, known as “mixed dementia”.  
Moreover, there is likely a complex interplay between the pathological processes leading to 
these various dementias.
Alzheimer’s disease is a complex, multifactorial disease that develops over a long period of 
time (15-20 years), and is associated with the presence of amyloid beta (Aβ) plaques in the 
brain. The Aβ42 isoform is primarily found in amyloid plaques, whereas the Aβ40 isoform is 
primarily found in amyloid angiopathy (Mawuenyega et al 2010). In addition to degrading the 
biologically active vasoactive peptides mentioned above, in vitro and non-clinical studies 
have shown that neprilysin is one of multiple enzymes involved in the proteolytic degradation 
of Aβ. Other proteases with Aβ-degrading properties include insulin-degrading enzyme, 
endothelin-converting enzyme, ACE, and plasmin (Wang et al 2006). Besides enzymatic 
degradation of Aβ, it is also removed from the brain by other processes including transport 
into cerebrospinal fluid (CSF) and the bloodstream (Saido and Leissring 2012). The relative 
importance of each of these pathways for proteolytic degradation of Aβ in humans is 
unknown, but neprilysin inhibition could potentially reduce the clearance of Aβ from the 
central nervous system (CNS). Reduced clearance of Aβ from the brain over a prolonged 
period of time could theoretically result in an accumulation of Aβ in brain parenchymal 
plaque, which may increase the risk of development of AD.  
To gain a better understanding of the impact of neprilysin inhibition on Aβ metabolism, a 2-
week study in young cynomolgus monkeys (2-4 year old) was undertaken, and Aβ 
concentrations in CSF and brain tissue were assessed during treatment with LCZ696. The
dosing regimen (50 mg/kg/day) in the monkey resulted in a systemic drug exposure similar to 
LCZ696 400 mg once daily dosing in man. In this study, LCZ696 treatment resulted in an 
acute decrease in clearance of CSF Aβ42 on Day 1, and increase in total CSF Aβ42 and Aβ38 


Novartis
Page 21
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
on Day 15. It is important to note that by Day 15 clearance of Aβ42 was no longer 
significantly decreased relative to controls, and brain tissue concentrations of Aβ were not 
affected by LCZ696 compared to vehicle. The human translatability and potential 
consequences of these changes in CSF Aβ clearance are currently not known.
In contrast to the sub-acute cynomolgus monkey study where increases in CSF Aβ42, Aβ40 
and Aβ38 concentrations in CSF were observed, oral administration of LCZ696 400 mg once 
daily in healthy subjects for 14 days did not result in changes in Aβ42 and Aβ40 in the CSF.
However, there was an increase in CSF Aβ38 in these healthy subjects. The clinical relevance 
of this increase in CSF Aβ38 in this study is unknown, as there is no evidence that an isolated 
increase in Aβ38 concentration facilitates Aβ plaque formation. These observations suggest 
that enzymes and disposition pathways other than neprilysin may be important in clearance of 
CSF Aβ in humans.
In a chronic toxicology study in cynomolgus monkeys treated with LCZ696 at 300 mg/kg/day 
for 39-weeks, there were no increases in brain immunostaining for Aβ42, plaque formation, or 
compound-related microscopic brain changes. This 300 mg/kg/day dose in monkeys resulted 
in an approximately 10-fold greater maximum concentration (Cmax) in plasma than a 400 mg 
once daily dose in humans.
Furthermore, in PARADIGM-HF where patients with HFrEF have been treated with LCZ696 
for up to 4.3 years, there was no increased incidence of AD or dementia-related adverse 
events compared to patients treated with current standard of care. The age of patients in 
PARADIGM-HF was 63.8 ± 11.5 (mean ± SD). Similarly, in the 36 week PARAMOUNT 
study in patients (70.9 ± 9.4 years of age) with HFpEF, there was no increased incidence of 
AD or dementia-related adverse events in LCZ696-treated patients compared to patients 
receiving valsartan. However, these studies were not prospectively designed to specifically 
evaluate the effect of LCZ696 on AD or dementia.
The overall net effect of these various factors on cognition has not been specifically studied. 
For example, the potential long-term effects on the clearance of Aβ as a result of neprilysin 
inhibition via LCZ696 and potential cognitive benefit derived from improved cardiac and 
hemodynamic function as a result of chronic LCZ696 treatment remain unknown. The 
primary goal of the current study is to assess the overall impact of long-term LCZ696 therapy
compared to valsartan on cognitive function assessed via a comprehensive battery of 
neuropsychological tests in patients with HFpEF. In addition, β-amyloid deposition in brain 
will be assessed using positron emission tomography amyloid (PET) imaging.
1.2
Purpose 
The purpose of this study is to evaluate the effect of LCZ696 compared to valsartan on 
cognitive function in patients with HFpEF.  Cognitive function will be assessed using the 
CogState comprehensive battery of tests, which include a longitudinal evaluation of key 
cognitive domains such as memory, executive function, and attention.  
In addition, the effect of LCZ696 therapy compared to valsartan on amyloid plaque deposition 
in the brain will be evaluated in a subset of patients using amyloid florbetapir 18F PET
imaging.






Novartis
Page 24
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Objective
Endpoint
Analysis
3
Investigational plan
3.1
Study design
This study is a multi-center, randomized, double-blind, parallel group, active comparator trial 
designed to evaluate the overall effect of LCZ696 compared to valsartan on cognitive function 
as assessed by a comprehensive cognitive battery in patients with HFpEF (Figure 3-1). The 
study population will consist of patients ≥60 years of age with chronic symptomatic HF 
(NYHA class II-IV) and a left ventricular ejection fraction (LVEF) >40%. Patients will be 
randomized in a 1:1 fashion to either LCZ696 200 mg bid or valsartan 160 mg bid.
Cognitive function will be assessed at baseline and every six months up to 3 years by a 
comprehensive cognitive battery, and MMSE will be assessed annually. Patients scoring <24 
on the MMSE scale during screening will be excluded from the study. Patients will be 
stratified based on age (< 75, ≥ 75 years), MMSE score (< 28, ≥ 28), and if participating in the 
PET imaging substudy, amyloid status (amyloid positive/negative). APOE4 is a strong 
predictor of cognitive impairment (Lim et al 2015) and Aβ accumulation. Therefore, patients 
will be genotyped for APOE4 allele status.
The study will also evaluate the impact of LCZ696 therapy compared to valsartan on -
amyloid deposition in the brain using florbetapir 18F PET imaging in a subset of patients. PET 
imaging requires specialist centers experienced in the technique that are in close proximity to 
a radiopharmaceutical production facility, thus a subset of centers will be selected as PET 
centers. To ensure high quality of imaging data, PET imaging will be conducted in all eligible 
patients at selected PET capable centers. Amyloid PET imaging will be performed at 
randomization, at 18 months, and at 3 years (EOS Visit). If a patient permanently discontinues 
treatment prior to 3 years, a PET scan should be done at the end of treatment visit (EOT visit) 
if a prior scan was performed more than twelve months ago. End of study (EOS) scan will not 
be required if EOT scan is performed within 12 months of end of study visit. All PET scans 
will be evaluated centrally.
Brain magnetic resonance imaging (MRI) will be performed at the Screening visit in all 
patients to evaluate exclusion criteria, at 18 months, at the end of treatment visit (EOT Visit, 
only if prior scans were performed more than twelve months previously), and at the end of 
study visit. With the exception of the screening MRI, subsequent MRI scans will only be 
performed in the sub-set of study patients for which PET is being performed. All MRI scans 
will be evaluated centrally.  Baseline MRI scans at screening will assist in determining patient 
eligibility for the study.  Magnetic resonance images will also be used to assess global and 
regional brain structural volume at baseline and at end of study. 


Novartis
Page 25
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Figure 3-1
Study design
bid – twice daily dosing
Screening epoch
A Screening epoch of approximately 3 weeks will be used to assess eligibility. 
To minimize unnecessary patient assessment burden, sites are strongly advised to administer 
Cognitive assessments (MMSE, 
 FAQ, 
 CCB) only after confirming that the 
screening laboratory data are available and the patient is considered otherwise eligible to 
participate in the study. Cognitive assessments should ideally be administered by the same 
assessor in a quiet environment and prior to any other clinical assessments scheduled during 
the day. The investigator must ensure patient eligibility on all inclusion/exclusion criteria 
including laboratory and MMSE assessments prior to performing the MRI scan. It takes up to 
five days to confirm eligibility from the central MRI reader. The sites should take this into 
consideration when scheduling MRI scans.
A patient who enters screening but is determined not to be eligible to enter the treatment run -
in period will be considered a screen failure. The investigator may consider re-screening the 
patient at a later time if he/she believes that the patient’s condition has changed and may 
potentially be eligible. A minimum of 2 weeks must elapse between re-screenings and a 
patient may be re-screened once only. Patients who have screen failed based on MRI criteria 
for cerebral and vascular pathology in the original protocol may be eligible to be rescreened 
after implementation of protocol amendment 1. In those patients if previous study MRI scan 
was performed within 6 months of re-screening date this will be considered baseline 
assessment for these patients and no further baseline scans will be acquired.


Novartis
Page 26
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Single-blind treatment run-in epoch
The single-blind treatment run-in period is designed to assess patient’s tolerability to study 
drug, and to determine patients who are likely to stay on study drug for the duration of the 
trial. 
The treatment run-in period consists of valsartan 40 mg bid (if necessary), followed by 
valsartan 80 mg bid and then followed by LCZ696 100 mg bid, over 3 to 8 weeks duration 
(Figure 3-2). During the run-in period, patients will continue their background HF 
medications with exception of ACEi, ARB or renin inhibitor which will be discontinued. The 
concomitant use of ACEi, ARB or renin inhibitor during the treatment run-in is strictly 
prohibited. Patients will enter the treatment run-in period based on their use of RAS blockade 
medications at the time of screening (Figure 3-2 and Table 3-1).  Patients unable to tolerate 
either valsartan or LCZ696 during the run-in will not be eligible for randomization, and will 
be discontinued from the study. This design will allow a careful assessment of the patient’s 
tolerability to study medications prior to randomization. 
Patients will enter different parts of the treatment run-in period based on their use of RAS 
blockade medications at the time of enrollment. Patients should enter the treatment run-in 
period at Visit 102 starting valsartan 80 mg bid if they have been on an ACEi or ARB 
medication at a dose which is equivalent to or above the total daily doses listed in Table 3-1.
Otherwise, patients should enter the treatment run-in epoch at Visit 101 starting with valsartan 
40 mg bid for 1 to 2 weeks before they start valsartan 80 mg bid at Visit 102. However, at the 
investigator’s discretion, those patients who are on ACEi or ARB medication at equivalent to 
or above the total daily dose listed in Table 3-1 can also enter the treatment run-in epoch at 
Visit 101 starting valsartan 40 mg bid.
Figure 3-2
Treatment run-in epoch overview
bid – twice daily dosing


Novartis
Page 27
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Table 3-1
Minimum pre-study total daily doses of commonly used ACEis and 
ARBs allowing patients to begin the treatment run-in epoch at Visit 
102 (valsartan 80 mg bid)
ACEI
Dose
ARB
Dose
Benazepril
20 mg 
Azilsartan
40 mg
Captopril
100 mg 
Candesartan
16 mg 
Cilazapril
2.5 mg
Eprosartan
400 mg 
Enalapril
10 mg 
Irbesartan
150 mg 
Fosinopril
20 mg
Losartan
50 mg 
Imidapril
10 mg
Olmesartan
10 mg 
Lisinopril
10 mg 
Telmisartan
40 mg 
Moxepril
7.5 mg
Valsartan
160 mg 
Perindopril
4 mg 
Quinapril
20 mg 
Ramipril
5 mg 
Trandolapril
2 mg 
Zofenopril
30 mg
Patients who meet the safety monitoring criteria (Table 3-2) at Visit 103 will proceed to 
treatment with LCZ696 100 mg bid for 2 to 4 weeks.
Study drug should not be dispensed unless the patient meets all inclusion criteria and none of 
the exclusion criteria at Visit 1 and subsequently at Visit 199/201.
Table 3-2
Safety monitoring criteria that must be met at Visit 1 (screening), Visit 
103 and Visit 199/201
Parameter
Visit 1 (Screening)
Visits 103 (treatment run-in) and Visit 199/201 
(end of treatment run-in/randomization)
Potassium level
K ≤5.2 mmol/L (mEq/L) 
K ≤5.4 mmol/L (mEq/L)
Kidney function
eGFR ≥30 mL/min/1.73m2
eGFR ≥25 mL/min/1.73m2
eGFR reduction <35% compared to Visit 1 
Blood pressure
SBP ≥110 mmHg 
No symptomatic hypotension as determined by 
the investigator and SBP ≥100 mmHg.
AEs or conditions
No conditions that preclude 
continuation according to 
the investigator’s judgment
No postural symptoms or any AEs that preclude 
continuation according to the investigator’s 
judgment
AE – adverse event
To assess the patient’s eligibility to continue in the study, either local or central laboratory 
should be used for the assessment of potassium and estimated glomerular filtration rate (eGFR)
at Visits 103 and 199/201 (end of treatment run-in visit/randomization). If central laboratory 
is used, since it may take up to 72 hours to obtain the results, it is recommended that the site 
take this into consideration when scheduling subsequent study visits, while keeping the 
patient on the study medication.  If a local laboratory is selected, the same samples should 
also be sent to the central laboratory, while the evaluation should be solely based on the local
laboratory results.  Patients should NOT enter Visits 103 or 199/201 without evaluating the 
safety monitoring criteria (Table 3-2).  


Novartis
Page 28
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Down-titration of study drug is not allowed during the treatment run-in period. Patients who 
are not able to tolerate study drug at the doses prescribed during the treatment run -in epoch 
will be discontinued. 
Investigators may consider adjusting (dose reduced or discontinued) background medications 
(e.g., diuretic(s), antihypertensive agents, cardiovascular medications such as beta blockers,
MRAs, nitrates, etc.) if the study drug is not tolerated (e.g., occurrence of AEs such as 
hyperkalemia, hypotension, and renal dysfunction) to ensure patients meet the safety criteria 
in Table 3-2 during the treatment run-in epoch.  Patients may be seen at any time for 
unscheduled visits during the treatment run-in epoch for re-evaluation of safety criteria 
parameters. 
Patients who experience angioedema at any time during the treatment run-in epoch must be 
discontinued from the study. 
Patients who are discontinued from the treatment run-in epoch due to intolerance to the study 
drug, development of angioedema or for failure to meet the specified safety criteria will be 
considered treatment run-in failures and are not eligible to be re-screened for study entry.
At the end of the treatment run-in epoch (Visit 199/201), patients who meet the safety criteria 
(Table 3-2) and tolerate LCZ696 100 mg bid for at least 2 weeks are eligible for 
randomization. For these patients, Visit 199 and 201 occurs over a period of multiple days.  
Patients should be instructed not to take their morning (am) dose of treatment run-in study 
drug on the day they start randomized study drug.
Randomized treatment epoch
At randomization (Visit 199/201), eligible patients will be randomized to 1 of 2 treatment 
arms, either LCZ696 200 mg bid or valsartan 160 mg bid in a 1:1 fashion.
Every attempt should be made to maintain patients on the target study drug dose (dose level 3) 
(Table 3-3) throughout the trial. If the patient does not tolerate the target study drug dose level 
the investigator should consider, if appropriate, adjusting background medications to rectify 
the situation before considering down-titration to the next lower study drug dose level 
(Section 5.5.5).
Table 3-3
Study drug dose levels during randomized treatment epoch
Dose level
LCZ696 Treatment Arm
Valsartan Treatment Arm
3
200 mg bid
160 mg bid
2
100 mg bid
80 mg bid
1
50 mg bid
40 mg bid
At each dose level the patient will also take matching placebo for the other treatment arm 
study drug.
Study drug dose level adjustments should be based on overall safety and tolerability with 
special focus on a) hyperkalemia, b) symptomatic hypotension, and c) clinically significant 
decrease in eGFR/increase in serum creatinine (SCr). Treatment guidance for hyperkalemia, 
management of BP, and renal dysfunction are provided in Appendix 3, Appendix 4, and 
Appendix 5, respectively.


Novartis
Page 29
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
3.2
Rationale for study design
The key study design features of this study, including the run-in period, target dose, 
comparator and dose selection are largely similar to the current ongoing PARAGON-HF
study (CLCZ696D2301) which is a Phase 3 outcome study comparing LCZ696 with valsartan 
in reducing CV death and HF hospitalization in patients with HFpEF. The data from this study 
are intended to be complementary to the data from the PARAGON-HF study.
Study Population: 
The study population will consist of patients 60 years and older with chronic heart failure 
(NYHA class II-IV) and LVEF > 40%. LCZ696 has been shown to improve survival and 
reduce heart failure-related hospitalization in patients with HFrEF (LVEF ≤40%). Hence the 
study population consists of patients with HFpEF (LVEF >40%), as it is considered unethical 
to randomize HFrEF patients in this long term study to the valsartan treatment group. HFpEF 
is a condition that predominantly affects an elderly population. Age is also an important risk 
factor for cognitive decline and amyloid deposition. The entry requirement of 60 years or 
older and symptomatic heart failure will ensure that patients who are likely to benefit from 
LCZ696 therapy are included in the study while allowing the ability to study the potential 
effects on cognitive function in a relevant population. As treatment with LCZ696 has been 
demonstrated to confer significant mortality and morbidity benefit compared to current 
standard of care (ACEI) to patients with HFrEF, these patients will be excluded from the 
study. However, given the similarity of the population and patient characteristics, the results 
of this study should be relevant to the heart failure population at large regardless of ejection 
fraction.
The study aims to assess the effect of LCZ696 compared to valsartan on cognitive function in 
patients with normal cognition and mild cognitive impairment (MCI), while excluding 
patients with significant impairment, (e.g. patients with an MMSE score of <24; Holsinger et 
al 2007). Available data suggest that amyloid plaque deposition may reach a plateau once a 
patient is clinically diagnosed with AD (Bateman et al 2012). The rate of cognitive decline in 
AD patients is not uniform as it is dependent on various factors. Hence patients with a clinical 
diagnosis of AD or dementia will also be excluded from this study.
Further details about the patient population are provided in Section 4.
Active run-in period:
The single-blind epoch will help ensure that only patients who are likely to tolerate and 
maintain study drug for the long term follow-up are randomized; this will  minimize the 
potential for early drop out, which is critical to assess the impact of long-term therapy of 
study medications for up to 3 years on cognitive function. In addition, the single blind 
treatment run-in epoch mimics clinical practice (where patients are only continued on 
treatments if they are tolerated). 
The current treatment run-in design will assess the safety and tolerability of patients to drug 
dose level 2 (LCZ696 100 mg bid). Drug dose level 3 (LCZ696 200 mg bid) is not included in 
the run-in design as the great majority of patients who tolerated 100 bid were able to tolerate 
200 bid in the run-in period of the PARADIGM-HF trial.


Novartis
Page 30
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Baseline assessments will be made at the time of randomization visit following exposure to 
both study medications in the run-in period. In addition, brief exposure with LCZ696 during 
the run-in period is unlikely to have an impact on baseline study assessments. 
Primary endpoint selection: 
The primary endpoint of the study is change in cognition, which is assessed as the change in 
the Global Cognitive Composite Z scores (GCCS) from baseline (randomization) over 3 years. 
There is no absolute or clear demarcation between cognitive domains affected in Alzheimer’s 
dementia compared to vascular dementia. However some distinctions can be made between 
the two conditions in terms of the domains that are predominantly affected. For example, 
executive function is typically the primary cognitive impairment in vascular dementia. In 
contrast, cognitive domains encompassing memory functions are more often affected in 
Alzheimer’s dementia although other faculties are also affected (Cavalieri et al 2010, Gorelick 
et al 2011, Lim et al 2012).  Thus a composite score of relevant domains provides a 
comprehensive assessment of cognitive function in the study population.
The principle of using cognitive composite is well established and has been used in multiple 
studies in AD and depression (Alzheimer’s disease assessment scale-cognitive subscale 
(ADAS-Cog), MATRICS cognitive assessment battery (MCCB); Raghavan et al 2013, Vellas 
et al 2015, Maruff and Jaeger 2015). The Alzheimer’s Prevention Initiative has recommended 
the use of a composite clinical assessment as a primary endpoint rather than selecting a single 
cognitive assessment or individually examining multiple cognitive assessments (Langbaum et 
al 2015). A similar approach has been advocated by the Alzheimer’s Disease Cooperative 
Study group (Donohue et al 2014).
The specific domains of cognition to be measured include psychomotor function, visual 
attention, working memory, executive function, visual learning and verbal learning and 
memory.  These cognitive functions have been selected on the basis of their known sensitivity 
to changes in amyloid levels (Villemagne et al 2013, Lim et al 2014) and cerebral vascular 
function (Collie et al 2002, Clark and McDougall 2006, Steinberg et al 2015,) in humans.  The 
cognitive functions will be measured using a set of computerized neuropsychological tests 
from the CogState Cognitive Battery (CCB) (Maruff et al 2013, Mielke et al 2014). The tests 
from the CCB have been selected on the basis of their extensive use and demonstrated 
sensitivity to cognitive decline associated with heart disease (Hammers et al 2013, Arslanian-
Engoren et al 2014, Cannon et al 2015, Lansky et al 2015, Chou et al 2015), preclinical 
Alzheimer’s disease (Darby et al 2011, Lim et al 2013, Lim et al 2015) and cerebrovascular 
disease (Silbert et al 2004, Steinberg et al 2015, Lansky et al 2015).  Changes in performance 
on the CCB have also been shown repeatedly in response to treatment with central nervous 
system (CNS) active drugs (Thomas et al 2008, Padmanabhan et al 2009, Kay et al 2012,
Grove et al 2014, Snyder et al 2014).
The CCB has been selected as it is designed specifically for repeated administration with 
minimal practice or learning effects and performance on the cognitive tests themselves are not 
influenced by the language, cultural or educational background of participants.  Computer 
based testing allows the CCB to be administered in clinical trials by trained but non -expert 
clinical trials staff, which makes it ideal for use in a heart failure population (Lim et al 2014).  


Novartis
Page 31
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
The three year duration was chosen for the study as available literature suggests that clinically 
relevant deterioration in cognition is associated with increases in amyloid deposition and is 
demonstrable over a period of 36 months (Villemagne et al 2011, Chen et al 2015). Although 
cognitive decline in the setting of AD occurs gradually, in several studies enrolling patients 
with mild cognitive impairment, patients progress to dementia at a rate of about 15% per year, 
with the majority of patients converting to frank dementia after 3 to 4 years (Belleville et al 
2014). 
Older adults who are cognitively normal but who show elevated levels of amyloid at their 
initial assessment have an increased rate of progression to clinically classified MCI or 
dementia over 36 months, when compared to those with low levels of amyloid.  This rate of 
clinical disease stage progression is increased dramatically if individuals with high levels of 
amyloid also meet clinical criteria for MCI at their initial assessment.  In addition , data from 
previous studies in heart failure suggest that more than a third of patients are no longer on 
study medication by 3 years (I-Preserve study; Massie et al 2008). Thus the 3 year duration is 
considered to provide an appropriate time period to study the trial objectives while retaining 
as many evaluable patients as possible.
Secondary endpoint selection: 
Amyloid PET imaging
Change in brain amyloid deposition assessed by PET scanning is a key secondary endpoint. 
Two studies (Chen et al 2015, Landau et al 2015) have shown that longitudinal change in 
brain amyloid plaque load over 2 years can be demonstrated using amyloid PET imaging. The 
data from these studies indicates that changes in amyloid deposition may be greater among 
non-demented elderly individuals with worsening cognitive function compared to stable 
cognitive function during a 2 year interval. Similar observations were reported from other 
prospective studies which have shown that high cerebral Aβ load in non-demented subjects 
was associated with greater decline in episodic and working memory and is demonstrable by 
18 months (Lim et al 2012). The current study enrolls non-demented patients regardless of 
their baseline amyloid status. Given that the expected rate of deposition of amyloid in this 
population is variable, this study will assess amyloid PET change and cognitive function over 
a 3 year period while the majority of patients are still likely to be continuing on study 
medication. The study will assess the change in a composite cortical florbetapir 18F 
standardized uptake value ratio (SUVr) as a measure of amyloid plaque load.
Instrumental activities of daily living (IADL) as assessed by Functional Activity 
Questionnaire (FAQ)
Performance of activities of daily living is an important factor that significantly impacts a 
patient’s quality of life. Intact activities of daily living (ADL) are often used as criteria to 
distinguish MCI from dementia. FAQ provides a standardized assessment of instrumental 
ADLs with high sensitivity to identify functional impairment. As functional changes in 
instrumental activities of daily living (IADL) that require higher cognitive ability are seen 
earlier in the dementia process, these will be evaluated using the Functional Activities 
Questionnaire (FAQ). This functional assessment of the patient using the FAQ will 


Novartis
Page 32
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
complement the GCCS by providing an additional tool to monitor cognitive function, physical 
health, and functional capacity (Castilla-Rilo et al 2007).
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
LCZ696 dose of 200 mg twice daily was chosen as the target dose because it delivers similar 
valsartan exposure (assessed by area under the curve (AUC)) as Diovan® (valsartan) 160 mg 
twice daily and is the approved target dose for patients with heart failure. Furthermore, 
biomarker analysis and modeling indicate that the 200 mg dose of LCZ696 delivers 
approximately 90% of its maximal NEP inhibition. Twice daily dosing schedule is considered 
necessary for sustained NEP inhibition over a 24-hour period and it is anticipated to reduce 
the incidence of hypotension in HF patients, particularly in elderly patients. LCZ696 200 mg 
bid has been utilized in the recently completed Phase 3 PARADIGM-HF trial in HFrEF, and 
Phase 2 trial in HFpEF (PARAMOUNT), as well as the currently ongoing Phase 3 
PARAGON-HF trial in HFpEF. The LCZ696 200 mg b.i.d dose was well tolerated and a 
significant majority of patients were maintained on this dose level in the completed studies.


Novartis
Page 33
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Dosing is based on the total amount of both components of LCZ696, that is, 24 mg/26 mg, 49 
mg/51 mg, and 97 mg/103 mg as sacubitril/valsartan sodium salt complex and is referred to as 
LCZ696 50 mg, 100 mg, and 200 mg respectively.
3.4
Rationale for choice of comparator
There is no proven therapy to date that has convincingly been shown to reduce morbidity and 
mortality in patients with HFpEF (Yusuf et al 2003, Cleland et al 2006, Massie et al 2008). 
Valsartan is being given to treat the comorbidities that are prevalent in HFpEF, such as 
hypertension (HTN), diabetes mellitus (DM), and coronary artery disease where there is an 
indication for RAS blocking therapy (McMurray et al 2012). Data from studies in patients 
with HFpEF suggest that background ACEi or ARBs for treating comorbidities is common 
practice, including the recent TOPCAT study where a RAS blocker was used in 85% of 
patients at baseline (Desai et al 2011). Valsartan was chosen as the RAS blocker comparator 
because it is one of the commonly prescribed ARBs, and the target dose of LCZ696 200 mg 
delivers systemic exposure similar to the target dose of valsartan 160 mg. Patients in both 
groups will receive a similar amount of valsartan, which will allow careful assessment of 
neprilysin inhibition on cognitive function and the sign/symptoms of HF. In the PARAGON-
HF study valsartan is also used as the comparator. Furthermore, a placebo comparator is not 
considered appropriate in this long term trial, as the comorbidities commonly present in 
HFpEF patients typically require RAS inhibition (i.e., ACEi or ARB).
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable
3.6
Risks and benefits 
LCZ696, through its unique mode of action potentiates beneficial endogenous vasoactive 
peptides via NEP inhibition while inhibiting the Renin Angiotensin System (RAS) via 
angiotensin II type 1 receptor blockade. Consistent with this mechanism of action, the 
recently completed landmark randomized trial (PARADIGM-HF, N=8442) demonstrated that 
LCZ696 was superior to enalapril (current standard of care) in reducing cardiovascular (CV) 
death and heart failure hospitalization in patients with HFrEF. The magnitude of these 
advantages of LCZ696 over an angiotensin converting enzyme (ACE) inhibitor was 
statistically significant and clinically relevant, particularly since the drug was compared with 
current standard of care with an established mortality benefit in HF patients (McMurray et al 
2014). In this study, compared with enalapril (ACEI), LCZ696 demonstrated a 20% risk 
reduction for HF hospitalization or CV death (primary endpoint, p = 0.0000002), 20% risk 
reduction in CV death alone (p=0.00004), and 21% risk reduction in HF hospitalization alone 
(p=0.00004), In addition, LCZ696 also demonstrated great benefit in symptom improvement, 
total HF hospitalization, all cause hospitalization and emergency room visits compared to 
enalapril.
The mechanism of action of LCZ696 suggests that it also may impact the suspected 
pathophysiology of HFpEF. In the Phase 2 PARAMOUNT study, 12 weeks of treatment with 
LCZ696 resulted in a significant reduction in N-terminal pro-brain natriuretic peptide (NT-
ProBNP) and the reduction was sustained at 36 weeks. Reductions in NT-proBNP have been 


Novartis
Page 34
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
associated with improved outcomes in patients with heart failure (Masson et al 2008).  NYHA 
class improved significantly and significant reductions in echocardiographic parameters of left 
atrial size were seen at 36 weeks supporting the hypothesis that LCZ696 might alter the 
pathophysiology and natural course of disease in HFpEF. LCZ696 was well tolerated in the 
completed Phase 2 trial in patients with HFpEF (PARAMOUNT) and Phase 3 trial in patients 
with HFrEF (PARADIGM-HF) with a safety profile similar to that of comparators.
Patients will be instructed not to take any RAS blockade medications (ACEi, ARB or renin 
inhibitor) on the day they start treatment run-in study drug to avoid excess RAS blockade. 
Concomitant ACEi or ARB will be replaced by study medication (valsartan). All patients will 
continue to receive RAS therapy (valsartan or LCZ696) for the entire study duration. All 
patients will be allowed to continue receiving the rest of their background CV medications.
The patient should be on an optimal medical regimen of diuretics and background
medications to effectively treat comorbidities, such as hypertension, diabetes mellitus, atrial 
fibrillation, and coronary artery disease.
PET scanning involves intravenous administration of radiotracers, but the exposure to 
radiation is very minimal as the dose of approximate 10 millicuries radiation is received at 
each PET scanning visit. Florbetapir 18F, similar to other radiopharmaceuticals, contributes to 
a patient’s overall long-term cumulative radiation exposure. 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria 
and close clinical monitoring.
Neprilysin (neutral endopeptidase or NEP) is one of several proteases capable of degrading 
Aβ. Although the relative contribution of neprilysin to Aβ clearance in humans is not 
understood, the potential exists for Aβ levels to be altered by inhibition of neprilysin. The 
clinical significance of this is unknown. Altered clearance of brain Aβ peptide has been 
suggested as a potential mechanism in the pathogenesis of Alzheimer’s disease.  Short term 
administration of LCZ696 400 mg once daily in healthy subjects for 14 days did n ot result in 
changes in CSF Aβ40 and Aβ42 concentrations, despite having measurable concentrations of 
LBQ657 (neprilysin inhibitor moiety of LCZ696) in the CSF relevant for neprilysin inhibition. 
The clinical relevance of the increase in CSF Aβ38 observed with LCZ696 is unknown. These 
observations suggest that enzymes and disposition pathways other than neprilysin appear to be 
more important in the clearance of CSF Aβ in humans.  Currently available data do not 
suggest that LCZ696 treatment in humans results in meaningful increases in CSF Aβ.  In 
clinical studies where patients with heart failure have been treated with LCZ696 for up to 4.5 
years, there was no increase of incidence of AD or dementia-related adverse events, though 
none of these studies was designed to evaluate the effect of LCZ696 on AD or dementia.  
In a large retrospective study it was observed that use of ACE inhibitors was associ ated with 
improvements in cognitive performance in patients with heart failure (Zuccala et al 2005). 
Similarly data from a small randomized trial indicate that in elderly hypertensive patients 
treatment with valsartan may be associated with improvement in some components of 
cognitive function (Fogari et al 2004). Although the long-term effects of treatment with 
LCZ696 on cognitive performance remains unknown, it is possible that an improvement in 
cardiovascular function as a result of treatment with LCZ696 might benefit cognition in 
patients with heart failure. 


Novartis
Page 35
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Since this is a long-term study, participating patients will benefit from careful monitoring and 
follow-up during the entire study duration regardless of whether they are receiving the study 
medication. In addition, patients can visit their doctors at an unscheduled visit as necessary.
4
Population
The study population will consist of male and female patients (≥60 years old) with chronic 
symptomatic HF (NYHA class II-IV). Eligible patients are those with the symptoms of HF, 
LVEF > 40%. 
The goal is to randomize a total of approximately 520 patients in more than 100 centers 
worldwide. With an expected screening and run-in failure rate of approximately 40%, it is 
estimated that approximately 870 patients will be screened.
A subset of about 430 randomized patients will be enrolled in the amyloid PET imaging 
substudy.
4.1
Inclusion criteria
To be eligible for inclusion in this study, patient must fulfill all of the following criteria:
1. Written informed consent including consent for APOE4 gene testing must be obtained 
before any assessment is performed.
2. Male or female patients aged ≥60 years of age.
3. Chronic heart failure with current symptom(s) (NYHA class II-IV) at Screening visit.
4. LVEF >40% 
a.
By any method using most recent assessment within 6 months prior to 
screening visit. OR
b. By an echocardiogram performed during the Screening visit, if previous 
assessment is not available.
5. NT-proBNP ≥ 125 pg/mL at Screening visit
6. Patient with evidence of adequate functioning (e.g.: intellectual, motor, visual and 
auditory) to complete the study assessments and has elementary education or 6 years 
of sustained employment.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Current acute decompensated HF requiring augmented therapy with diuretics, vasodilators 
and/or inotropic drugs.  If hospitalized for any medical conditions including heart failure 
patients should be clinically stable and be discharged from hospital for at least 2 weeks 
prior to screening.
2. Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other 
major CV surgery, or urgent percutaneous coronary intervention (PCI), carotid surgery or 


Novartis
Page 36
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
carotid angioplasty, history of stroke or transient ischemic attack within the 3 months prior 
to Screening visit or an elective PCI within 30 days prior to Screening visit.  
3. Patients with history of hereditary or idiopathic angioedema or angioedema related to 
previous ACEi or ARB therapies.
4. Patients with one of the following:
a.
Patients with serum potassium >5.2 mmol/L (mEq/L) at Screening visit
b. Patients with serum potassium >5.4 mmol/L (mEq/L) at any visit during run-in 
treatment period or at randomization visit
c.
Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or 
d. SBP <110 mmHg at Screening visit, or
e.
SBP <100 mmHg or symptomatic hypotension as determined by the investigator at 
Visit 103 or at randomization visit
f.
Body mass index (BMI) >45 kg/m2
5. Patients who require treatment with 2 or more of the following: an ACEi, an ARB or a 
renin inhibitor.
6. Patients with 
a.
known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative 
cardiomyopathy or
b. hemodynamically significant obstructive valvular disease.
7. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained 
ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate >110 
beats per minute.
8. Evidence of hepatic disease as determined by any one of the following: SGOT (aspartate
aminotransferase (AST)) or SGPT (alanine aminotransferase (ALT)) values exceeding 3 x 
the upper limit of normal (ULN), bilirubin >1.5 mg/dl at screening visit.
9. Patients with one of the following:
a.
eGFR <30 mL/min/1.73m2 as calculated by the Modification of Diet in Renal Disease  
(MDRD) formula at Screening visit, or
b. eGFR <25 mL/min/1.73m2 at Visit 103 or at end of run-in/randomization visit, or
c.
eGFR reduction >35% (compared to Visit 1) at Visit 103 or Visit 199/201
10. Presence of known functionally significant bilateral renal artery stenosis
11. MMSE score <24 at screening visit 
12. Patients with a clinical diagnosis of Alzheimer’s disease or other dementia syndromes or
any indication for or current treatment with cholinesterase inhibitors and/or another 
prescription AD treatment (e.g. memantine).
13. Any history of medical or neurological condition likely to affect the participant’s 
cognition (e.g., clinically significant brain trauma with loss of consciousness >3 minutes
within 6 months prior to screening, Huntington’s disease, Parkinson’s disease, Lyme’s 
disease, syphilis, HIV dementia, uncontrolled seizure disorder) or clinically significant 
abnormalities in thyroid function tests, Vitamin B12 or folate deficiency requiring 
treatment at screening (Patients who are adequately treated may be included at 
investigator discretion).


Novartis
Page 37
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
14. Inability to perform cognitive battery or other study evaluations based on significant 
motor (e.g. hemiplegia, muscular-skeletal injury) or sensory (blindness, decreased or 
uncorrected visual or auditory acuity) skill.
15. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this 
ideation occurred in the past 6 months, or “yes” on any item of the Suicidal Behavior 
section, except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the 
Suicidal Behavior section), if this behavior occurred in the past 2 years.
16. Clinically significant cerebral pathology, for example large cerebral aneurysm, space 
occupying lesion etc. that may impact cognition as assessed by MRI central reader.
17. Any contraindication or intolerance to MRI or PET investigations (with fluorinated 
radiopharmaceuticals), including but not limited to: presence of pacemakers not 
compatible with MRI, aneurysm clips, artificial heart valves, ear implants, or foreign 
metal objects in the eyes, skin, or body that would contraindicate an MRI scan; or any 
other clinical history or examination finding that, in the judgment of the investigator, 
would pose a potential hazard in combination with MRI.
18. Previous or planned Nuclear Medicine Radiology research that will exceed the dosimetry 
acceptable exposure in the country, when adding the scheduled study PET scans.
19. 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.
20. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of study drugs, including but not limited to history 
of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within 
the last 5 years
21. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes.
22. History of non-compliance to medical regimens and patients who are considered 
potentially unreliable.
23. History or evidence of drug or alcohol abuse within the last 12 months
24. History or presence of any other disease with a life expectancy of <3 years
25. Women of child bearing potential defined as all women physiologically capable of 
becoming pregnant. Women are considered post-menopausal and not of child bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea with an 
appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have 
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment.
26. Persons directly involved in the execution of this protocol
27. Use of other investigational drugs at the time of enrollment, or within 30 days, or within 5 
half-lives of enrollment, whichever is longer.
28. Patients who previously received treatment with LCZ696.
29. Patients who are on current treatment with sedative hypnotics, selective serotonin re-
uptake inhibitors (SSRIs, e.g. paroxetine, sertraline, citalopram, escitalopram), serotonin 


Novartis
Page 38
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
norepinephrine re-uptake inhibitors (SNRIs, e.g. venlafaxine, duloxetine), atypical 
antipsychotics, and low dose tricyclic anti-depressants should be on a stable regimen 
(defined as no change to the participant’s medication intake pattern rather than adherence 
to the prescribed regimen) for at least 12 weeks prior to screening.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The sponsor will provide the following study drugs:
Single-blind treatment run-in period
All eligible patients will enter a treatment run-in epoch where they will receive valsartan 
followed by LCZ696.
The following study drugs will be provided:

Valsartan 40 mg and 80 mg tablets

Placebo to match valsartan 40 mg and 80 mg tablets

LCZ696 50 and 100 mg tablets

Placebo to match LCZ696 50 mg and 100 mg tablets 
The use of an ACEi, ARB or renin inhibitor in addition to study drug during the treatment 
run-in epoch is strictly prohibited.
Randomized treatment period
All eligible patients will be randomized to either LCZ696 200 mg bid (dose level 3) or 
valsartan 160 mg bid (dose level 3). In addition, patients will continue to take optimal 
background therapy to treat co-morbid conditions, as considered appropriate by the 
investigator and in accordance with local standard, with the exception of an ACEi or ARB as 
this will be replaced by study drug. The use of an open-label ACEi, an ARB or renin inhibitor
in addition to randomized study drug is strictly prohibited.
The following study drugs will be provided:

LCZ696 50 mg, 100 mg and 200 mg tablets

Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets

Valsartan 40 mg, 80 mg and 160 mg tablets

Placebo to match valsartan 40 mg, 80 mg, 160 mg tablets
In some countries where LCZ696 is approved the 50, 100 and  200 mg doses of LCZ696 are 
referred as 24/26 mg (sacubitril/valsartan), 49/51 mg (sacubitril/valsartan) and, 97/103 mg 
(sacubitril/valsartan), respectively.
All study medications will be supplied in bottles. Sufficient medication will be provided for 
the treatment according to study protocol, including additional medication to allow for 


Novartis
Page 39
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
delayed visits. Medication labels will be in the local language and comply with the legal 
requirements of the country. They will include storage conditions for the drug and the 
medication number, but no information about the patient.
5.1.2
Additional treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
Patients will be assigned to one of the following two treatment arms in a ratio of 1:1 at the 
randomization visit.

LCZ696 200 mg bid

Valsartan 160 mg bid
5.3
Treatment assignment and randomization 
At Visit 199, patients will be scheduled to undergo a PET scan.  PET scan images will be 
centrally read by the imaging vendor to classify a patient as amyloid positive or amyloid 
negative. Patients will be stratified at Visit 201 according to their amyloid status within 3 to 5 
days after acquisition of the baseline PET image. The investigator will remain blinded to the 
amyloid status. Since it may take several days to obtain results, it is recommended that the site 
take this into consideration when scheduling Visit 201, while keeping the patient on study 
medication.  All eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of 
investigational treatment to be dispensed to the patient. The randomization number will not be 
communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified by three factors, age (<75, ≥75 years old), MMSE summary 
score at baseline (<28, ≥28), and brain amyloid status (unknown, amyloid (+) or amyloid ( -)).  
Note that patients who do not participate in the PET imaging sub-study will be classified as 
having unknown amyloid status.
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Randomization Group.


Novartis
Page 40
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
5.4
Treatment blinding
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blinded to the identity of the treatment from the time of randomization until database lock, 
using the following methods: 

Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone involved in the study with the following exceptions: 
1. The independent and unblinded statistician, programmer and data personnel who are 
involved in preparing safety review reports for the Data Monitoring Committee 
(DMC).  These personnel will not be involved in any other trial conduct related 
activities. 
2. The DMC members who review the interim safety data.

The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, labeling, schedule of administration, appearance, taste 
and odor.

A double-dummy design is used because the identity of the investigational treatment 
cannot be disguised due to their different forms.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9), at the time 
of safety and efficacy data review by the DMC and at the conclusion of the study. An 
assessment will be done by the appropriate site personnel and the Medical Lead (or designee) 
after treatment code break and the patient must discontinue the study treatment.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed of the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form (ICF), the patient is assigned the next sequential 
number by the investigator. The investigator or his/her staff will contact the IRT and provide 
the requested identifying information for the patient to register them into the IRT. The site 
should select the Case Report Form (CRF) book with a matching Subject Number from the 
Electronic Data Capture (EDC) system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Disposition CRF. Patients that take treatment run-in study drug and are not randomized are 
considered run-in failures. The reason for failure to randomize will be entered on the Run-in 
Disposition CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.


Novartis
Page 41
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the two treatment arms and a dose level. 
Investigator staff will identify the study drug package(s) to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing 
the package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
subject number.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization (CPO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment 
Novartis will supply the investigators with all study medications required for the course of the 
study. Patients will be provided with medication packs containing study drug corresponding 
to their assigned treatment arm and dose level, sufficient to last until the next scheduled office 
visit. In order to adequately blind the study, patients will be required to take a total of two 
tablets (one tablet from the LCZ696/LCZ696 matching placebo pack and one tablet from the 
valsartan/valsartan matching placebo pack) twice a day for the duration of the study. Table 5-
1 summarizes the study drug that will be taken during the run-in epoch and Table 5-2
summarizes the study drug that will be taken during the randomized treatment epoch.


Novartis
Page 42
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Table 5-1
Study drug dispensed for the treatment run-in epoch by study visit
Study visit
Dose level
LCZ696
Valsartan
101a
1
50 mg matching placebo bid
40 mg bid
102
2a
100 mg matching placebo bid
80 mg bid
103
2a
100 mg bid
80 mg matching placebo bid
a Investigators may consider initiating treatment on dose level 2 (valsartan 80 mg bid and 100 mg matching 
placebo bid) at Visit 102 (see Figure 3-2) in those patients being treated with at least the minimum dose of ACEi
or ARB at Visit 1 (see Table 3-1); bid – twice daily dosing
Table 5-2
Study drug dispensed during the randomized treatment epoch by 
study visit
Study visit
Dose level
LCZ696
Valsartan
201
3a
200 mg or matching 
placebo bid
160 mg or matching 
placebo bid
Available for any visit 
after Visit 201
2b
100 mg or matching 
placebo bid
80 mg or matching 
placebo bid
Available for any visit 
after Visit 201
1c
50 mg or matching 
placebo bid
40 mg or matching 
placebo bid
a This dose level must be maintained for as long a duration as possible. If down-titration is necessary due to side 
effects, the patient should be re-challenged as soon as medically possible per the investigator’s judgment.
b Only if dose level 3 is not tolerated despite modification of other concomitant medications.
c Only if dose levels 2 or 3 are not tolerated despite modification of other concomitant medications.
bid – twice daily dosing
Patients will be instructed to take their morning study drug doses between 06:00 and 09:00 (6-
9 AM) and their evening study drug doses between 18:00 and 21:00 (6-9 PM). The study 
drugs should be taken with water, with or without food. If the patient misses taking any study 
drug dose, he/she should take it as soon as possible, unless it is almost time for the following 
scheduled dose. In this case, the patient should skip the missed dose and return to his/her 
regular study drug administration schedule.
All kits of investigational treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator should promote compliance by instructing the patient to take the study drug
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the investigator 
if he/she is unable for any reason to take the study drug as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
For patients who are unable to tolerate the protocol-specified dosing scheme, dose level 
adjustments and interruptions of study treatment are permitted in order to keep the patient on 
study drug. The following guidelines should be followed:
Every attempt should be made to maintain patients at the target study drug dose level 
throughout the trial. If the patient cannot tolerate the target study drug dose level, the 
investigator should consider adjusting or stopping concomitant background medications for 
co-morbid conditions, before considering down titration to the next lower dose level of study 


Novartis
Page 43
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
drug. For hypotension or dizziness, consideration should be given to reducing the dose or to 
stopping concomitant medications that lower BP, or reducing the dose of diuretic.
There are three dose levels of study medication (both LCZ696 and Valsartan) as depicted in 
Table 5-2 with target dose level as ‘3’. Two other dose levels (dose level 1 and 2) are 
available for down-titrating the patient depending on the clinical need and investigator’s 
discretion.
The target dose level for this study is LCZ696 200 mg bid and valsartan 160 mg bid (Dose 
level 3).
Adjustment of study drug dose level
If despite adjustment of concomitant medications per the guidance provided and the situation 
is not being corrected, then the investigator may consider down titrating the study drug dose 
level according to the following instructions:
During the randomized treatment epoch, 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 Appendix 3, Appendix 4, and Appendix 5. If down titration is necessary, 
the patient should be down titrated to the next lower study drug dose level (Table 5-2). The 
patient may continue receiving the lower dose level for a recommended period of 1 to 4 weeks 
before being re-challenged at the next higher dose level. For example, a patient who 
encounters tolerability problems at the dose level 3 (the target study drug dose level), should 
receive the study drug at dose level 2 for 1 to 4 weeks at the discretion of the investigator. 
Then, he/she should be re-challenged with up-titration back to dose level 3.
If the tolerability issues are not alleviated despite down titration by one dose level, the 
investigator may down titrate further to the next lower study drug dose level for 1 to 4 weeks, 
up to temporary discontinuation of the study drug. Again, once stable, the patient should be 
re-challenged with up titration to the next higher dose level every 1 to 4 weeks in an attempt 
to bring back the patient gradually to dose level 3 (the target study drug dose level). The 
investigator may choose the next dose level for down- or up-titration according to his or her 
judgment (Table 5-2). As discussed in Section 5.5.4, the IRT system should be contacted to 
register any changes in the patient’s study drug dose level, including in cases of temporary 
and permanent discontinuation of the study drug, and to obtain the medication numbers of the 
study drug supplies required for the new study drug dose level.
In some instances, according to the safety and tolerability criteria and the investigator’s 
judgment, dose level 1 or 2 could be maintained if he/she considers that the patient’s 
condition would not allow any further up titration to the target dose level of study drug (dos e 
level 3). In this case, it would be acceptable to maintain the patient at dose level 1 or level 2, 
whichever is the higher and tolerated dose level by the patient. The adjustment of the study 
drug dose levels must be recorded on the Dosage Administration Record CRF.
Study drug restart after temporary treatment interruption
Study drug should be reintroduced in those patients who temporarily discontinue it as soon as 
medically justified in the opinion of the investigator. 


Novartis
Page 44
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
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 dose 
level (Table 5-2) per his/her medical judgment. If tolerated, the patient should be up-titrated to 
a dose level every 1 to 4 weeks to the target dose level 3, as per the investigator’s judgment. 
Should the patient not tolerate the re-start study drug dose level, he/she may be down-titrated 
again (if appropriate) or temporarily discontinue the study medication again and a new 
attempt to up-titrate or reintroduce the study drug could be considered by the investigator as 
soon as medically justified in his/her judgment.
The use of an open-label ACEi, ARB or a renin inhibitor is strongly discouraged while patient 
is off study drug. However, if for any reason a patient off study drug has started open -label
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 5-3).
These changes must be recorded on the Dosage Administration Record CRF.
In case of pregnancy discovered during the screening or run-in epochs or during double-blind 
epochs, the patient will be withdrawn from the study immediately. 
See Section 7.7 for further details on pregnancies and reporting guidelines.
5.5.6
Rescue medication
Guidance on handling hyperkalemia, hypotension, and renal dysfunction will be provided to 
investigators (Appendix 3, Appendix 4, and Appendix 5 respectively). Patients may receive 
open-label ACEis, ARBs or a renin inhibitor during the study ONLY if the study drug has 
been temporarily or permanently discontinued. If for any reason a patient off study drug has 
started open-label treatment with an ACEi it must be discontinued ≥36 hours prior to 
restarting study drug.
Use of rescue medication must be recorded on the Concomitant medications/Significant non-
drug therapies CRF.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient is enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
Drugs known to affect cognition:
Initiation of cholinesterase inhibitors or other prescription, AD treatments, anti-depressant or 
psychotropic medication should be documented in the concomitant medication page. The 


Novartis
Page 45
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
relevant follow up questionnaire CRF page should be completed providing detail of the 
indication for initiation of such therapies and the clinical investigations and diagnosis.
Sedative hypnotics may be allowed if participants are currently on a stable regimen (defined 
as no change to the participant’s medication intake pattern rather than adherence to the
prescribed regimen) for at least 12 weeks prior to screening. If initiated during study these 
must be withheld for 72 hours unless maintained on a stable regimen for 6 weeks prior to 
scheduled cognitive assessment.  
Selective serotonin re-uptake inhibitors (SSRIs, e.g. paroxetine, sertraline, citalopram, 
escitalopram), serotonin norepinephrine re-uptake inhibitors (SNRIs, e.g. venlafaxine, 
duloxetine), atypical antipsychotics, and low dose tricyclic antidepressants are allowed 
provided participants are currently treated with a stable regimen for at least 12 weeks prior to 
screening.
Medications known to raise potassium levels
Potassium-sparing diuretics, potassium supplements, mineralocorticoid receptor antagonist 
(MRA) and any other medications known to raise potassium levels should be used with 
caution while the patient is receiving the study drug due to the increased possibility of 
occurrence of hyperkalemia. The investigator is encouraged to assess patients’ potassium 
levels regularly, especially in those who are receiving these medications.
Phosphodiesterase-5 (PDE-5) inhibitors
PDE-5 inhibitors should be used with caution while the patient is receiving study medication 
due to the increased possibility of the occurrence of hypotension.
Nesiritide and intravenous (IV) nitrates
The concomitant administration of LCZ696 with nesiritide and IV nitrates has not been 
studied. In the event a study patient requires the concomitant administration of nesiritide 
and/or IV nitrates with the study medications, the investigator should consider starting them at 
a lower dose or slower infusion rate while monitoring the patient’s BP carefully.
HMG-CoA reductase inhibitors
Caution is recommended when co-administering LCZ696 with statins because of the potential
to raise plasma statin levels.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-3 is NOT allowed after the start of study drug due 
to safety reasons, unless the actions specified are taken.
Table 5-3
Prohibited treatment
Medication
Action to be taken
Any ACEi
Discontinue study drug. The open label ACEi must be stopped for ≥36 hours 
prior to re-initiation of study drug
Any ARB
Discontinue study drug. The open label ARB must be stopped prior to re-


Novartis
Page 46
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Medication
Action to be taken
initiation of study drug
Any Renin inhibitor
Discontinue study drug. The open label renin inhibitor must be stopped prior to 
re-initiation of study drug
ACEi – angiotensin converting enzyme inhibitor; ARB – angiotensin receptor blocker
ACEis, ARBs and renin inhibitors
The concomitant use of open-label ACEis, ARBs or a renin inhibitor is strictly prohibited 
while the patient is receiving study drug. If there is a strong need for open label use of ACEi, 
ARB or renin inhibitor, then study drug must be temporarily discontinued. If the patient is to 
be started on open-label ACEi, the study drug must be stopped for ≥36 hours prior to 
initiating ACEi. The same is true for restarting the study medication for those patients who are 
on open label ACEi therapy. ARBs or a renin inhibitor should be stopped prior to resuming 
study drug.
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un -
blinding can be performed at any time. 
An assessment will be done by the appropriate site personnel and the Medical Lead (or 
designee) after an emergency treatment code break and the patient must discontinue the study 
treatment.


Novartis
Page 47
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment 
At the end of the study, all patients will return for the final end of study (EOS) visit (Visit 299) 
and be asked to return the remaining study drug. The study will be completed once all 
assessment up to the last participant reaches Month 36 (Visit 299) or a recommendation is 
made by the DMC to prematurely stop the study. 
The study will be complete when the last patient enrolled has completed their last visit.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment occurs when study drug is stopped earlier than the protocol 
planned duration, and this 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 risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances:  

Patient wish

Pregnancy (see Section 6.5.9 and Section 7.7)

Use of prohibited treatment as per recommendation in Table 5-3

Any situation in which study participation might result in a safety risk to the patient
However; study treatment discontinuation does not constitute withdrawal from the study and 
should not lead to the patient being withdrawn from the study. 
Every effort should be made to complete end of treatment (EOT) assessments within 3 months 
of the last study drug dose for patients who have discontinued study drug permanently. For 
patients who terminate the study early, they are expected, and should be encouraged, to attend 
all the protocol specified study visits and perform all measurements as stipulated in the visit 
schedule (Table 6-1) and remain in follow up for the duration of the trial. 
If they fail to return for these assessments for unknown reasons, every effort shou ld be made 
to contact them. If the patient cannot or is unwilling to attend any visit(s), the site staff should 
maintain regular telephone contact with the patient, or with a person pre-designated by the 
patient. This telephone contact should preferably be done according to the study visit schedule.
The investigator must contact the IRT to register the patient’s discontinuation from study 
treatment and must determine the primary reason for the patient’s premature discontinuation 
of study treatment and record this information on the Dosage Administration eCRF.
The emergence of the following circumstances will require permanent study drug 
discontinuation:


Novartis
Page 48
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320

Withdrawal of informed consent

Investigator thinks that continuation would be detrimental to the patient’s well-being

Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically 
significant angioedema should be thoroughly evaluated by the investigator
Use of an open label ACEi, ARB or renin inhibitor will require temporary or permanent 
discontinuation (study drug may be restarted once these medications are stopped).
Study drug may be discontinued at the investigator’s discretion if any of the following occurs:

Any severe suspected drug-related AE

Any other protocol deviation that results in a significant risk to the patient’s safety.
The appropriate personnel from the site and Novartis will assess whether study drug should be 
permanently discontinued for any patient whose treatment code has been broken inadvertently 
for any reason.
If study drug discontinuation occurs because treatment code has been broken, please refer to
Section 5.5.9.
The details about study assessment to be completed for patients who permanently 
discontinued study drug are provided in Section 6.
5.6.3
Withdrawal of informed consent
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason 
at any time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1.


Novartis
Page 49
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
5.6.4
Loss to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit-risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. 
After randomization, study drug discontinuation (permanent or temporary) for any reason 
does not constitute withdrawal from the study and should not lead to the patient being 
withdrawn from the study. Patients who discontinue study drug should be requested to return 
for an End of Treatment visit (EOT) in which all of the assessments outlined in Table 6-1 will 
be performed.
Patients who prematurely discontinue the study for any reason should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the end of study visit will 
be performed. At the end of study visit, all dispensed investigational product should be 
reconciled and the adverse event and concomitant medications reconciled on the CRF.
Every effort should be made to complete end of treatment (EOT) assessments within 3 months 
of the last study drug dose for patients who have discontinued study drug permanently. 
Patients who terminate study drug early are expected, and should be encouraged to, attend all 
the remaining protocol specified study visits and perform all measurements as stipulated in 
the visit schedule (Table 6-1). 
For EOT / End of Study (EOS) visit, the PET and MRI scans will only be performed if prior 
scans were performed more than twelve months ago. The CCB, 
 FAQ, 
 
assessments will only be performed if prior assessments were performed more than three 
months ago.
Documentation of attempts to contact the patient should be recorded in the source 
documentation.




Novartis
Page 51
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Table 6-1
Assessment schedule
Epoch
Screen
ing
Active Run-in
Randomized Treatment
Visit
1
101
102
103
199/ 
201††
202
203
2041
205
2061
207
2081
209
2101, 
2121
211
EOT3
UNS
2997
End 
of 
Study
Week (w)
-11/-7
-8/-4
-6/-3
-4/-2
0
13
26
39
52
65
78
91
104
117,
143
130
156
Month
3
6
9
12
15
18
21
24
27, 33
30
36
Informed consent
DS
X
Inclusion/Exclusion criteria
DS
X
X
X
X
X
Safety monitoring criteria
DS
X
X8
X
X
Demography/Relevant 
Medical history/Current 
medical conditions
DS
X
Heart Failure/ Smoking 
history/Alcohol history 
DS
X
Echocardiography4
DS
X
Concomitant medications
DS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NYHA classification 
(HF signs/symptoms)
DS
X
X
X
X
X
X
X
X
X
X
Florbetapir 18F PET scan
DS
Xλ
X
X5
X5
MRI Scan15
DS
X
X
X5
X5
Cognitive Assessment 
(CogState Battery)6,12
DS
X
X
Xλ
X
X
X
X
X
X
X


Novartis
Page 52
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Epoch
Screen
ing
Active Run-in
Randomized Treatment
Visit
1
101
102
103
199/ 
201††
202
203
2041
205
2061
207
2081
209
2101, 
2121
211
EOT3
UNS
2997
End 
of 
Study
Week (w)
-11/-7
-8/-4
-6/-3
-4/-2
0
13
26
39
52
65
78
91
104
117,
143
130
156
Month
3
6
9
12
15
18
21
24
27, 33
30
36
Functional Activity 
Questionnaire (FAQ) 6
DS
X
Xλ
X
X
X
X
X
X
X
Physical Exam9
S
X
X
X
X
X
X
X
X
X
X
X
X
Height
DS
X
Weight
DS
X
X
X
X
X
X
X
X
X
X
Abbreviated laboratory 
evaluations10
DS
X8
X
X
X
X
X
X
Local laboratory11
(X)
(X)
(X)
(X)
Vitamin B12 and Folate
S
X
Thyroid stimulating hormone
S
X
FSH2
S
X
APOE4 genotyping/
13
DS
X
NT-proBNP14
DS
X
Dispense study medication
S
X
X
X
Xλ
X
X
X
X
X
X
(X)
Contact IVRS
S
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Accountability
DS
X
X
X
X
X
X
X
X
X
X
(X)
X
Plasma -amyloid16
DS
X
Xλ
X
X
X
X
X


Novartis
Page 53
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Epoch
Screen
ing
Active Run-in
Randomized Treatment
Visit
1
101
102
103
199/ 
201††
202
203
2041
205
2061
207
2081
209
2101, 
2121
211
EOT3
UNS
2997
End 
of 
Study
Week (w)
-11/-7
-8/-4
-6/-3
-4/-2
0
13
26
39
52
65
78
91
104
117,
143
130
156
Month
3
6
9
12
15
18
21
24
27, 33
30
36
Screening disposition
DS
X
Run-in disposition
DS
X
Treatment disposition
DS
X
X
DS= assessment to be recorded in clinical database; S= assessment to be recorded on source document; UNS = unscheduled visit;
EOT=(end of treatment); Patients will be contacted for safety evaluations during the 30 days following the last administration of study treatment
(X) = optional assessment
††= Visit 199/201 (end of treatment run-in) will be completed for all patients who enter the treatment run-in epoch. For patients who discontinue during the 
treatment run-in epoch, Visit 199 will be their discontinuation visit. For patients that have completed a PET scan and are randomized at Visit 201, procedures 
marked as ‘λ’ will be performed.
1 Telephone visit
2 Female subjects only with oophorectomy without hysterectomy.
3 If patient discontinues study drug permanently these assessments should be done within 3 months of last dose.
4 Qualifying LVEF measurements/documentation will be based on locally obtained most recent assessments performed ≤ 6 months prior to Visit 1. If an EF 
assessment performed ≤ 6 months prior to Visit 1 is not available, an echo must be performed during the Screening epoch.
5 The PET and MRI scans will be done at EOT/EOS only if prior scans were performed more than twelve months ago.
6 The CCB, 
 FAQ, 
 will be done at EOT/EOS only if prior assessments were performed more than three months ago
7 Visit 299 (end of study visit) will be completed for all patients that enter the randomized treatment epoch.
8 Serum potassium and eGFR to be performed at Visit 102 only if patient enters the run-in epoch at Visit 101.
9 Complete physical exam will be performed at Screening Visit 1, EOS, and EOT, all other visits will be a short physical exam.
10 Abbreviated laboratory assessments includes: serum creatinine, potassium and eGFR
11 Serum potassium and serum creatinine for eGFR. If patient enters run-in period at Visit 102, laboratory evaluation at this visit is not required
12 Cognitive assessments should ideally be administered by the same assessor in a quiet environment and prior to any other clinical assessments scheduled 
during the day
13 If the PG sample is not collected at Visit 201, it may be obtained at any visit thereafter and is only analyzed in patients consenting to the PG analysis
14 NT-proBNP will be analyzed in serum and collected as part of the clinical chemistry sample
15 MRI scans at Visit 207 and Visit 299 are performed only in patients participating in the PET substudy
16 Plasma β-amyloid will be assessed only in patients participating in the PET substudy






Novartis
Page 56
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
5. International Shopping List Test (ISLT) is a verbal list learning paradigm shown to assess 
verbal learning. 
6. The International Shopping List Test delayed recall (ISLT-DR) is a delayed recall 
condition from a verbal list learning paradigm shown to assess verbal memory.
7. The Groton Maze Learning Test (GMLT) is a hidden pathway maze learning paradigm 
shown to assess executive function.
The individual cognitive functions measured by the CogState cognitive battery can be 
organized into three main cognitive domains; 
1. Attention: defined by performance on the Detection, and Identification tests 
2. Episodic Memory: defined by performance on the CPAL, ISLT and, ISLT-DR
3. Executive function: defined by performance on the GMLT and ONB test  
Performance across these three domains can then be organized to provide a measure of 
general cognitive function.
These individual cognitive functions and their related cognitive domains have been selected 
for the current study on the basis that they have been shown to be relevant to characterizing 
the cognitive impairment that can occur in patients with heart failure and underlying CV
disease (Bauer et al 2011). They also have been shown to be associated with both absolute 
levels of amyloid and rates of changes in amyloid deposition in older adults (Lim et al 2012). 
The cognitive test battery evaluates the most relevant cognitive domains associated with 
changes in brain Aβ and changes as a result of progressive CV disease.
The cognitive tests that will be utilized in this study exhibit appropriate sensitivity to detect 
changes that would occur in the early, prodromal stage of AD, especially in patients positive 
for amyloid (Lim et al 2014).
Each of the cognitive tests in the CCB will be administered electronically to patients using a 
computer or tablet in an area suitable for testing without distraction. While subjects 
themselves perform the tests on the computer or tablet, this performance is guided by an 
appropriately trained and credentialed rater. The electronic administration ensures standard 
administration of tests and also means that the CCB can be administered with high fidelity by 
non-expert but appropriately trained clinical staff (e.g., research assistants or nurses).  
Assessment with the CCB should take place in a location free from distraction and all site 
staff nominated to administer the CCB will undergo specific training to ensure that they 
understand the testing software, the testing processes, the administration of each test and the 
transfer of test results to CogState. Further details about CogState battery will be provided in 
CCB manual.
The cognitive test battery will be administered at Screening visit (Visit 1), Visit 103, and 
randomization visit (Visit 201), and throughout the duration of the study at 6 month intervals, 
including the end of treatment visit (if prior assessments were performed more than three 
months ago) and end of study visit (Visit 299).


Novartis
Page 57
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6.4.2
Individual cognitive domains
Change from baseline in individual cognitive domains (memory, executive function, and 
attention) as assessed by composite z-scores by individual components of the cognitive 
assessment battery at 3 years will be evaluated.  
6.4.4
Instrumental activities of daily living as assessed by functional activity 
questionnaire
The functional activities questionnaire will be used as a standardized assessment of activities 
of daily living. This questionnaire is typically used to distinguish normal subjects from 
subjects with mild to moderate cognitive impairment. FAQ evaluation will be performed at 
Screening visit (Visit 1), randomization visit (Visit 201), at 6 months (Visit 203), 12 months 
(Visit 205), 18 months (Visit 207), 24 months (Visit 209), 30 months (Visit 211), end of 
treatment visit (if prior assessments were performed more than three months ago), and at 36 
months end of study (Visit 299). The changes from baseline to 3 years will be analyzed.
6.4.5
Appropriateness of efficacy assessments 
6.4.5.1
Cognitive function assessment 
The comprehensive battery of cognitive tests has been selected as the primary endpoint for 
this study as it will provide a measure of general cognitive function based on the performance 
in working memory, executive function, psychomotor speed, visual attention, visual episodic 
memory, verbal learning and delayed verbal recall. 
The CogState Cognitive Battery (CCB) will be used to measure these cognitive domains 
because the performance measures from tests of these cognitive functions have been validated 
extensively, including in older patients with heart failure (Clark and McDougall 2006), 
healthy older individuals with increased levels of amyloid (Lim et al 2014) and in older 
patients with mild cognitive impairment and clinically classified dementia (Maruff et al 2013).  
Each test in the CCB has also been designed specifically for the repeated administration 
necessary in clinical trials in that they are brief to administer, reliable and that once they are 
learned, repeated administration is not associated with performance improvement, even over 
relatively short retest intervals (e.g. 1-hour) (Maruff et al 2013, Mielke et al 2014).  This 
validity, brevity and repeatability has meant the performance on the CogState tests is sensitive 


Novartis
Page 58
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
to true cognitive change (improvement or decline) in response to disease progression or 
treatment with pharmaceutical or surgical intervention in various disorders, diseases and 
injuries. 
When considered together the measurement of cognitive function using the CCB enables 
optimal evaluation of any cognitive decline or cognitive improvement associated with 
LCZ696 treatment.
6.4.5.2
Individual cognitive domains
In addition to an overall cognitive function assessment using the GCCS, the three main 
cognitive domains comprising the GCCS, attention, memory, and executive function, will be 
further analyzed independently.  
These individual cognitive functions and their related cognitive domains have been selected 
for the current study on the basis that they have been shown to be relevant to characterizing 
the cognitive impairment that can occur in patients with heart failure and underlying CV 
disease (Bauer et al 2011). They also have been shown to be associated with both absolute 
levels of amyloid and rates of changes in amyloid deposition in older adults (Lim et al 2012). 
The cognitive tests that will be utilized in this study exhibit appropriate sensitivity to detect 
changes that would occur in the early, prodromal stage of AD, especially in patients positive 
for amyloid (Lim et al 2014).  The cognitive test battery evaluates the most relevant cognitive 
domains associated with changes in brain Aβ and changes that may occur as a result of 
progressive CV disease.
6.4.5.4
Instrumental activities of daily living as assessed by functional activity 
questionnaire
The functional activities questionnaire (FAQ) will be used as a standardized assessment of 
instrumental activities of daily living (IADL; Pfeffer et al 1982, Teng et al 2010). This 
questionnaire is typically used to distinguish normal subjects from subjects with mild to 
moderate cognitive impairment. The test is made up of 10 questions that reflect a subject’s 
ability to perform activities of daily living and to function independently. Test scores range 
for 0 to 30, with a 0 score representing no impairment and a 30 score, as severely impaired. 
Each of 10 questions is scored from 0, representing normal to 3, dependent on someone else 
to perform the activity.  The FAQ should be administered to the subject and will provide an 
assessment of patient’s physical and social functioning.






Novartis
Page 61
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
A short physical exam will include the examination of general appearance 
 
. A short physical exam will be conducted at all visits starting from 
Visit 102 except where a complete physical examination is required (see Table 6-1). 
Information from all physical examinations must be included in the source documentation at 
the study site. Significant findings that are present prior to signing informed consent must be 
included in the Medical History part of the CRF. Significant findings made after signing the 
informed consent which meet the definition of an AE must be recorded on the AE section of 
the CRF.
6.5.7
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured.


Novartis
Page 62
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320


Novartis
Page 63
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6.5.8.3
Plasma beta-amyloid
Plasma β-amyloid will be assessed in patients in the PET substudy from select centers. Blood 
sample for plasma β-amyloid will be taken at Visit 1 (screening), 199/201 (randomization), 
Visit 202 (Week 13), Visit 205 (Week 52), Visit 209 (Week 104), end of treatment (EOT), 
and Visit 299 (Week 156).
6.5.8.4
eGFR
Estimated eGFR will be calculated by the central or local laboratory using the following 
MDRD formula   (Stevens et al 2006): 
Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154 × (age in years)
-0.203 × (0.742 if female) or × (1.212 if black), where SCr is the standardized serum creatinine 
value.
6.5.8.5
APOE4 genotyping
The APOE4 gene has been identified as a genetic marker that predicts predisposition to 
cognitive decline and Alzheimer’s disease (Corder et al 1993). To control for this 
predisposing factor, patients will be asked to provide blood samples for genotyping which will 
include assessment of their APOE4 genotype so that genetic predisposition is taken into 
account when assessing the cognitive function of the study participants. APOE4 genotyping 
will be done at Visit 199/201 in all patients. The sites will remain blinded to the APOE4 status 
during the study.
6.5.8.6
Other lab assessments
Other laboratory tests that will be performed at Visit 1 are:

NT-proBNP
NT-proBNP will be performed by the central lab in all patients at Visit 1.

Thyroid stimulating hormone (TSH)

Vitamin B12 and Folate

Follicle stimulating hormone (FSH)
FSH levels will be measured to confirm menopausal status in patients who have 
undergone oophorectomy without hysterectomy.
6.5.9
Pregnancy and assessments of fertility 
Women of child bearing potential defined as all women physiologically capable of becoming 
pregnant are excluded. FSH levels, determined only in women who underwent oophorectomy
without hysterectomy at Screening visit (Visit 1), should be in a range consistent with 
menopausal status for the patient to continue into the run-in period.


Novartis
Page 64
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6.5.11
Appropriateness of safety measurements 
Changes in amyloid accumulation as assessed by PET imaging are assessed as a safety 
endpoint in this study.
Amyloid PET imaging
A key secondary objective is to evaluate the effect of LCZ696 compared to valsartan on Aβ 
deposition in the brain assessed by PET imaging at 3 years. Changes in amyloid plaque 
deposition over time will be assessed using florbetapir 18F. Longitudinal studies have 
demonstrated the usefulness of this tracer to detect changes in amyloid plaque load over a 2 
year observation period in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Chen et 
al 2015, Landau et al 2015). These data demonstrate that relevant changes in amyloid plaque 
deposition can be detected at 2 years using amyloid PET imaging (Villemagne et al 2011, 
Landau et al 2015) and that utilization of a cerebral white matter reference region may 
improve the power  to track longitudinal changes in florbetapir 18F (Chen et al 2015).
6.6
Other assessments


Novartis
Page 65
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6.6.2
Resource utilization
Not applicable 
6.6.3
Pharmacokinetics
Not applicable


Novartis
Page 66
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events should 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, laboratory tests, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patients and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
Cognitive function test scores including the CogState battery 
 scale will not be
communicated to the patients or sites routinely. Significant outlier scores will be flagged and 
the investigator will be notified. The investigator will ascertain if any unforeseen factors may 
have contributed to the outcome. An individual abnormal value on a cognitive scale by itself 
is not diagnostic of improvement or decline in cognitive function. The investigator should 
make appropriate decisions as to the need for further neuropsychological assessments at any 
time during the study based on clinical assessment irrespective of the cognitive scores. Results 


Novartis
Page 67
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
of SUVr assessments on amyloid PET imaging and MRI volumetric assessments will not be 
communicated to the investigators. Patients who receive a diagnosis of MCI, dementia or 
stroke during the course of study may continue in the study.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information.

The severity grade 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment, 

“No Relationship to study treatment or other investigational treatment” or

“Relationship to study treatment” or

“Relationship to other investigational treatment” or 

“Relationship to both study treatment and other investigational treatment or 
indistinguishable”

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - see Section 7.2 for definition of SAE) 
and which seriousness criteria have been met.

action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (i.e. further observation only) 

study treatment dosage increased/reduced

study treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition 
of SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.  Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 


Novartis
Page 68
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Notification (IN) or an Aggregate Safety Finding. New information might require an update to 
the informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of an SAE refers to a reaction in which the patient was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if it were more severe (see Annex IV, ICH-E12D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E12D Guideline).


Novartis
Page 69
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 30 days period following the last administration of study 
treatment should only be reported to Novartis if the investigator suspects a causal relationship 
to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs.  The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. Liver events are divided into two categories:

Liver events of special interest which consist of liver function test (LFT) elevations


Novartis
Page 70
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320

Medically significant liver events which are considered as SAEs and which consist of 
marked elevations of LFTs and / or pre-specified AEs.
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver events.
Any liver event which meets the criteria for “medically significant” event as outlined in Table 
14-1 of Appendix 2 should follow the standard procedures for SAE reporting as described in 
Section 7.2.
Every liver event as defined in Table 14-1 of Appendix 2 should be followed up by the 
investigator or designated personnel at the trial site as summarized below. Detailed 
information is outlined in Table 14-2 in Appendix 2.

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., 
disease, co-medications)

An investigation of the liver event which needs to be followed until resolution.
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring 
Details of monitoring and management of renal dysfunction are provided in Appendix 5.
7.5
Cognition safety monitoring
If dementia or dementia-related event occurs, the investigator will complete a Dementia-
related Event form (provided by Novartis) in addition to the standard AE reporting. If a 
dementia or dementia-related event satisfies the definition of an SAE, the investigator must 
submit an SAE report in addition to the Questionnaire for the Dementia-related Event.  
Submission of a dementia report is not a substitution for the submission of an SAE report.
7.6
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 (European Medicines Agency) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 


Novartis
Page 71
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE (Table 7-1).
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
AE – adverse event; eCRF – electronic case report form; SAE – serious adverse event
7.7
Pregnancy reporting
Given the age of the patient population and exclusion of women of child bearing potential no 
pregnancies are expected during the study. However, should a pregnancy be discovered 
during the course of study, the following procedure must be followed. In case of pregnancy 
discovered during the screening or run-in epochs or during double-blind epochs, the patient 
will be withdrawn from the study immediately.
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.


Novartis
Page 72
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
8
Data review and database management 
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to 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 (clinical research associate) organization. Additionally, a central analytics 
organization may analyze data and identify risks and trends for site operational parameters, 
and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed.


Novartis
Page 73
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the clinical 
database system.  Designated investigator site staff will not be given access to the system until 
they have been trained.
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
8.3
Database management and quality control 
Novartis staff or Contract Research Organization (CRO) working on behalf of Novartis 
review the data entered into the CRFs by investigational staff for completeness and accuracy 
and instruct the site personnel to make any required corrections or additions. Queries are sent 
to the investigational site using an electronic data query. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. If the electronic query system 
is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete 
and sign the faxed copy and fax it back to Novartis staff that will make the correction to the 
database. The signed copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
CogState will provide cognitive battery data; imaging vendor will provide MRI and PET data. 
A selected vendor will provide
FAQ,
data electronically to Novartis. 
Each of these vendors will manage the database and these data will be generated 
electronically using a computer or tablet. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.




Novartis
Page 75
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
9.1
Analysis sets 
The following analysis sets will be used for the statistical analyses:

Screened set (SCR) – All patients who signed the informed consent. The screened set 
includes only unique screened patients, i.e., in the case of re-screened patients only the 
chronologically last screening data is counted. 

Enrolled set (ENR) (run-in phase) – All patients who received at least one dose of run-in 
study drug. 

Valsartan run-in set (VRS) – All patients who are in the ENR and received at least one 
dose of run-in valsartan.

LCZ696 run-in set (LRS) – All patients who are in the ENR and received at least one 
dose of run-in LCZ696.

Randomized set (RAN) – All patients who received a randomization number, regardless 
of receiving trial medication.

Full analysis set (FAS) – it consists of all randomized patients with the exception of those 
patients who have not been qualified for randomization and have not received study drug, 
but have been inadvertently randomized into the study. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment to which they were assigned 
at randomization. 

Safety set (SAF) – it consists of all randomized patients who received at least one dose of 
study drug. Patients will be analyzed according to the treatment actually received. The 
safety population will be used for the analyses of safety variables. 

Per-protocol set (PPS) – it is a subset of the FAS which will consist of the patients who 
meet the following conditions:

No major deviations from the protocol procedures in the randomized treatment epoch

Have been exposed to study medication for at least 30 months and have 80% 
compliance on study medication.
Major protocol deviations will be pre-specified prior to unblinding treatment codes for 
analyses.
9.2
Patient demographics and other baseline characteristics 
Unless specified otherwise, baseline value is defined as the measurement obtained at the 
randomization visit date (Day 1), or the measurement obtained at an earlier visit (scheduled or 
unscheduled) which was closest to Day 1, if the Day 1 measurement is missing.
Summary statistics will be provided by treatment group for demographics and baseline 
characteristics, including age, age group (<65 years vs. ≥65 years; <75 years vs. ≥75 years), 
sex, race, ethnicity, country, region, weight, height, body mass index (BMI), education level, 
category of prior CV medication, prior HF hospitalization, NYHA class, NT-proBNP, vital 
signs, MMSE overall summary score, MMSE category (<28, ≥28), cerebrovascular disease 
burden factors as measured by MRI (e.g. lacunar infarcts > 2; cortical or subcortical infarct > 
1cm3; white matter lesion Fazekas score of 3; micro hemorrhages ≥4) and APOE4 allele status 
(carrier vs. non-carrier). BMI will be calculated as weight (kg) / height2 (m2) from the 
collected height and weight at Visit 1 (Screening Visit). Continuous variables will be 




Novartis
Page 77
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
6. International Shopping List Test – delayed recall (ISLT-DR) - Assesses verbal memory 
using the accuracy (number of words recalled correctly) of delayed recall in a verbal list 
learning paradigm
7. Groton Maze learning Test (GMLT) – Assesses executive function using the number of 
total errors (number of error responses over 5 trials) in a hidden pathway maze learning 
paradigm
Standardized z-scores for each outcome measure and visit will be calculated using the sample 
baseline mean and standard deviation of individual tasks as follows:

ZDET = − (Log10(DET) – baseline mean of log10(DET))/SD of log10(baseline DET), 

ZIDT = − (Log10(IDT) – baseline mean of log10(IDT))/SD of log10(baseline IDT),

ZCPAL = (CPAL total errors – baseline mean of CPAL total errors/SD of baseline 
CPAL total errors), 

ZONB = − (Log10(ONB) – baseline mean of log10(ONB))/SD of log10(baseline ONB), 

ZISLT = (ISLT – baseline mean of ISLT))/SD of baseline ISLT, 

ZISLT-DR = (ISLT-DR) – baseline mean of ISLT-DR))/SD of baseline ISLT-DR,

ZGMLT = − (GMLT – baseline mean of GMLT))/SD of baseline GMLT
Note that negative sign is included in the calculation for tasks where increasing values 
indicate worsening performance (i.e., ZDET, ZIDT, ZONB and ZGMLT) so that for all standardized 
change scores negative values indicate a decline from baseline while positive scores indicate 
improvement from baseline.
These seven individual z-scores are then combined to generate the GCCS: 
CogState GCCS = average of (ZDET, ZIDT, ZCPAL, ZONB, ZISLT, ZISLT-DR, ZGMLT)
The composite score will be computed if five of the seven tests are completed and the five 
tests provide an assessment of the three cognitive domains as defined below being 
assessed. That is, a composite score requires that each cognitive domain be measured by at 
least one cognitive test.
In addition to the GCCS, composite scores for three main subdomains memory, attention and 
psychomotor function will also be generated by combining the standardized change from 
baseline scores for individual tests from the CCB using the following formulae:

Composite score of memory tests = average of (ZCPAL, ZISLT, ZISLT-DR)

Composite score of executive function tests = average of (ZONB, ZGMLT)

Composite score of attention tests = average of (ZDECT, ZIDT)
Each composite score will be the average of the non-missing individual test z-scores
9.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in the GCCS of CogState test battery will be analyzed using a 
repeated measures analysis of covariance (ANCOVA) model in which treatment, age 
stratification factor, MMSE stratification factor, education level, APOE4 status (carrier vs. 
non-carrier), baseline cerebrovascular disease burden as measured by MRI (calculated based 
on four factors: lacunar infarcts > 2; cortical or subcortical infarct > 1cm3; white matter lesion


Novartis
Page 78
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Fazekas score of 3; micro hemorrhages ≥4), visit (Weeks 26, 52, 78, 104, 130 and Week 156) 
and treatment-by-visit interaction are included as fixed-effect factors and baseline GCCS and 
visit by baseline GCCS interaction as covariates, with a common unstructured covariance 
matrix among visits between treatment group. The adjusted mean changes at 3 years (Week 
156) within each treatment, the difference in mean changes at 3 years (Week 156) between the 
two treatments, and its 95% confidence interval obtained from the above model will be 
presented. In addition, the treatment difference (LCZ696-valsartan) in mean changes from 
baseline to 3 years will also be expressed based on a standardized effect size (Cohen’s d) with 
a 2-sided 95% confidence interval. The Cohen’s d will be estimated by using the adjusted 
between-treatment mean difference, divided by the estimated standard deviation, which is 
calculated from the standard error of the adjusted mean change and the sample number of 
patients within each group (the pooled SD) from the above modeling. The analysis is based on 
likelihood method with an assumption of missing at random (MAR) for missing data.
As the primary analysis, this repeated measure ANCOVA model will be performed in the 
Safety set including ‘on-treatment’ data collected prior to the start of treatments for AD or 
cognitive impairment. The Cohen’s d based on the adjusted difference in mean changes at 3 
years (Week 156) between two treatments and its 95% confidence interval from this model 
will be used to draw the main conclusion for the primary objective. On-treatment data refer to 
cognitive test data collected while patients are on-study-medication (regardless of treatment 
interruption) or within three months after final study drug intake date.
In addition, the same repeated measure ANCOVA model will be performed in the following 
two analysis sets as supportive analyses:

in the FAS, including all available data (even after treatment discontinuation and after 
start of treatments for AD or cognitive impairment)

in the per-protocol set, including ‘on-treatment’ data collected prior to the start of 
treatments for AD or cognitive impairment only.  
Summaries of absolute values and change from baseline in the GCCS and domain-specific 
composite z-scores by treatment group and visit will be presented. Figures will be produced to 
visually show both the raw and the model-based mean global composite z-scores and mean 
domain-specific composite z-scores by visit over study period for each treatment group. These 
will be done in both the Safety and FAS with the same data inclusion rules as for the above 
repeated measure ANCOVA modeling in the Safety and FAS.
9.4.3
Handling of missing values/censoring/discontinuations
The repeated ANCOVA modeling as described in the previous section is based on likelihood 
method with an assumption of missing at random for missing data. That means, missing data, 
including those from dropouts, will be implicitly represented in the analysis by data from 
patients with similar baseline covariates and measurement histories. 
Data collected more than three months after patients permanent discontinuation of the study 
medication will be excluded from analyses in both the Safety and PPS analyses. In addition, 
data collected after patients starting treatments for AD or cognitive impairment will be 
excluded from “on-treatment” analyses.


Novartis
Page 79
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
For missing values at a specific post-baseline visit, any post-baseline unscheduled 
measurements taken within three-month window may be re-mapped to this scheduled visit.
9.4.4
Sensitivity analyses 
Although the MAR assumption is deemed appropriate choice for the primary analysis, it is not 
possible to verify its correctness based on the observed data (CHMP, 2010, National Research 
Council, 2010). Indeed it is conceivable that censoring, respectively the missing data 
mechanism (e.g., due to death) may be informative and that the cognitive function decline in 
patients who died would have been steeper than estimated under the MAR assumption. Thus, 
the primary analysis would favor the valsartan group in the presence of a reduction in 
mortality in the LCZ696 group.  
Due to this uncertainty, analyses based on multiple imputations, such as those using a pattern
mixture model approach, will be performed to investigate the sensitivity of the primary 
analysis results based on the MAR assumption. These sensitivity analyses assume that 
missing CogState test battery scores after death, HF hospitalizations, and stroke were missing 
not at random (MNAR).
Data censored at the start of treatments for AD or cognitive impairment may be imputed using 
similar MNAR-based imputation approach. This analysis will be performed for the primary 
analysis in the Safety set and for the supportive analysis in the FAS.  In addition, a shared 
parameter model (Vonesh et al 2006) to jointly model longitudinal GCCS measurements and 
time to starting treatments for AD or cognitive impairment will be further explored. This 
provides an analysis of CogState test battery scores that accounts for potential informative 
censoring due to starting treatments for AD or cognitive impairment. It should be noted that 
this joint modeling approach might fail to work or interpretation of the results may be difficult 
if the incidence rate of patients starting treatment for AD or cognitive impairment in the 
present study is low.
To fully assess the effect of the missing data on the conclusions, an additional sensitivity 
analysis will be performed for subjects with missing cognitive function measurements due to 
withdrawal for unknown reasons.
In addition, the following subgroup analyses will be performed for the primary endpoint on 
the Safety set including ‘on-treatment’ data collected prior to the start of treatments for AD or 
cognitive impairment. The analysis will be done using a similar repeated ANCOVA model as 
for the primary analysis at individual subgroup level separately, while the p-values of the 
subgroup-by-treatment interaction will be derived from a similar model but with additional 
terms including the subgroup, the interaction term of subgroup-by-treatment. 

Age group (<65 vs. ≥65 years), age group (<75 vs. ≥75 years) 

Gender (male/female) 

Region 

Education level

Baseline MMSE cut-off (<28, ≥28)

Baseline LVEF cut-off (<50%, ≥50%)

Baseline NYHA class (II and III/IV)


Novartis
Page 80
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320

Baseline diabetes status (yes/no)

Baseline cerebrovascular disease burden as measured by MRI

APOE4 allele status (carrier/non-carrier)
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The secondary variables are:
1. Change from baseline in individual cognitive domains (memory, executive function, and 
attention) as assessed by the individual components of the cognitive assessment battery at 
3 years;
2. Change from baseline in the summary score of the instrumental activities of daily living 
(IADL) as assessed with Functional Activity Questionnaire (FAQ) at 3 years.
The composite z-scores by individual cognitive domains (memory, executive function, and 
attention) are defined in Section 9.4.1.
For secondary variables composite z-scores by individual domain (memory, executive 
function and attention) and IADL, the changes from baseline to 3 years will be analyzed using 
the same repeated measures ANCOVA model as described in Section 9.4.2 but with baseline 
GCCS replaced with respective secondary variable baselines. The adjusted mean changes at 3 
years (Week 156) within each treatment, the difference in mean changes at 3 years (Week 156) 
between two treatments, its 95% confidence interval obtained from the above model will be 
presented. The analysis is based on likelihood method with an assumption of missing at 
random for missing data, and will be performed in the Safety set including ‘on-treatment’ data 
collected prior to the start of treatments for AD or cognitive impairment. On-treatment data 
are those collected while patients are on-study-medication (regardless of treatment 
interruption) or within three months after final study drug intake date. This analysis will be 
performed in the SAF.
In addition, as supportive analysis, similar repeated measure ANCOVA model will be also 
performed for these secondary endpoints for all data in the FAS.
Summaries of absolute values and change from baseline by treatment group and visit will be 
presented. Figures will be produced to visually show the endpoint values (SUVr, composite z-
scores by cognitive domain and IADL) by visit over the study period for each treatment group.
These analyses will be done in both SAF and FAS, for ‘on-treatment’ data and for all data, 
respectively.
For these secondary variables, a three month window will be applied to re-map any 
unscheduled visit assessments to a missing scheduled visit assessment.
9.5.2
Safety variables 
Safety evaluations to be analyzed are listed as below:

Change from baseline in a cortical composite SUVr (standardized uptake value ratio) at 3 
years 




Novartis
Page 82
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
may be performed, which assumes that missing values after death, HF hospitalizations, stroke 
were missing not at random (MNAR).
A shift table to summarize the proportion of patients’ amyloid status change over time from 
baseline by treatment will be provided as well.
All analyses will be performed in patients in the Safety set who participate in the PET image 
substudy, including ‘on-treatment’ data only. On-treatment data refer to the SUVr values 
obtained while patients are on-study-medication (regardless of treatment interruption) or 
within six months after final study drug intake date.
9.5.3
Resource utilization 
Not applicable
9.5.4
Pharmacokinetics 
Not Applicable




Novartis
Page 84
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320


Novartis
Page 85
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320


Novartis
Page 86
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
9.7
Interim analyses
No formal interim efficacy analyses are planned. Refer to Section 8.4 for planned regular 
interim safety data review by an independent Data Monitoring Committee.
9.8
Sample size calculation
9.8.1
Sample size calculation for the primary endpoint
It is currently estimated that approximately 180 patients per group 

would provide at least 80% probability that the 2-sided 95% confidence interval (CI)  
excludes a standardized effect size (Cohen’s d) of 0.3 (or greater) in change in composite 
z-score of the battery test over 3 years, given that there is no expected difference between 
two treatments. 

Would provide at least 80% probability that the 2-sided CI excludes 0 (corresponding to 
p<0.05), if the true effect size is 0.3 or greater (in either direction).
An effect size of 0.3 in Cohen’s d corresponds to a margin of 0.3xSD (SD=standard deviation)
on the original scale for the difference between treatments in mean global score change from 
baseline, and is generally considered as small (Cohen 1988). In a systematic review of studies 
for health-related quality of life instruments that have reported the minimally important 
difference (MID), it was found that for the majority of studies the MID estimates were 
consistently close to 0.5xSD (Norman et al 2003). In addition, socially accepted benchmarks 
for conditions that induce cognitive impairment such as low level alcohol intoxication within 
legal driving limit in most countries (0.05%) are generally associated with declines of 0.3 or 
higher for psychomotor speed, attention and working memory. Therefore, the sample size of 
the study was determined to be able to detect (or exclude) effect sizes in the magnitude of 0.3 
in Cohen’s d with high probability, as it appears to be an appropriate choice to guide the 
interpretation of the cognitive function results. 
In addition, defining the magnitude of the MID using a measure of effect size, rather than a 
raw difference score has additional advantages:

Expressing the magnitude of an important difference in scale free units (Cohen’s d) allows 
models of clinically meaningful difference to be based on integration of outcomes from a 
broad set of studies whose characteristics are relevant to the current study (i.e. magnitude 
of change in cognition related to amyloid, magnitude of change occurring after heart 
failure, and magnitude of change related to cardiovascular disease). 

Estimates of clinically meaningful difference can be referenced to the magnitude of 
cognitive decline detected from studies where compounds with accepted central nervous 
system adverse effects, at known doses are administered to older adults (e.g. scopolamine, 
alprazolam).
Sample size calculation was performed using N-Query 7.0.
9.8.2
Sample size calculation for the PET imaging substudy 
Approximately 300 patients (in 1:1 allocation ratio to LCZ696 and valsartan) will provide at 
least 80% probability that the 2-sided 95% CI excludes a between-treatment absolute 


Novartis
Page 87
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
difference of 0.01 (corresponding to an incremental 33% increase in LCZ696 vs. valsartan) in 
change from baseline in SUVr over 3 years if there is no expected difference between two 
treatments. This calculation is based on the assumptions that the mean change over 3 years 
from baseline in SUVr is 0.03 in the control group, the common standard deviation is 0.03 
(estimated from ADNI data, Chen et al 2015). It is noted that the ADNI data presented in 
Chen’s paper are by patients’ cognitive status (normal, MCI, dementia) and for changes over 
two years. The assumptions used here are guestimates from the 2 year data in normal 
cognitive and MCI subjects.
An absolute difference in SUV ratio of 0.01 was considered small as it represents a value that 
is lower than the rate of SUVr change that distinguishes between amyloid positive and 
negative patients (0.026 vs. 0.011).  
Sample size calculation was performed using N-Query 7.0.
9.8.3
Blinded sample size re-estimation
Approximately 520 patients will be randomized in order to provide overage to account for the 
information loss caused by an estimated 30% “drop-out” (including death, lost-to-follow-up, 
permanent discontinuation of study medication and start of treatments for AD or cognitive 
impairment) during 3 year period.  In the PET imaging substudy approximately 430 patients
will be randomized.
A loss of 30% of information is a crude estimate therefore it is planned to monitor the ‘drop-
out’ pattern as the trial is ongoing in order to provide a better prediction of the information 
loss for a given number of patients.  The final number of patients randomized may be reduced 
if there is sufficient evidence that the information loss will be less than 30% and that the 
precision of the estimates of treatment effect (as described in the sample size section above), 
will be maintained.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent. He/she must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the patient source documents. 




Novartis
Page 89
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.
12
References 
References are available upon request
Ampadu J, Morley JE (2015) Heart failure and cognitive dysfunction. Int J Cardiol; 178:12-23.
Arslanian-Engoren C, Giordani BJ, Algase D, et al (2014) Cognitive dysfunction in older 
adults hospitalized for acute heart failure. J Card Fail; 20:669-78.
Bateman RJ, Xiong C, Benzinger TLS, et al (2012) Clinical and biomarker changes in 
dominantly inherited Alzheimer’s disease. N Engl J Med; 367(9):795-804.
Bauer LC, Johnson JK, Pozehl BJ (2011) Cognition in heart failure: An overview of the 
concepts and their measures. J Amer Acad Nurse Practition; 23:577-85.
Belleville S, Fouquet C, Duchesne S, et al (2014) Detecting early Alzheimer’s Disease via 
cognition, neuropsychiatry, and neuroimaging: Qualitative review and recommendations for 
testing. J Alzheimers Dis; 42:S375-82.
Cannon JA, McMurray JJ, Quinn TJ (2015) “Hearts and minds”: association, causation, and 
implication of cognitive impairment in heart failure. Alz Res Ther; 7:22.
Cash DM, Frost C, Iheme LO, et al (2015) Assessing atrophy measurement techniques in 
dementia: Results from the MIRIAD atrophy challenge. Neuroimage; 123:149-64.


Novartis
Page 90
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Castilla-Rilo J, López-Arrieta J, Bermejo-Pereja F, et al (2007) Instrumental activities of daily 
living in the screening of dementia in population studies: a systematic review and meta-
analysis. Int J Geriatr Psychiatry; 22:829-36.
Cavalieri M, Enzinger C, Petrovic K, et al (2010) Vascular dementia and Alzheimer’s Disease 
– are we in a dead end road? Neurodegenerative Dis; 7:122-6.
Chen K, Roontiva A, Thiyyagura P, et al (2015) Improved power for characterizing 
longitudinal amyloid-β PET changes and evaluating amyloid-modifying treatments with a 
cerebral white matter reference region. J Nucl Med; 56(4):560-6.
Chou CC, Pressler SJ, Giordani B, et al (2015) Validation of the Chinese version of the 
CogState computerized cognitive assessment battery in Taiwanese patients with heart failure. 
J Clin Nurs; 24:3147-54.
Clark AP, McDougall G (2006) Cognitive impairment in heart failure. Dimens Crit Care Nurs;
25(3):93-100.
Cleland GF, Tendera M, Adamus J (2006) The perindopril in elderly people with chronic 
heart failure (PEP-CHF) study. Eur Heart J; 27:2338-45.
Cohen J (1988) Statistical Power Analysis for the Behavioral Sciences. 2nd Edition New 
Jersey: Lawrence Erlbaum Associates.
Collie A, Darby DG, Falleti MG, et al (2002) Determining the extent of cognitive change after 
coronary surgery: a review of statistical procedures. Ann Thorac Surg; 73:2005-11.
Committee for human medicinal products (CHMP), European Medicines Agency (EMA). 
(2004) ICH Topic E2D: Post approval safety data management, London, UK.
Committee for Medical Products for Human Use. Guideline on missing data in confirmatory 
clinical trials. London: European Medicines Agency, July 2, 2010. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC5
00096793.pdf. (Accessed 5 April 2016).
Corder EH, Saunders AM, Strittmatter WJ, et al (1993) Gene dose of apolipoprotein E type 4 
allele and the risk of Alzheimer's disease in late onset families. Science; 261:921-3.
Darby DG, Brodtmann A, Pietrzak RH, et al (2011) Episodic memory decline predicts cortical 
amyloid status in community-dwelling older adults. J Alzheimers Dis; 27:627-37.
Desai AS, Lewis EF, Li R, et al (2011) Rationale and design of the treatment of preserved 
cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled 
study of spironolactone in patients with symptomatic heart failure and preserved ejection 
fraction. Am Heart J; 162:966-72.
Donohue MC, Sperling RA, Salmon DP (2014) The preclinical Alzheimer cognitive 
composite: measuring amyloid-related decline. JAMA Neurol; 71(8):961-70.
Fogari R, Mugellini A, Zoppi A (2004) Effects of valsartan compared with enalapril on blood 
pressure and cognitive function in elderly patients with essential hypertension. 
Eur J Clin Pharmacol; 59:863-8.
Gorelick PB, Nyenhuis D (2012) Blood pressure and treatment of persons with hypertension 
as it relates to cognitive outcomes including executive function. J Am Soc Hypertens;
6(5):309-15.






Novartis
Page 93
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Simoni D, Rafanelli M, Ungar A, et al (2014) Neurocognitive profile of patients with 
continuous flow left ventricular assist device. Monaldi Arch Chest Dis; 82(2):75-9.
Skoog I, Lernfelt B, Landahl S, et al (1996) 15-year longitudinal study of blood pressure and 
dementia. Lancet; 347:1141-5.
Snyder PJ, Lim YY, Schindler R, et al (2014) Microdosing of scopolamine as a “cognitive 
stress test”: rationale and test of a very low dose in an at-risk cohort of older adults. 
Alzheimers Dement; 10:262-7.
Steinberg SI, Sammel MD, Harel BT, et al (2015) Exercise, sedentary pastimes, and cognitive 
performance in healthy older adults. Am J Alzheimers Dis Other Demen; 30(3):290-8.
Stevens LA, Coresh J, Greene T, Levey AS (2006) Assessing kidney function – measured and 
estimated glomerular filtration rate. N Engl J Med; 354:2473-83.
Teng E, Becker BW, Woo E, et al (2010) Utility of the functional activities questionnaire for 
distinguishing mild cognitive impairment from very mild Alzheimer’s disease. Alzheimer Dis 
Assoc Disord; 24(4):348-53.
Thomas E, Snyder PJ, Pietrzak RH, et al (2008) Specific impairments in visuospatial working 
and short-term memory following low-dose scopolamine challenge in healthy older adults. 
Neuropsychologia; 46:2476-84.
Vellas B, Bateman R, Blennow K, et al (2015) Endpoints for pre-dementia AD trials: A report 
from the EU/US/CTAD Task Force. J Prev Alzheimers Dis; 2(2):128-35.
Vemuri P, Jack CR (2010) Role of structural MRI in Alzheimer’s disease. Alzheimers Res 
Ther; 31:23-33.
Villemagne VL, Burnham S, Bourgeat P, et al (2013) Amyloid β deposition, 
neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective 
cohort study. Lancet Neurol; 12:357-67.
Villemagne VL, Pike KE, Chételat G, et al (2011) Longitudinal assessment of Aβ and 
cognition in aging and Alzheimer disease. Ann Neurol; 69(1):181-92.
Vonesh EF, Greene T, and Schluchter MD (2006) Shared parameter models for the joint 
analysis of longitudinal data and event times. Stat Med; 25(1):143-63.
Wang DS, Dickson DW, Malter JS (2006) β-Amyloid degradation and Alzheimer's disease. J 
Biomed Biotechnol; 2006:1-12.
Yusuf S, Pfeffer MA, Swedberg K (2003) Effects of candesartan in patients with chronic heart 
failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet; 
362:777-81.
Zuccala G, Onder G, Marzetti E, et al (2005) Use of angiotensin-converting enzyme inhibitors 
and variations in cognitive performance among patients with heart failure. Eur Heart J;
26(3):226-33.


Novartis
Page 94
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320


Novartis
Page 95
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
14
Appendix 2: Liver event definition and follow-up 
requirements
Table 14-1
Liver event definitions
Definition/ threshold
AE of special interest
Laboratory values

ALT or AST > 3 x ULN

ALP > 2 x ULN

TBL > 1.5 x ULN
Medically significant event 
(SAE)
Laboratory values

ALT or AST > 5 x ULN 
(with or without TBL > 2 x ULN [mainly conjugated fraction])

ALP > 5 x ULN 
(with or without TBL > 2 x ULN [mainly conjugated fraction])

TBL > 3 x ULN

Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and TBL > 2 x ULN 
[mainly conjugated fraction] without notable increase in ALP to > 2 x ULN
AEs

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal 
pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal 
Table 14-2
Follow up requirements for liver events 
Criteria
Event type
Actions required
Follow-up monitoring
Potential Hy’s 
Law casea
Medically 
significant
Discontinue the study drug immediately
Hospitalize, if clinically appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue the study 
drug immediately
Hospitalize if clinically appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 x ULN
Medically
significant
Repeat LFT within 48 hours
If elevation persists for more than 2 
weeks, discontinue the study drug
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 x ULN
accompanied by 
symptomsb
Medically 
significant
Discontinue the study drug immediately
Hospitalize if clinically appropriate
Report to Novartis as an SAE
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc
(frequency at investigator 


Novartis
Page 96
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
Criteria
Event type
Actions required
Follow-up monitoring
Establish causality
discretion)
> 3 to ≤ 5 x ULN 
(patient is 
asymptomatic)
Adverse event 
of special 
interest (AESI)
Central laboratory to report to Investigator 
& Novartis
Repeat LFT once or twice in the week
If elevation persists, establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 3 x ULN 
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
ALP (isolated)
> 5 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, report to Novartis as 
an SAE
Establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
> 2 to ≤5 x ULN 
(patient is 
asymptomatic)
AESI
Central laboratory to report to Investigator 
& Novartis
Repeat LFT once or twice in the week. If 
elevation persists, establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 2 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
TBL (isolated)
> 3 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue the study 
drug immediately
Hospitalize if clinically appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 3 x 
ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to Novartis
Repeat LFT once or twice in the week. If 
elevation persists, establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤ 1.5 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
Preferred terms
Jaundice
Medically 
significant
Discontinue the study drug immediately
Hospitalize the patient
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
“Drug-related 
hepatic 
disorders -
severe events 
only” SMQ AE
Medically 
significant
Discontinue the study drug 
Hospitalization if clinically appropriate
Report to Novartis as an SAE
Establish causality
Investigator discretion
a
Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN
b
General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia
c
Resolution is defined as an outcome of one of the following: return to baseline values, stable values at three 
subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a maximum of 6 months, liver 
transplantation, and death.


Novartis
Page 97
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
15
Appendix 3: Treatment guidelines for hyperkalemia (serum 
potassium greater than or equal to 5.3 mmol/L [mEq/L])
General principles
Elevation of potassium levels above the predefined values should be repeated and confirmed 
before any action is taken.
Any patient with a serum potassium > 5.3 mmol/L (mEq/L) at any time after randomization 
requires the Investigator to confirm the 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, 
tomatoes, coffee, etc.) 

Correct metabolic acidosis if necessary. 

Review medical regimen (including dietary supplements and over-the-counter medications) 
for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of 
these agents:
1. MRAs (if they are believed to be the most likely cause of hyperkalemia)
2. Potassium-sparing diuretics (e.g., amiloride and triamterene) including in combination 
products with thiazide or loop diuretics 
3. Potassium supplements, e.g., potassium chloride
4. Salt substitutes 
5. Non-steroidal anti-inflammatory drugs (NSAIDs)
6. Cyclo-oxygenase-2 (COX-2) inhibitors
7. Trimethoprim and trimethoprim-containing combination products, such as Bactrim®
and Septra® (trimethoprim/sulfamethoxazole fixed combination)
8. 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


Novartis
Page 98
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320

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.


Novartis
Page 99
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
16
Appendix 4: Guidelines for the management of blood 
pressure
Guidelines
1. Investigator should monitor BP closely 
2. If symptomatic hypotension occurs:
a. Correct any treatable cause, e.g. hypovolemia
b. If hypotension persists, any 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 
withdrawn. The dose re-challenge and medications adjust guidelines described in 
Section 5.5.5 should be adhered to as much as possible.


Novartis
Page 100
Amended Clinical Trial Protocol Version 02  (Clean)
Protocol No. CLCZ696B2320
17
Appendix 5: Guidelines for the management of renal 
dysfunction
General principles:
Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance 
between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a 
stimulation of angiotensin II and could be affected by either study 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 randomization, eGFR decreases by ≥25% from baseline (Visit 1) (or if 
serum creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will 
check for potentially reversible causes of renal dysfunction such as:

Non-steroidal anti-inflammatory drug intake, antibiotics, or other treatments known to 
affect 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 baseline (Visit 1) (or if serum creatinine 
concentration rises above 3 mg/dL (265 µmol/L), the investigator will check for potentially 
reversible causes of renal dysfunction (see above).
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.

SAP_001.pdf: 




Novartis
Page 3
SAP Final version 1.0
CLCZ696B2320
Date
Time 
point
Reason for update
Outcome for 
update
Section and title impacted 
(Current)
(2) Update APOE4 category;
(3) Add baseline 
cerebrovascular disease 
burden subgroup due to 
protocol amendment. 
(4) In Table 2.1: MMSE at 
randomization is used to 
define subgroup in order 
to be consistent with 
MMSE randomization 
stratification factor.
4.
Section 2.3.2: correct APOE4 
summary 
at 
randomization 
baseline instead of screening.
5.
Section 2.3.3: remove dementia 
from protocol solicited medical 
history 
summary 
to 
be 
consistent with CRF. Remove 
medical 
history 
(MH) 
by 
subgroup summary. MH is only 
summarized by treatment group. 
6.
Section 2.4.1: update formula to 
be more clear and consistent 
with Paragon.
7.
Section 2.4.2:
(1) Update ATC WHO Drug 
version;
(2) Category “HF 
medications” removed to 
be consistent with 
Perspective CRF;
(3) AD/CI Concomitant 
medications at 
randomization summary 
removed due to 
randomized patients 
should not be on these 
medications.
8.
Section 2.5.1:
(1) formula and text are 
updated to make it more 
clear in terms of missing 
values. 
(2) Typo “DECT” is corrected
to “DET”.
9.
Removed 
“Assessments 
at 
unscheduled visit remapped to 
the missing scheduled visit 










Novartis
Page 8
SAP Final version 1.0
CLCZ696B2320
Date
Time 
point
Reason for update
Outcome for 
update
Section and title impacted 
(Current)
(2) Section 2.5.5 Joint Model 
approach: A constant baseline 
hazard function over time is 
used in the time to starting AD 
or CI related medications due to 
limited such events over study 
duration.
An
exponential 
regression 
instead 
of 
Cox 
proportional hazard is fitted.
4. Due to very limited 
patients with positive 
baseline amyloid status
and convergence issue, 
the imputation model 
used in change from 
baseline in SUVr is 
updated.
Section 2.7.1:
(1)
There are very limited 
patients with positive baseline 
amyloid status, and imputation 
cannot be done for this stratum.
Therefore, baseline amyloid 
status 
is 
included 
in 
the 
imputation model as factor 
instead.
(2) 
SAS 
proc 
MCMC 
programing detail is provided. 
5. Details are added in 
safety related sections 
after dry run review.
Section 2.7.2: 
(1) specify analysis set for run-
in epoch and double-blind 
randomized treatment epoch.
Section 
2.7.3: 
Remove 
“confirmed 
by 
adjudication 
committee” because death is not 
adjudicated.
6. Visits numbers are 
updated 
in 
plasma 
Aβ1-40
to 
be 
consistent 
with 
Section 2.11: Week 13, 52, 104 
and Week 156 are the post-
baseline scheduled visits for 
plasma Aβ1-40
assessments.


Novartis
Page 9
SAP Final version 1.0
CLCZ696B2320
Date
Time 
point
Reason for update
Outcome for 
update
Section and title impacted 
(Current)
protocol 
assessment 
schedule Table 6-1.
Analysis set for plasma Aβ1-40
is PET substudy set with non-
missing baseline.
7. Updates related to 
protocol 
deviations 
impacting analysis sets
(1) Deviation ID OTH02 in 
Table 5-1: Site has been closed 
down for GCP reasons are not 
excluded from Safety set (SAF). 
(2)
Per 
clinical 
review: 
EXCL01, EXCL13, EXCL23, 
EXCL24, EXCL25, EXCL26, 
EXCL27, TRT07 are removed, 
and OTH21 is added in Table 5-
1.
(3) Table 5-2 is updated to be 
aligned with Table 5-1. 
8. Additional statement 
for different endpoints
PET substudy set
Section 2.2: Separate flag will 
be create for different endpoint
due to non-missing baseline 
condition for PET substudy set
9. Remove subgroup 
analysis for disposition 
related summary, add 3
subgroups
for 
CogState 
GCCS, 
minor 
update 
to 
NYHA category, and 
remove 
Central 
America from
Latin 
America definition
Table 2-1: (1) CTT reviewed 
and decided to remove
the 
subgroup 
analyses 
of 
disposition
from 
CSR; (2)
Randomization baseline SBP 
<=140 
and 
>140 
mmHg 
subgroup, Age < 65 and >= 65
subgroup, and diabetes mellitus 
status at screening (Yes, No)
subgroup 
are
added 
for 
CogState GCCS endpoint; (3)
subgroup categories of NYHA 
class at randomization are: I/II 
versus III/IV; (4) update Latin 
America to remove “including 
Central America” because no 
Central 
America 
countries 
participated in the study.
10. Remove by-visit 
from 
average 
daily 
dose summary, remove 
one obsolete phrase,
and update categories 
for summary. Add 2 
class of HF and CV 
medications.
Section 2.4.1: (1) Average daily
dose summary is calculated for 
randomized
treatment
epoch, 
not by visit; (2) Categories for 
summary are updated per dry 
run review comment.
Section 2.4.2: Add SGLT2 
class.
11. Remove supportive
analyses added in SAP 
Amendment V 3.0 that 
Almost all randomized patients
have at least one missing 
assessment during COVID-19 


Novartis
Page 10
SAP Final version 1.0
CLCZ696B2320
Date
Time 
point
Reason for update
Outcome for 
update
Section and title impacted 
(Current)
assess if there is a shift 
in 
change 
from 
baseline for those who 
have 
missing 
assessment(s) 
during 
COVID-19 pandemic.
pandemic for CogState GCCS
(Section 2.5.3), SUVr (Section 
2.7.1.1),
 
 endpoints, therefore, the 
analyses are not meaningful and 
removed.
12. (1) Shift table of 
SUVr 
positive/negative 
based on PET scan is 
removed since PET 
visual assessment of 
positive/negative 
is 
done only once at 
randomization; 
(2) 
correct 
analysis 
set 
used 
in 
SUVr 
supportive analysis; (3) 
Add 
one 
more 
supportive analysis for 
SUVr endpoint.
Section 2.7.1.1: 
(1) 
Shift 
table 
of 
SUVr 
positive/negative based on PET 
scan is removed since PET 
visual 
assessment 
of 
positive/negative is done only 
once at randomization; 
(2) PET substudy set instead of 
safety 
set 
is 
used 
SUVr 
supportive analysis;
(3) Supportive analysis of SUVr 
analysis excluding patients with
no
post-baseline 
SUVr 
assessments from analysis.
30-
Jun-
2022
Before 
DBL
Handling 
of 
data
collected
on/after 
withdrawal 
of 
informed consent
in 
the statistical analyses
Handling of biological data and 
non-biological data collected on 
or after withdrawal of informed 
consent in statistical analyses 
are provided in Section 2.1.
Protocol 
amendment 
2.0 is in effect when 
this SAP amendment 
takes place.


Novartis
Page 11
SAP Final version 1.0
CLCZ696B2320
Table of contents
Table of contents ...............................................................................................................11
List of abbreviations..........................................................................................................13
1
Introduction .......................................................................................................................14
1.1
Study design...........................................................................................................14
1.2
Study objectives and endpoints .............................................................................16
2
Statistical methods.............................................................................................................18
2.1
Data analysis general information .........................................................................18
2.1.1
General definitions................................................................................19
2.2
Analysis sets ..........................................................................................................20
2.2.1
Subgroup of interest ..............................................................................21
2.3
Patient disposition, demographics and other baseline characteristics ...................23
2.3.1
Patient disposition.................................................................................23
2.3.2
Demographic and baseline characteristics ............................................23
2.3.3
Medical history......................................................................................24
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................24
2.4.1
Study treatment / compliance................................................................24
2.4.2
Prior, concomitant and post therapies...................................................27
2.5
Analysis of the primary objective..........................................................................28
2.5.1
Primary endpoint...................................................................................28
2.5.2
Statistical hypothesis, model, and method of analysis..........................30
2.5.3
Handling of missing values/censoring/discontinuations.......................31
2.5.4
Supportive analyses...............................................................................33
2.5.5
Sensitivity analysis................................................................................33
2.6
Analysis of secondary efficacy objective(s)..........................................................37
2.6.1
Secondary endpoints .............................................................................37
2.6.2
Statistical hypothesis, model, and method of analysis..........................37
2.6.3
Handling of missing values/censoring/discontinuations.......................38
2.6.4
Sensitivity analysis for mis-stratification..............................................38
2.7
Safety analyses.......................................................................................................38
2.7.1
Change from baseline in SUVr at 3 years.............................................38
41
2.7.3
Deaths....................................................................................................45
46
47
2.8
Pharmacokinetic endpoints....................................................................................47


Novartis
Page 12
SAP Final version 1.0
CLCZ696B2320
2.9
PD and PK/PD analyses.........................................................................................47
2.10
Patient-reported outcomes .....................................................................................47
2.11
Biomarkers.............................................................................................................48
48
48
2.13
Interim analysis......................................................................................................52
3
Sample size calculation .....................................................................................................53
3.1
Sample size calculation for the primary endpoint .................................................53
3.2
Sample size calculation for the PET imaging substudy.........................................54
3.3
Blinded sample size re-estimation.........................................................................54
4
Change to protocol specified analyses ..............................................................................54
5
Appendix ...........................................................................................................................54
5.1
Imputation rules.....................................................................................................54
5.1.1
AE date imputation ...............................................................................54
5.1.2
Concomitant medication date imputation .............................................55
5.2
Statistical models...................................................................................................55
5.2.1
Primary analysis....................................................................................55
5.2.2
Key secondary analysis.........................................................................55
5.3
Rule of exclusion criteria of analysis sets..............................................................55
5.4
Cerebrovascular disease burden scoring................................................................56
6
Reference...........................................................................................................................57


Novartis
Page 13
SAP Final version 1.0
CLCZ696B2320
List of abbreviations
AD
Alzheimer’s Disease
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CCB
CogState Cognitive Battery
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


Novartis
Page 14
SAP Final version 1.0
CLCZ696B2320
1
Introduction
The statistical analysis plan (SAP) describes the detailed methodology and implementation of 
the planned statistical analyses outlined in the study protocol for CLCZ696B2320. The analyses 
performed following the SAP below will be used for clinical study reporting purposes. It is 
important to note that this version of statistical analysis plan details the statistical methodology 
for the analyses planned and agreed in the CLCZ696B2320 protocol (protocol version 02).
1.1
Study design
This study is a multi-center, randomized, double-blind, parallel group, active-controlled trial 
designed to evaluate the overall effect of LCZ696 compared to valsartan on cognitive function 
as assessed by a comprehensive cognitive battery in patients with HFpEF. The study population 
will consist of patients ≥60 years of age with chronic symptomatic HF (NYHA class II-IV) and 
a left ventricular ejection fraction (LVEF) >40%. 
As per the study design (Figure 1-1), patients with signed informed consent first undergo a 
screening epoch, followed by a treatment run-in epoch before entering the randomized double-
blind treatment epoch.
Screening epoch
Patients with signed study informed consent will undergo a screening epoch of approximately 
3 weeks duration used to assess their eligibility to participate in the trial based on protocol 
specified inclusion/ exclusion criteria. 
Single-blind treatment run-in epoch
Eligible patients enter a single-blind treatment run-in epoch which is designed to assess 
patient’s tolerability to study drug, and to determine patients who are likely to stay on study 
drug for the duration of the trial. During the treatment run-in epoch, each patient undergoes 
Valsartan 80 mg bid treatment and followed by LCZ696 100 mg bid treatment over 3-8 weeks 
duration. Patients who have been on a prior dose of ACEi or ARB medication lower than the 
total daily doses mentioned in Table 1-1, should start on Valsartan 40 mg bid for 1-2 weeks 
before up-titrating to Valsartan 80 mg bid. However, at the investigator’s discretion, those 
patients who are on ACEi or ARB medication at equivalent to the total daily doses mentioned 
in Table 1-1, can enter Valsartan 40 mg bid treatment run-in before starting Valsartan 80 mg 
bid. 


Novartis
Page 15
SAP Final version 1.0
CLCZ696B2320
Figure 1-1
Study Design
Table 1-1
Minimum pre-study total daily doses of commonly used ACEis and 
ARBs allowing patients to begin the treatment run-in epoch with 
valsartan 80 mg bid
ACEI
Dose
ARB
Dose
Benazepril
20 mg
Azilsartan
40 mg
Captopril
100 mg
Candesartan
16 mg
Cilazapril
2.5 mg
Eprosartan
400 mg
Enalapril
10 mg
Irbesartan
150 mg
Fosinopril
20 mg
Losartan
50 mg
Imidapril
10 mg
Olmesartan
10 mg
Lisinopril
10 mg
Telmisartan
40 mg
Moxepril
7.5 mg
Valsartan
160 mg
Perindopril
4 mg
Quinapril
20 mg
Ramipril
5 mg
Trandolapril
2 mg
Zofenopril
30 mg


Novartis
Page 16
SAP Final version 1.0
CLCZ696B2320
Randomized treatment epoch
At the end of treatment run-in, patients who meet the protocol specified safety criteria as 
assessed by central or local laboratories and tolerate LCZ696 100 mg bid for at least 2 weeks 
are eligible for randomization. Patients will be randomized in a 1:1 fashion to either LCZ696 
200 mg bid or valsartan 160 mg bid. The randomization will be stratified based on age (< 75, ≥ 
75 years), MMSE score (< 28, ≥ 28), and baseline brain amyloid status (unknown, amyloid 
positive, amyloid negative).
With an expected screening and run-in failure rate of approximately 40%, it is estimated that 
approximately 870 patients will be screened at more than 150 centers worldwide to randomize 
approximately 520 patients. A subset of about 430 randomized patients will be enrolled in the 
amyloid PET imaging substudy.
There is no formal interim analysis planned for efficacy. Interim safety data will be reviewed 
by an external Data Monitoring Committee (DMC)  regularly as specified in the DMC charter. 
The final analysis is planned to be executed at the completion of all planned assessments for 
last randomized patient. 
1.2
Study objectives and endpoints
Table 1-2
Objectives and related endpoints 
Objective
Endpoint
Analysis
Primary
To evaluate the effects of LCZ696 
compared to valsartan on cognitive 
function over 3 years in patients with 
HFpEF as assessed by the CogState 
cognitive assessment battery.
Change from baseline to 3 years in the
CogState Global Cognitive Composite
Score (GCCS)
Section 2.5
Secondary
To evaluate the effect of LCZ696 
compared to valsartan on -amyloid 
deposition in the brain in a subset of 
patients using amyloid positron 
emission tomography (PET) imaging 
over 3 years
Change from baseline in a cortical
composite SUVr (standardized uptake 
value ratio) at 3 years
Section 2.7.1
To evaluate the effects of LCZ696
compared to valsartan on individual
cognitive domains (memory, executive
function, and attention) as assessed 
by the individual components of the 
CogState battery over 3 years
Change from baseline in individual
cognitive domains (memory, executive
function, and attention) as assessed 
by the individual components of the
cognitive assessment battery at 3
years
Section 2.6
To compare LCZ696 to valsartan in
evaluating changes in instrumental
activities of daily living (IADL) as 
assessed with Functional Activity 
Questionnaire (FAQ) over 3 years
Change from baseline in the summary
score of the instrumental activities of
daily living (IADL) as assessed with
Functional Activity Questionnaire
(FAQ) at 3 years
Section 2.6






Novartis
Page 19
SAP Final version 1.0
CLCZ696B2320
2.1.1
General definitions 
Study treatment or drug
In future sections through this document, ‘study treatment’ or ‘study drug’ will be used to refer 
to investigational therapy assigned to a patient in a specific study phase. For instance, for run-
in phase, study treatment refers to valsartan in the valsartan run-in phase, and LCZ696 in the 
LCZ run-in phase. For the double-blind treatment phase, study treatment refers to LCZ696 or 
valsartan as assigned to a patient at randomization.
Single-blind run-in phase (Treatment run-in epoch)
The single-blind run-in phase (or treatment run-in epoch) is defined as the period between the 
start of the study drug (in general it should be Visit 101 or Visit 102) and the time prior to 
randomization (Visit 201). The run-in phase will be divided further into the valsartan run-in 
phase and the LCZ696 run-in phase. 
The start of the valsartan run-in phase is the date when the patient receives the first run-in dose 
of valsartan. In principle, the day before a patient receives the first dose of LCZ696 (any dose 
level) will be the end of the valsartan run-in phase and the day patient receives the first run-in 
dose of LCZ696 will be the start day for the LCZ696 run-in phase for that patient. If the date of 
the start day of receiving LCZ696 is missing, then the date of Visit 103, which is the protocol 
specified run-in drug switching day, will be used as the start date for the LCZ696 run-in phase. 
If the date of the last dose of valsartan run-in medication falls on the same day of the first dose 
of LCZ696 run-in medication, this day will be considered the end of the valsartan run-in phase 
and the following day will be considered as the start of the LCZ696 run-in phase. In general, 
the LCZ696 run-in phase ends when the patient receives the randomization drug. For run-in 
failure patients, the LCZ696 run-in phase ends on the date patient failed run-in. During these 
two run-in phases, patients will be on the run-in medications in a single blind manner.
Randomized treatment phase
The randomized treatment phase begins at the time of randomization (Visit 201) and ends with 
the last study drug intake or  last study visit date, whichever is earlier. During the randomized 
treatment phase, patients will return for scheduled clinic visits. For all related safety analyses 
randomized treatment starts with the first intake of randomized, double-blind study drug. 
Temporary discontinuation of the study drug will not be counted as randomized treatment phase 
discontinuation.
Post-randomized treatment phase
The post-randomized treatment phase (usually after unscheduled, permanent study drug 
discontinuation) begins after last study drug intake + 1 day and ends up on the date of end of 
study visit (Visit 299).
Double-blind (DB) phase (Randomized treatment epoch)
The double-blind randomized phase starts with the randomization visit (visit 201) and ends with 
the end of study visit (visit 299). Hence, this combines the randomized treatment phase and 
post-randomized treatment phase.


Novartis
Page 20
SAP Final version 1.0
CLCZ696B2320
Study Day
Study day is determined as number of days relative to the randomization visit (Visit 201) which 
is considered as day 1 unless other specified.
Baseline
For the analysis purpose, baseline for run-in phase and baseline for double blind phase are 
identified separately as below.
Baseline for run-in phase 
The treatment run-in baseline is defined as the last available measurement prior to starting 
valsartan run-in treatment or at time of Visit 101 or Visit 102, whichever is earlier. They usually 
are collected at screening (Visit 1).
Baseline for double blind phase
Baseline for double blind phase is defined depending on the parameter of interest. In general, 
the baseline for double blind phase is defined as the measurement obtained at the randomization 
visit date (visit 201/ Day 1). Any missing baseline value due to missing value for parameters 
designed to be assessed at randomization will be imputed by the most recent measurement
(scheduled/ unscheduled) taken prior to randomization. 
For the parameters which are not scheduled to be assessed at randomization (height, NT-pro-
BNP), the baseline is defined as the measurement obtained at an earlier visit (scheduled or 
unscheduled) which was closest to Day 1.
On-treatment data
In all the analyses planned in this document, on-treatment data refer to data collected while 
patients are on-study-medication (regardless of treatment interruption) or within a specified 
window after final study drug intake date based on the endpoint of interest.

For cortical SUVr 
 based endpoints, data collected within 6 months after 
final study drug intake date will be considered as on-treatment data.

For all other primary, secondary and exploratory endpoints, data collected within 3 
months after final study drug intake date will be considered as on-treatment data.
2.2
Analysis sets
The following analysis sets will be used for the statistical analyses:

Screened set (SCR) – All patients who signed the informed consent. The screened set
includes only unique screened patients, i.e., in the case of re-screened patients only the
chronologically last screening data is counted.

Enrolled set (ENR) (run-in phase) – All patients who received at least one dose of run-in
study drug.

Valsartan run-in set (VRS) – All patients who are in the ENR and received at least one 
dose of run-in valsartan.

LCZ696 run-in set (LRS) – All patients who are in the ENR and received at least one 
dose of run-in LCZ696.


Novartis
Page 21
SAP Final version 1.0
CLCZ696B2320

Randomized set (RAN) – All patients who received a randomization number, regardless 
of receiving trial medication.

Full analysis set (FAS) – it consists of all randomized patients with the exception of those 
patients who have not been qualified for randomization and have not received study drug, 
but have been inadvertently randomized into the study. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment to which they were assigned 
at randomization.

Safety set (SAF) – it consists of all randomized patients who received at least one dose of 
study drug. Patients will be analyzed according to the treatment actually received. The 
safety population will be used for the analyses of safety variables.

Per-protocol set (PPS) – it is a subset of the FAS which will consist of the patients who 
meet the following conditions:

No major deviations from the protocol procedures in the randomized treatment epoch

Have been exposed to study medication for at least 30 months and have 80% 
compliance on study medication.

Per-protocol set 2 (PPS2): it is defined same as PPS except for the second condition
being patients whose study medication exposure (in months) multiplied by compliance on 
study treatment is at least 24 or above.

PET substudy set (PET) – it consists of SAF patients who participate in PET substudy 
and have non-missing baseline assessment. Separate flags will be created for different 
endpoints.
Appendix 5-3 presents a sample of study specific protocol deviations that lead to exclusion from 
analysis sets in the study. The final list may be different from this and will be signed off before 
DB lock.
2.2.1
Subgroup of interest
Subgroups will be formed to explore the consistency of treatment effects and safety profiling 
on selected parameters between the subgroups and the overall population.
In general, subgroups will be defined based on baseline information. In this study, since we 
have a run-in phase to test patients’ tolerability to the study drugs before they can enter the 
double blind phase, we have defined two baselines (Section 2.1): the run-in baseline and the 
double-blind baseline. Subgroups will be formed using one of these baselines according to their 
analysis purposes.
In Table 2-1, we have listed all subgroups defined for this study and the ways to derive them. 
Subset of these subgroups will be used depending on the parameter under consideration. Also 
note that only important parameters or variables in these analyses will have subgroup analyses. 
The details about the parameters having subgroup analyses will be presented in the 
corresponding sections as appropriate. Also, additional subgroups may be formed later for 
regional or country-wide analyses.


Novartis
Page 22
SAP Final version 1.0
CLCZ696B2320
Table 2-1
Specification of subgroups
Subgroup
Method of 
derivation
Background & 
Demographics / 
Exposure
Efficacy
Safety
Age groups: 
(<65 vs. ≥65 
years)
Screening 
(derived)
X (CogState 
GCCS)
Age groups: 
(<75 vs. ≥75 
years)
Screening 
(derived)
X
X
X
Gender 
(male/female)
Screening
X
X
X
Region*
Derived (pooled
countries or 
country), using
Screening data
X
X
X
Education level
(<12, >=12 years)
Derived using 
screening data
X
X
Baseline MMSE 
cut-off (<28, ≥28)
Derived using 
MMSE at 
randomization
X
X
X
Baseline LVEF 
cut-off (<50%, 
≥50%)
Screening 
X
X
Baseline NYHA 
class (I/II and 
III/IV)
Derived using 
randomization 
data for DB phase 
and screening 
data for run-in 
phase
X
X
APOE4 allele 
status** (+/+, -/+, -
/-)
Randomization
X
X (Dementia 
related AE 
summaries)
Baseline brain 
amyloid status 
(unknown, 
positive, negative)
Randomization
X
X
X
Baseline 
cerebrovascular 
disease burden***
Screening
X
X
X (Dementia 
related AE 
summaries)
Baseline diabetes 
mellitus (Yes, No)
Screening
X (CogState 
GCCS)
SBP status 
(<=140, >140 
mmHg) 
Randomization
X (CogState 
GCCS)
* North America: USA, Canada
Latin America: Argentina
Western Europe: Belgium, France, Germany, Italy, Spain, Switzerland, UK, Netherland


Novartis
Page 23
SAP Final version 1.0
CLCZ696B2320
Central Europe: Bulgaria, Croatia, Lithuania, Russia, Turkey, Poland
Asia Pacific and Others: Australia, Korea, Taiwan
** APOE4 allele status: “+” means e4 is present ; “-” means e4 is absent.
*** Cerebrovascular disease burden score will be assigned to each patient and subgroup will be formed based 
on the grouping of the scores. See Appendix Table 5-3 for the scoring.
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Based on the screened set (SCR), the number and percentage of patients successfully screened 
will be presented. In addition, the primary reasons for screen failures will be summarized by 
presenting number and percentage of patients that screen fail by category. For patients who are 
screened more than once, the information from the last screening will be used in the summary. 
The number and percentage of subjects enrolled, completed, and failed in run-in will be 
summarized for the valsartan run-in and LCZ696 run-in separately. The reasons for run-in 
failures will be provided for all patients in the enrolled set (ENR). The same information for the 
valsartan run-in set (VRS) and LCZ696 run-in set (LRS) will also be summarized.
The number of subjects randomized (RAN) and number of randomized subjects included in 
each of the analysis sets will be presented by treatment group. The number and percentage as 
well as the reasons that subjects had been excluded from the RAN will be summarized by 
treatment group. The number and percentage of randomized subjects who completed the study, 
who discontinued the study and the reasons for discontinuation will be presented for each 
treatment group.
The number and percentage of subjects with protocol deviations as well as the criteria leading 
to exclusion from analysis sets will be presented in separate tables for the RAN. Furthermore, 
the number of subjects enrolled and randomized per region and per country will be presented 
descriptively for the ENR and the FAS, respectively. All the disposition data will also be listed 
at a patient level.
In addition, the number and percentage of subjects in the PET imaging sub-study who 
completed the study, who discontinued the study and the reasons for discontinuation will be 
presented for each treatment group.
2.3.2
Demographic and baseline characteristics
For the run-in phase, summary statistics will be provided by total number of patients based on 
the enrolled set (ENR) for background and demographic characteristics, disease characteristics, 
and cardiovascular risk factors for the run-in phase baseline (Screening visit), including the 
following parameters: 

Continuous variables: Age (in years), weight (in Kg), height (in cm), body mass 
index (BMI, in kg/m2), education level (number of years), number of years of 
continuous employment, number of HF hospitalizations in last 12 months, Ejection 
fraction (in %), NT-pro-BNP, systolic blood pressure (in mmHg), diastolic blood 
pressure (in mmHg), pulse (in bpm), MMSE overall summary score




Novartis
Page 25
SAP Final version 1.0
CLCZ696B2320
The valsartan run-in period (as defined in section 2.1.1), starts at the date when the patient 
receives the first dose of run-in valsartan and ends at the day prior to receiving LCZ696 or when 
the patient discontinued, whichever comes first. The LCZ696 run-in starts at the date when the 
patient receives the first dose of run-in LCZ696 and ends at the day prior to randomization or 
when the patient discontinued, whichever comes first. Accordingly, the duration of treatment 
exposure in each run-in treatment phase is calculated as –

Overall valsartan run-in treatment exposure (days) = min(date patient received the 1st dose 
of run-in LCZ696-1, date when patient failed during run-in, date patient died during run-
in) – date patient received the 1st dose of run-in valsartan +1

Overall LCZ696 run-in treatment exposure (days) = min(date of randomization-1, date 
when patient failed during run-in after 1st dose of LCZ696, date patient died after 1st run-
in dose of LCZ696 during run-in) – date patient received the 1st dose of run-in LCZ696+1 
As specified in section 2.1.1, if the date of the last dose of valsartan run-in medication falls on 
the same day of the first dose of LCZ696 run-in medication, this day will be considered the end 
of the valsartan run-in phase and the following day will be considered as the start of the LCZ696 
run-in phase. In this situation, the above exposure algorithms need to be adjusted accordingly.
Duration of valsartan  run-in treatment exposure will be summarized for all patients in VRS by 
presenting summary statistics (n, mean, standard deviation, min, Q1, median, Q3, max). 
Treatment exposure data for valsartan run-in will also be summarized by presenting frequency 
and percentage of patients with following duration categories-

0 Days

<=1 Week

>1-2Weeks

> 2Weeks
Similarly, duration of LCZ696 run-in treatment exposure will be summarized for all patients in 
LRS by presenting summary statistics (n, mean, standard deviation, min, Q1, median, Q3, max) 
and also by presenting frequency and percentage of patients with following duration categories-

0 Days

<=1 Week

>1-2 Weeks

>2-4 Weeks

>4 Weeks
Treatment exposure during the double-blind Epoch
The duration of the double-blind treatment exposure for a patient, regardless of temporary 
interruptions of usage of the study drug, is defined as date of last study drug intake – first study 
drug intake date  + 1.
Table 2-2
Study drug dose levels during randomized treatment epoch 
Dose level
LCZ696 Treatment arm
Valsartan Treatment arm
3
200 mg bid
160 mg bid


Novartis
Page 26
SAP Final version 1.0
CLCZ696B2320
Dose level
LCZ696 Treatment arm
Valsartan Treatment arm
2
100 mg bid
80 mg bid
1
50 mg bid
40 mg bid
Duration of overall double-blind treatment exposure will be summarized descriptively by 
treatment group (i.e. n, mean, standard deviation, min, Q1, median, Q3, max) and the number 
(percentage) of patients with following by duration categories will also be provided:

<=6 months

>6 months - 12 months

>12 months - 18 months

>18 months - 24 months

>24 months - 30 months

>30 months
Duration of treatment exposure in double-blind period will be summarized by dose levels 
permitted for titration in each treatment arm according to Table 2-2. 
Overall patient-years on-treatment and average patient-year on-treatment will be reported by 
each treatment group.

Overall patient-years on-treatment = Sum of duration of treatment exposure (in days) 
from all patients / 365.25

Average patient-years on-treatment = Overall patient-years on-treatment / Number of 
patients randomized to the treatment
Duration of overall double-blind treatment exposure excluding treatment interruptions, 
computed as date of last study drug intake – first study drug intake date + 1 – number of days 
of treatment interruption, will also be summarized descriptively and by duration categories as 
above. For overlapping start date of current dose level and end date of previous dose level, 
“+0.5” day will be used instead of “+1” day.
Average daily dose for each patient during double-blind period will be summarized by treatment 
group, by providing summary statistics (i.e. n, mean, standard deviation, min, Q1, median, Q3, 
max). Average daily dose for each patient is calculated as:
∑
(Number of days on dose level ′i′)x(Dose level ′i′)x2
!
"#$
∑
(Number of days on dose level ′i′)
!
"#$
The number and percentage of patients at each dose level (Table 2-2) will be summarized by 
visit and treatment group as well. 
Apart from the above analyses, dose administration records for double-blind period will also be 
listed at a patient level for the patients in safety set with reasons for changing dose.
Number and percentage of patients with treatment interruption and permanent treatment 
discontinuations will be provided by reason for treatment interruption or discontinuation. Time 
from randomization to permanent study treatment discontinuation will be summarized by 
treatment group by providing Kaplan-Meier estimate of cumulative rate of permanent treatment 
discontinuation.


Novartis
Page 27
SAP Final version 1.0
CLCZ696B2320
Compliance with respect to protocol specified study treatment will be summarized based on the 
site reported compliance for by actually received treatment group and overall during 
randomized treatment epoch for all patients in Safety set (SAF) 
All these analyses pertaining to treatment exposure during double-blind period will be carried 
out for all patients in Safety set (SAF). Compliance summary will also be provided for patients 
in Full Analysis set (FAS). 
Summaries of duration of treatment exposure in the double-blind phase will also be provided 
separately for subjects included in the PET imaging substudy. 
2.4.2
Prior, concomitant and post therapies
Medications will be identified using Novartis Drug and Therapy Dictionary, NovDTD which is 
a modified Novartis internal version WHO Drug Dictionary Enhanced (DDE) including 
Anatomical Therapeutic Chemical (ATC) code. The latest version at the time of database lock 
will be used.
For the run-in phase, the run-in concomitant medication information will be summarized based 
on the ENR. 
Prior and run-in concomitant medications taken at any time between the screening visit and 
the randomization visit will be summarized in sequential format by treatment of valsartan for 
the VRS and LCZ696 for the LRS based on the latest version of the dictionary. Medications 
will be presented in alphabetical order, by ATC codes and grouped by anatomical main group 
(the 1st level of the ATC codes). Tables will show the overall number and percentage of patients 
receiving at least one drug of a particular ATC code and at least one drug in a particular 
anatomical main group.
Prior medications are defined as drugs taken prior to first dose of run-in study medication. 
Any medication given at least once between the day of first dose of run-in study medication and 
the last day prior to randomization visit will be a run-in concomitant medication, including 
those which were started pre-screening and continued into the run-in phase. Prior or run-in 
concomitant medication will be identified based on recorded or imputed start and end dates of 
taking medication. The rules for imputing incomplete (start and end) dates are described in 
Section 5. 
The concomitant medication information for the double blind phase will be summarized based 
on the SAF. 
Concomitant medications taken at any time since the randomization visit will be summarized 
by treatment group based on the latest version of the dictionary. As before, medications will be 
presented in alphabetical order, by ATC codes and grouped by anatomical main group (the 1st
level of the ATC codes). Tables will also show the overall number and percentage of subjects 
receiving at least one drug of a particular ATC code and at least one drug in a particular 
anatomical main group.
Any medication given at least once between the day of first dose of randomized study 
medication and the last day of study visit will be a double-blind concomitant medication, 
including those which were started pre-randomization visit and continued into the double blind 
treatment phase.


Novartis
Page 28
SAP Final version 1.0
CLCZ696B2320
Heart Failure and CV medications
The following important classes of concomitant heart failure and CV medications administered 
during run-in and during double blind phase will be summarized separately in a similar way as 
described above.

ARBs

ACE inhibitors

Renin inhibitors

Diuretics

Beta blockers

Aldosterone antagonists

Cardiac glycosides (Digoxin/digitalis glycoside)

Calcium antagonists

Other vasodilators

Oral anticoagulants

Antiarrhythmic agents

Aspirin

Other antiplatelet agents

Statins

Nitrates

Other lipid lowering agents

SGLT2
Medications for treating AD or cognitive impairment
Concomitant use of AD or cognitive impairment related medication will be summarized by 
treatment group separately for patients newly starting such medications during post-
randomization phase. Treatments for AD or cognitive impairment include:

Glutamate receptor antagonists (memantine) 

Cholinesterase inhibitors (donepezil, galantamine, and rivastigmine).
The classes of medications criteria searching the heart failure, CV medications and AD or 
cognitive impairment medications will be defined in a separate EXCEL sheet with ATC 
preferred term and WHO drug code. This EXCEL sheet will be stored in CREDI at the RAP 
level after the content is agreed to by the Global Program Medical Director (GPMD) and prior 
to CDBL
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary variable is the change from baseline (baseline definition as in section 2.1.1) to 3 
years in the CogState Global Cognitive Composite Score (GCCS). The CogState cognitive test 
battery includes the following seven tasks:


Novartis
Page 29
SAP Final version 1.0
CLCZ696B2320
1. Detection Test (DET) – Assesses psychomotor function using the speed 
(milliseconds) of correct responses in a simple reaction time paradigm 
2. Identification Test (IDT) – Assesses visual attention using the speed (milliseconds) 
of correct responses in a simple reaction time paradigm
3. Continuous Paired Associate Learning (CPAL) – Assesses visual episodic memory 
measuring accuracy of performance by the number of errors made over 6 learning 
trials
4. One back (ONB) - Assesses working memory using the speed (milliseconds) of 
correct responses in a n-back paradigm
5. International Shopping List Test (ISLT) – Assesses verbal learning using the 
accuracy (number of words recalled correctly) of recall in a verbal list learning 
paradigm
6. International Shopping List Test – delayed recall (ISLT-DR) - Assesses verbal 
memory using the accuracy (number of words recalled correctly) of delayed recall in 
a verbal list learning paradigm
7. Groton Maze learning Test (GMLT) – Assesses executive function using the 
number of total errors (number of error responses over 5 trials) in a hidden pathway 
maze learning paradigm
Standardized z-scores for each outcome measure and visit will be calculated using the sample 
baseline mean and standard deviation of individual tasks as follows:

ZDET = − (Log10(DET) – baseline mean of log10(DET))/SD of log10(baseline DET),

ZIDT = − (Log10(IDT) – baseline mean of log10(IDT))/SD of log10(baseline IDT),

ZCPAL = (CPAL total errors – baseline mean of CPAL total errors/SD of baseline 
CPAL total errors),

ZONB = − (Log10(ONB) – baseline mean of log10(ONB))/SD of log10(baseline ONB),

ZISLT = (ISLT – baseline mean of ISLT))/SD of baseline ISLT,

ZISLT-DR = (ISLT-DR) – baseline mean of ISLT-DR))/SD of baseline ISLT-DR,

ZGMLT = − (GMLT – baseline mean of GMLT))/SD of baseline GMLT
Note that negative sign is included in the calculation for tasks where increasing values indicate 
worsening performance (i.e., ZDET, ZIDT, ZCPAL, ZONB and ZGMLT) so that for all standardized 
change scores negative values indicate a decline from baseline while positive scores indicate 
improvement from baseline.
These seven individual z-scores are then combined to generate the GCCS: 
CogState GCCS = average of (ZDET, ZIDT, ZCPAL, ZONB, ZISLT, ZISLT-DR, ZGMLT)
The composite score will be computed if at least five of the seven tests are completed and the 
five tests provide an assessment of the three cognitive domains as defined below being assessed. 
That is, a composite score requires that each cognitive domain be measured by at least one 
cognitive test.
In addition to the GCCS, composite scores for three main subdomains memory, attention and 
psychomotor function will also be generated by combining the standardized change from 
baseline scores for individual tests from the CCB using the following formulae:


Novartis
Page 30
SAP Final version 1.0
CLCZ696B2320

Composite score of memory tests = average of (ZCPAL, ZISLT, ZISLT-DR)

Composite score of executive function tests = average of (ZONB, ZGMLT)

Composite score of attention tests = average of (ZDET, ZIDT)
Each composite score will be the average of the non-missing individual test z-scores.
2.5.2
Statistical hypothesis, model, and method of analysis
The change from baseline in the GCCS of CogState test battery will be analyzed using a 
repeated measures analysis of covariance (ANCOVA) model in which treatment, age 
stratification factor, MMSE stratification factor, education level, APOE4 status (carrier vs. non-
carrier), baseline cerebrovascular disease burden, visit (Weeks 26, 52, 78, 104, 130 and Week 
156) and treatment-by-visit interaction are included as fixed-effect factors and baseline GCCS 
and visit-by-baseline GCCS interaction as covariates, with a common unstructured covariance 
matrix among visits between treatment groups. The adjusted mean changes at 3 years (Week 
156) within each treatment, the difference in mean changes at 3 years (Week 156) between the 
two treatments, and its 95% confidence interval obtained from the above model will be 
presented. In addition, the treatment difference (LCZ696-valsartan) in mean changes from 
baseline to 3 years will also be expressed based on a standardized effect size (Cohen’s d) with 
a 2-sided 95% confidence interval. The Cohen’s d will be estimated by using the adjusted 
between-treatment mean difference, divided by the estimated pooled standard deviation. The 
estimated standard deviation for the mean difference is:
%&
= ( 1
*+
+ 1
*
-
+/
	/
where n1 and n2 are the number of patients within each treatment group and 	/ is the pooled 
standard deviation of the within treatment group adjusted mean change. Cohen’s d can be re-
written in terms of t value of the estimated between treatment group difference based on the 
adjusted mean changes from the model mentioned above:
 = 0+
1 −0
1
%&
=
0+
1 −0
1
3 1
*+ + 1
*4
+
 	/
56 = 0+
1 −0
1
	/
= ( 1
*+
+ 1
*
-
+

× 
Confidence interval (CI) of Cohen’s d is based on 95% CI of the noncentrality parameter of t 
value divided by the square root of the degrees of freedom from the estimated between treatment 
group adjusted mean change (Cumming and Finch 2001). The analysis is based on a direct 
likelihood method with an assumption of missing at random (MAR) for the missing data 
mechanism.
As the primary analysis, the repeated measure ANCOVA model will be performed in the Safety 
set including ‘on-treatment’ data (section 2.1.1) collected prior to the start of treatments for AD 
or cognitive impairment. The Cohen’s d based on the adjusted difference in mean changes at 3 


Novartis
Page 31
SAP Final version 1.0
CLCZ696B2320
years (Week 156) between two treatments and its 95% confidence interval from this model will 
be used to draw the main conclusion for the primary objective. As defined in section 2.1.1, on-
treatment data refer to cognitive test data collected while patients are on-study-medication 
(regardless of treatment interruption) or within three months after final study drug intake date.
When above mentioned model does not converge, the primary analysis model will be modified 
by replacing the common unstructured covariance matrix with a compound symmetry 
covariance matrix between treatment groups and provide above mentioned estimates. If 
convergence issue remains after implementing the compound symmetry covariance matrix, the 
model will be simplified by removing baseline cerebrovascular disease burden as explanatory 
factor from the model.
2.5.3
Handling of missing values/censoring/discontinuations
The repeated measure ANCOVA modeling as described in the previous section is based on a 
direct likelihood method with an assumption of missing at random for the missing data 
mechanism. That means, missing data, including those from dropouts, will be implicitly 
predicted based on similar patients. By similar we mean patients with similar baseline 
covariates, measurement histories and who were randomized to the same treatment arm. 
Various analyses to assess the sensitivity of the primary analysis results to the MAR assumption 
are described in section 2.5.5.
Data collected more than three months after patients permanent discontinuation of the study 
medication will be excluded from analyses in both the Safety and PPS analyses. In addition, 
data collected after patients starting treatments for AD or cognitive impairment will be excluded 
from “on-treatment” analyses.
Patients with no post-baseline assessments available will be excluded from the primary analysis. 
However, these patients will contribute to the imputation model for the missing GCCS scores 
in the sensitivity analyses. 
Table 2-3
Overview of missing data handling in analyses for primary endpoint
Analysis
Analysis Set
Data excluded
Missingness 
assumption
Analysis 
method
Time points 
included
Imputed 
dataset 
required?
Estimand: The treatment effect had all patients stayed ‘on-treatment’ for the 3-year planned follow-up duration
(Under ‘as-treated’ principle)
Primary
SAF
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MAR
Repeated 
measure 
ANCOVA
Weeks 26, 52, 
78, 104, 130 
and Week 156
No
Sensitivity
to Primary 
analysis
SAF
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MNAR for 
missing data 
due to death, 
HF hosp., 
stroke 
Tipping point 
analysis 
followed by 
ANCOVA
Baseline,
Weeks 26, 52, 
78, 104, 130 
and Week 156
Yes


Novartis
Page 32
SAP Final version 1.0
CLCZ696B2320
SAF
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MNAR for 
missing data 
after starting 
treatments for 
AD or cognitive 
impairment 
Tipping point 
analysis 
followed by 
ANCOVA
Baseline, 
Weeks 26, 52, 
78, 104, 130 
and Week 156
Yes
SAF
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MNAR for 
missing values 
due to 
withdrawal for 
unknown 
reasons 
Tipping point 
analysis 
followed by 
ANCOVA
Baseline, 
Weeks 26, 52, 
78, 104, 130 
and Week 156
Yes
SAF
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MNAR for 
missing data 
after starting 
treatments for 
AD or cognitive 
impairment 
Jointly model 
longitudinal 
measurements 
and time to 
starting 
treatments for 
AD or cognitive 
impairment
Baseline, 
Weeks 26, 52, 
78, 104, 130 
and Week 156
No
Estimand: The treatment effect had all patients completed the planned follow-up of 3 years regardless of premature 
study drug discontinuation (under ‘Intention-To-Treat’ principle) 
Supportive
FAS
No
MAR
Repeated 
measure 
ANCOVA
Weeks 26, 52, 
78, 104, 130 
and Week 156
No
Sensitivity to 
supportive 
analysis
FAS
No
MNAR due to 
death, HF 
hosp., stroke 
Tipping point 
analysis 
followed by 
ANCOVA
Baseline, 
Weeks 26, 52, 
78, 104, 130 
and Week 156
Yes
FAS
No
MNAR after 
starting 
treatments for 
AD or cognitive 
impairment 
Tipping point 
analysis 
followed by 
ANCOVA
Baseline, 
Weeks 26, 52, 
78, 104, 130 
and Week 156
Yes
Estimand: The treatment effect had all patients completed the study treatment as per protocol schedule without 
major protocol deviations (under ‘as treated’ principle)
Supportive
PPS
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MAR
Repeated 
measure 
ANCOVA
Weeks 26, 52, 
78, 104, 130 
and Week 156
No
PPS2
Off-treatment 
(>3 months 
after last dose)
After start of 
treatment for 
AD or cognitive 
impairment
MAR
Repeated 
measure 
ANCOVA
Weeks 26, 52, 
78, 104, 130 
and Week 156
No
Estimand: Measure of treatment effect of interest
MAR = Missing At Random; MNAR = Missing Not At Random; MI = Multiple Imputation
Following sections provide more detail on the specifications for supportive and sensitivity 
analyses on primary endpoint as outlined above.


Novartis
Page 33
SAP Final version 1.0
CLCZ696B2320
2.5.4
Supportive analyses
In addition to the planned primary analysis in Section 2.5.2, the same repeated measure 
ANCOVA will be performed in the following three analysis sets as supportive analyses as 
described in Table 2-3:

Targeting treatment effect had all patients completed planned follow up of 3 years 
regardless of early study drug discontinuation
Based on FAS, including all available data (even after treatment discontinuation and after 
start of treatments for AD or cognitive impairment)

Targeting treatment effect had all patients completed the study treatment as per 
protocol schedule without major protocol deviations 
Based on the per-protocol set, including ‘on-treatment’ data collected prior to the start of 
treatments for AD or cognitive impairment only.

Targeting treatment effect had all patients completed the study treatment as per 
protocol schedule without major protocol deviations and study treatment exposure 
and compliance defined in PPS2 
Based on the per-protocol set 2 (PPS2), including ‘on-treatment’ data collected prior to the 
start of treatments for AD or cognitive impairment only.
Summaries of absolute values and change from baseline in the GCCS and domain-specific 
composite z-scores by treatment group and visit will be presented. Figures will be produced to 
visually show both the raw and the model-based mean global composite z-scores and mean 
domain-specific composite z-scores by visit over study period for each treatment group. These 
will be done in both the Safety and FAS with the same data inclusion rules as for the above 
repeated measure ANCOVA modeling in the Safety and FAS.
Analysis of primary endpoint will also be performed based on pre-defined subgroups as in 
Section 2.2.1 on the Safety set including ‘on-treatment’ data collected prior to the start of 
treatments for AD or cognitive impairment. The analysis will be done using a similar repeated 
ANCOVA model as for the primary analysis at individual subgroup level separately, while the 
p-values of the subgroup-by-treatment interaction will be derived from a similar model but with 
additional terms including the subgroup, the interaction term of subgroup-by-treatment.
2.5.5
Sensitivity analysis
The primary analysis methods are consistent under the assumption of ‘missing at random 
(MAR)’ for the missingness mechanism. Though this is deemed to be an appropriate choice for 
the primary analysis, this is an untestable assumption based on the observed data (CHMP, 2010, 
National Research Council, 2010). Indeed it is conceivable that censoring, respectively the 
missing data  mechanism (e.g., due to death) may be informative and that the cognitive function 
decline in patients who died would have been steeper than estimated under the MAR assumption. 
Thus, the primary analysis would favor the valsartan group in the presence of a reduction in
mortality in the LCZ696 group. Alternatively, patients starting medications for treatment of AD 
or cognitive impairment may have had a steeper decline than estimated under the MAR 
assumption, if they would have not started the medication.  


Novartis
Page 34
SAP Final version 1.0
CLCZ696B2320
Due to this uncertainty on the missingness mechanism, the following sensitivity analyses will 
be performed to investigate the sensitivity of the primary analysis results to the MAR 
assumption. 
Tipping point analysis
First, a tipping point analysis (Permutt 2016), which falls into the class of pattern mixture 
models, will be performed to evaluate the MAR assumption for missing data due to death, HF 
hospitalization and stroke. 
This sensitivity analysis assumes that missing data due to death, HF hospitalization and stroke
are missing not at random (MNAR). More specifically, it assumes that missing GCCS values 
due to death, HF hospitalization and stroke could have been worse than those imputed under 
the MAR assumption.  It is implemented in the following steps:
1. Multiple (e.g. 100) imputations of missing GCCS values under a MAR assumption are 
generated, resulting in multiple (100) complete data sets. This imputation is based on 
predicted GCCS values from the fitted repeated measures ANCOVA model for the 
GCCS values (at baseline, Weeks 26, 52, 78, 104, 130 and Week 156) with treatment, 
age group (<75, ≥75 years), baseline MMSE status (<28, ≥28), baseline cerebrovascular
disease burden, visit and treatment-by-visit interaction as factors having fixed effects 
assuming a common unstructured covariance matrix among visits between treatment 
group. SAS proc MI FCS statement is used to impute missing values in the following 
sequence: factor variables in the increasing order of missing frequency, the GCCS at 
baseline, Weeks 26, 52, 78, 104, 130 and Week 156. 
2. For each completed data set, the imputed GCCS values at a given visit for patients who 
died, or had a HF hospitalization or stroke since the preceding visit, a penalty factor 
would be applied to the imputed values to reflect that the MAR approach may have 
overestimated the missing values, e.g. by assuming the actual GCCS values could be a 
certain percentage (e.g. 5%) worse than MAR based imputations for discontinuations 
due to death, HF hospitalization and stroke. If the MAR-imputed GCCS value is 
positive, the final value will be 95% x the imputed value; if the MAR-imputed GCCS 
value is negative, the final value will be 105%  x the imputed value.
3. The primary analysis model as described above will be fitted to the 100 completed data 
sets following the application of the penalty factor in step 2 which produces 100 sets of 
parameter estimates and associated covariance matrices.
4. These 100 sets of parameter estimates are then combined by using Rubin’s rules to 
derive overall estimates and their confidence intervals. In a similar manner to the 
primary analysis, a standardized effect size estimate (Cohen’s d) and 95% CI will also 
be reported using the pooled SD.
The analysis will be repeated for varying penalty factors in a range between 0 and 50%. It is 
performed using ‘on-treatment’ data in the SAF, as done in the primary analysis. Tipping point 
analyses will be performed separately to assess the sensitivity of the results to MAR 
assumptions under the following situations:


Novartis
Page 35
SAP Final version 1.0
CLCZ696B2320

for missing data due to censoring at the start of AD and cognitive impairment treatments, 
including on-treatment data only in the SAF

for missing data due to withdrawal for unknown reasons, including on-treatment data 
only in the SAF

for missing data due to censoring at the start of AD and cognitive impairment treatments, 
including all data in the FAS

for missing data due to withdrawal for unknown reasons, including all data in the FAS
In a similar procedure, missing values due to respective reasons will be imputed assuming 
MNAR while assuming all other missingness mechanism to be MAR.
If model convergence issue arises in the tipping point analysis, the model in step 1 above will 
be modified by replacing the common unstructured covariance matrix with a compound 
symmetry covariance matrix between treatment groups. If convergence issue remains after 
implementing the compound symmetry covariance matrix, the model will be simplified by 
removing baseline cerebrovascular disease burden as explanatory factor from the model.
Joint model approach
To adjust for the non-ignorable missingness in the primary endpoint due to starting AD/CI 
related medication, a joint modeling of the primary longitudinal process and missingness 
mechanism will be performed using a shared parameter approach (Vonesh et al 2006). 
Specifically, a generalized linear mixed model (GLMM) for the longitudinal GCCS outcome 
and a Cox proportional hazard model for the time to starting AD/CI related medication will be 
fitted which share common unobserved patient-specific random effect. It is assumed that the 
longitudinal outcome process is independent of the time to starting AD/CI related medication 
conditional on the random effects.
Model for longitudinal outcomes
The repeated GCCS outcomes will be analyzed following a repeated measures ANCOVA 
model with treatment, age stratification factor, MMSE stratification factor, education level, 
baseline cerebrovascular disease burden, APOE4 status (carrier vs. non-carrier) are included as 
factors and baseline GCCS, assessment time (in days), assessment time by baseline GCCS and 
assessment time by treatment interaction as covariates having fixed effects. Further, a patient-
specific random intercept and random slope (on time) is fitted to the model. In general, the 
model has the following mathematical form: 
8() = 9() + ()
9() = :
;()< + (=$ + =+)
where
8() =GCCS outcome for i-th patient at time t (assessment time in months)
9() =’True’ (unobserved) patient-specific mean GCCS outcome for i-th patient at time t
:() = Covariate vector having fixed effects on mean GCCS outcome for i-th patient 
(treatment, age stratification factor, MMSE stratification factor, education level, baseline 


Novartis
Page 36
SAP Final version 1.0
CLCZ696B2320
cerebrobascular disease burden, APOE4 status, baseline GCCS, assessment time, assessment 
time by baseline GCCS and assessment time by treatment)
< = Parameter vector representing fixed effects of covariate vector :() on mean GCCS 
outcome at time t
=$ =Patient-specific random intercept 
=+ =Patient-specific random slope on time
() = Measurement error, 
Assumption: 

(=$, =+)’s are assumed to be following bivariate normal distribution with mean 
vector 0 and unstructured covariance matrix independently for all patients

()’s are assumed to be independently normally distributed with mean vector 0 and 
an covariance matrix with no correlation between the time points and an common 
variance 	
 on the diagonal elements
Model for time to starting AD or CI related medication
Time to starting AD or CI related medication from randomization will be calculated as –

Date of starting AD or CI related medication – Randomization date +1
Patients who do not start AD or CI related medication, their data will be censored at the earlier 
of –

Last known date patient took study medication

Date of withdrawal of consent 

Date of last visit 
A exponential regression is fitted to the time to starting AD or CI related medication. 
?(|A(), :) = ?$exp(:
;C + D9())
where 
?(|A(), :) =Conditional intensity function at time t for i-th patient given the covariate and 
history of outcomes until time t, A()
?$ =Baseline hazard function that is constant over time
C = Parameter vector representing fixed effects of time-independent covariate vector : on 
event risk (hazard) at time t
D =Fixed effect of ‘true’ patient-specific mean outcome at time t
A constant function will be assumed for the baseline intensity function. over time. Assuming 
that the longitudinal GCCS outcome process and event process of starting AD or CI related 
medication are independent conditional on the random effects, the conditional likelihood is 
computed as multiplication of the likelihood from GCCS outcome process and event process. 
Parameter estimation will be done through numerically maximizing the marginal likelihood 
obtained from numerically integrating the conditional likelihood over the distribution of random 
effects.


Novartis
Page 37
SAP Final version 1.0
CLCZ696B2320
Of note, the modeling may fail to converge yielding unreliable or no estimate for parameters if 
the incidence of start of AD/CI related medication are low. In such a case, restrictions may be 
imposed on the form of baseline intensity function to change to a parametric baseline intensity 
(e.g. Weibull function) which will be documented in the clinical study report section 9.7. If the 
model still fails to converge, the results may be excluded from the clinical study report.
2.5.5.1
Mis-stratification
For randomization stratification that is done incorrectly due to transciption error or inconsistent 
site and central reviewer readings, primary analysis described in Section 2.5.2 will be repeated 
using the final data entered in the clinical database, instead of the stratification factors in IVR 
system. 
2.6
Analysis of secondary efficacy objective(s)
2.6.1
Secondary endpoints
The secondary efficacy variables are –
1. Change from baseline in individual cognitive domains (memory, executive function, and 
attention) as assessed by the individual components of the cognitive assessment battery at 
3 years.
2. Change from baseline in the summary score of the instrumental activities of daily living 
(IADL) as assessed with Functional Activity Questionnaire (FAQ) at 3 years.
Composite scores for three main subdomains memory, attention and psychomotor function will 
also be generated by combining the standardized change from baseline scores for individual 
tests from the CCB using the following formulae:
Composite score of memory tests = average of (ZCPAL, ZISLT, ZISLT-DR)
Composite score of executive function tests = average of (ZONB, ZGMLT)
Composite score of attention tests = average of (ZDET, ZIDT)
Each composite score will be the average of the non-missing individual test z-scores.
2.6.2
Statistical hypothesis, model, and method of analysis
For secondary efficacy variables composite z-scores by individual domain (memory, executive 
function and attention) and IADL, the changes from baseline to 3 years will be analyzed using 
the same repeated measures ANCOVA model as described in Section 2.5.2 but with baseline 
GCCS replaced with respective secondary variable baselines. The adjusted mean changes at 3 
years (Week 156) within each treatment, the difference in mean changes at 3 years (Week 156) 
between two treatments, its 95% confidence interval obtained from the above model will be 
presented. In addition, the treatment difference (LCZ696-valsartan) in mean changes from 
baseline to 3 years will also be expressed in terms of a standardized effect size (Cohen’s d) with 
a 2-sided 95% confidence interval. The Cohen’s d will be estimated as in a similar manner as 
planned for the primary endpoint analysis (Section 2.5.2). The analysis is based on likelihood 
method with an assumption of missing at random for missing data, and will be performed in the 
Safety set including ‘on-treatment’ data collected prior to the start of treatments for AD or 
cognitive impairment. On-treatment data are those collected while patients are on-study-




Novartis
Page 39
SAP Final version 1.0
CLCZ696B2320
mechanism. Following table provides an overview of missing data handling for cortical 
composite SUVr data with corresponding assumptions on missingness.
Table 2-4
Overview of missing data handling in analysis of change from 
baseline in SUVr at 3 years
Analysis
Analysis Set
Data excluded
Missingness 
assumption
Analysis 
method
Time points 
included
Imputed 
dataset 
required?
Estimand: The treatment effect had all patients stayed ‘on-treatment’ for the 3-year planned follow-up duration
(Under ‘as-treated’ principle)
Primary
SAF (restricted 
to PET imaging 
substudy)
Off-treatment 
(>6 months 
after last dose)
MAR
MI followed by 
ANCOVA
Baseline, 
Month 18, Year 
3, and all other 
post-BL 
measurements 
<= 6 months 
after last dose 
Yes
Sensitivity
SAF
(restricted to 
PET imaging 
substudy)
Off-treatment 
(>6 months 
after last dose)
Data outside 6-
months 
window from 
scheduled visit
MAR
Repeated 
measure 
ANCOVA
Month 18, Year 
3
No
Sensitivity 
SAF
(restricted to 
PET imaging 
substudy)
Off-treatment 
(>6 months 
after last dose)
MNAR for 
missing due to 
death, HF 
hospitalization 
and stroke -
tipping point 
anaysis
MI (tipping 
point anaysis) 
followed by 
ANCOVA
Baseline, 
Month 18, Year 
3, and all other 
post-BL 
measurements 
<= 6 months 
after last dose
Yes
Estimand: Measurement of treatment effect of interest
MAR = Missing At Random; MNAR = Missing Not At Random; MI = Multiple Imputation
The imputation model will include age stratification factor, MMSE stratification factor, region, 
baseline cerebrovascular disease burden, APOE4 status (carrier vs non-carrier), baseline 
amyloid status (positive/negative) and time (when the SUVr is assessed in days) as fixed effects 
with random intercept and slope (time) and a common unstructured covariance. This will be 
done separately within each treatment. Missing values will be imputed by the predicted values 
following from the fitted imputation model with random effects and random errors simulated 
from their respective distributions. SAS proc MCMC is used to impute missing values described 
above.
This imputation process will first create multiple imputations of missing SUVr at 3 years under 
a MAR assumption, resulting in multiple complete data sets after combining the imputed 
missing SUVr at 3 years values with the available SUVr at 3 years (so every patient with 
baseline SUVr in these multiple complete data sets will have an SUVr value at 3 years). An 
ANCOVA model using change from baseline to 3 years in SUVr as response variable, with 
treatment, age stratification factor, MMSE stratification factor, region, baseline cerebrovascular 
disease burden, APOE4 status, baseline amyloid status as factors and baseline SUVr value and 
treatment-by-baseline SUVr interaction as covariates will be run on each of these multiple 
completed data sets. Overall results and inference, including adjusted mean change at 3 years 
within each treatment, the difference in mean change at 3 years between two treatments, its 95% 


Novartis
Page 40
SAP Final version 1.0
CLCZ696B2320
confidence interval, are obtained by applying Rubin’s rules on the estimates obtained from the 
imputed/completed data sets.
If covergence issue arises, the imputation model will be modified by replacing the common 
unstructured covariance with a common compound symmetry covariance between treatment 
groups. If convergence issue remains after implementing the compound symmetry covariance 
matrix, the model will be simplified by removing baseline cerebrovascular disease burden as 
explanatory factory from the model.
2.7.1.1
Supportive analysis
Both the actual SUVr values and change from baseline values will be descriptively summarized 
for each treatment group by each assessment visit over study period by providing summary 
statistics (n, mean, SD, median, Q1, Q3, min, max). Additionally, number and percentage of 
patients with positive PET scan will be reported for each treatment group by each assessment 
visit. Available SUVr data at ‘end of treatment’ and ‘end of study’ will be summarized 
separately as above.
To assess the sensitivity of the primary analysis method results to the imputation model, a 
sensitivity analysis will be performed on the change in a cortical composite SUVr from baseline 
to 3 years by incorporating information from other assessments still under the assumption of 
MAR. The change from baseline in SUVr will be analyzed based on a repeated measures 
ANCOVA model in which treatment, age stratification factor, MMSE stratification factor, 
region, baseline cerebrovascular disease burden, APOE4 status (carrier vs. non-carrier), 
baseline amyloid status (positive/negative), visit (18 months, 3 years), and treatment-by-visit 
interaction will be included as fixed-effect factors and baseline value and baseline-by-treatment 
as covariates, with a common unstructured covariance matrix among visits between treatment 
groups. The adjusted mean changes at 3 years (Week 156) within each treatment, the difference 
in mean changes at 3 years (Week 156) between two treatments, its 95% confidence interval 
obtained from the above model will be presented. The analysis is based on likelihood method 
with an assumption of missing at random for missing data.
To assess the sensitivity of the primary analysis methods results to the baseline amyloid status
(positive/negative) based on quantitative (numerical) cutoff instead of qualitative (visual) 
assessment, a sensitivity analysis will be performed using the same ANCOVA model specified 
in Section 2.7.1 but with the quantitative positive/negative assessment of the baseline brain 
amyloid status. A shift table to summarize the proportion of patients’ amyloid status change 
over time from baseline i.e. patients transitioning from negative to positive based on 
quantitative assessment will also be provided by treatment group.
In addition, to assess the sensitivity of the analysis results to the MAR assumption used in the 
multiple imputation for primary analysis method, a tipping point analysis will be performed on 
the change from baseline in SUVr which assumes that missing values after death, HF 
hospitalization and stroke are missing not at random (MNAR). This analysis will follow the
same procedure as described in section 2.5.5 for the primary endpoint, with the exception that 
the imputations under MAR are obtained from a regression based imputation as described in 
the primary analysis method of this endpoint (Section 2.7.1). The analysis will be repeated for 
varying penalty factors in a range between 1 and 1.6.


Novartis
Page 41
SAP Final version 1.0
CLCZ696B2320
If convergence issue arises in any of above described supportive analyses, the handling 
approach described in Section 2.7.1 will be used to address the convergence issue.
Furthermore, to assess the sensitivity of the analysis results to the randomization stratification 
that is done incorrectly due to transciption error or inconsistent site and central reviewer 
readings, analysis described in Section 2.7.1 will be repeated using the final data entered in the
clinical database, instead of the stratification factors based on IVR system.
To address missing assessments due to COVID-19 pandemic, the analysis mentioned in Section 
2.7.1 will be repeated using PET substudy set with a wider assessment window extending from 
6 months to 9 months for assessments that are scheduled to take place starting Mar 1, 2020 and 
onwards. This also applies to the data excluded from analysis if assessment is done more than 
9 months after last study drug intake instead of 6 months.
All analyses will be performed in patients in the Safety set who participate in the PET image 
substudy and with non-missing baseline, including ‘on-treatment’ data only. On-treatment data 
refer to the SUVr values obtained while patients are on-study-medication (regardless of 
treatment interruption), or within defined window in each supportive analysis (six months or 
nine months) after the final study drug intake date.
In addition, for patients who do not have any post-baseline SUVr assessments and part of the 
reason is due to concerns over exposure to COVID-19 by visiting the site, the analysis 
mentioned in Section 2.7.1 will be repeated using PET substudy set excluding patients without 
any post-baseline assessments, including ‘on-treatment’ data only (within six months after the 
final study drug intake date).


Novartis
Page 42
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 43
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 44
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 45
SAP Final version 1.0
CLCZ696B2320
2.7.3
Deaths
Patients that died during the study period will be reported separately for run-in and double-blind 
treatment epochs. Deaths occurring during the double-blind treatment epoch will be 
summarized by actually received treatment group to present number and percentage of patients 
that died by overall and reason categories (CV/non-CV causes as reported by investigator). In 
addition, listings will be provided for patients that died during the study period with the primary 
reason of death. 
The analysis will consider all patients in the Safety set (SAF) for reported deaths during the 
double-blind treatment epoch while deaths during the run-in epoch will be reported based on 
patients in the Enrolled set (ENR).


Novartis
Page 46
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 47
SAP Final version 1.0
CLCZ696B2320
2.8
Pharmacokinetic endpoints  
Not applicable
2.9
PD and PK/PD analyses
Not applicable.
2.10
Patient-reported outcomes
Following Patient reported outcomes (PRO) are collected by sites at respective visits.
1. Instrumental activities in daily life (IADL) as assessed through Functional activity 
questionnaire (FAQ)


Novartis
Page 48
SAP Final version 1.0
CLCZ696B2320
Analysis method for outcome (1) has been outlined in section 2.6.2 for secondary endpoints. 
The analysis methods for other outcomes will be described in Section 2.12 as part of the 
exploratory endpoint analyses. 
2.11
Biomarkers
For plasma Aβ1-40, the log-transformed ratio to baseline i.e. log (post-dose value/baseline) will 
represent the change from baseline in logarithmic change for each subject at every post-dose 
time point, The change from baseline to a pre-defined time-point (Weeks 13, 52, 104 and 156) 
in logarithmic scale will be analyzed using a repeated measures ANCOVA model in which 
treatment, age stratification factor, MMSE stratification factor, education level, APOE4 status 
(carrier vs. non-carrier), visit (Weeks 13, 52, 104 and Week 156) and treatment-by-visit 
interaction are included as fixed-effect factors and baseline log-transformed plasma Aβ1-40 and 
visit by baseline log-transformed plasma Aβ1-40 interaction as covariates, with a common 
unstructured covariance matrix among visits between treatment groups. The adjusted mean 
changes within each treatment, the difference in mean changes between the two treatments, and 
its 95% confidence interval obtained from the above model will be presented for all the 
assessment visits. All the estimates will be back-transformed to natural scale for reporting. 
Descriptive summaries of absolute values and change from baseline in Aβ1-40 by treatment 
group and visit will be presented using summary statistics (n, mean, SD, median, minimum, 
maximum, Q1, Q3, geometric mean and Coefficient of Variation). Mean Aβ1-40 levels will 
also be graphically presented by each visit over study period for each treatment group.
All of the above analyses will be performed for patients for whom the biomarker data is obtained 
in the PET imaging substudy with non-missing baseline including all data.


Novartis
Page 49
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 50
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 51
SAP Final version 1.0
CLCZ696B2320


Novartis
Page 52
SAP Final version 1.0
CLCZ696B2320
2.13
Interim analysis
There is no planned interim efficacy analysis but an external DMC will review the unblinded 
safety data every 6 months. The relevant analyses will be executed by a group of external 


Novartis
Page 53
SAP Final version 1.0
CLCZ696B2320
independent statisticians and independent programmers privileged to access unblinded clinical 
trial data.
3
Sample size calculation
It is planned to randomize a total of 520 patients for the main study and a subset of 430 
randomized patients will be enrolled in the PET imaging substudy. With an assumed drop-out 
rate of 30%, this will result in approximately 360 randomized patients for the main study.
3.1
Sample size calculation for the primary endpoint
It is currently estimated that approximately 180 patients per group having data on 3-year 
planned follow up –

Would provide at least 80% probability that the 2-sided 95% confidence interval (CI) 
excludes a standardized effect size (Cohen’s d) of 0.3 (or greater) in change in composite 
z-score of the battery test over 3 years, given that there is no expected difference between 
two treatments.

Would provide at least 80% probability that the 2-sided CI excludes 0 (corresponding to 
p<0.05), if the true effect size is 0.3 or greater (in either direction). 
An effect size of 0.3 in Cohen’s d corresponds to a margin of 0.3xSD (SD=standard deviation) 
on the original scale for the difference between treatments in mean global score change from 
baseline, and is generally considered as small (Cohen 1988). In a systematic review of studies 
for health-related quality of life instruments that have reported the minimally important 
difference (MID), it was found that for the majority of studies the MID estimates were 
consistently close to 0.5xSD (Norman et al 2003). In addition, socially accepted benchmarks 
for conditions that induce cognitive impairment such as low level alcohol intoxication within 
legal driving limit in most countries (0.05%) are generally associated with declines of 0.3 or 
higher for psychomotor speed, attention and working memory. Therefore, the sample size of 
the study was determined to be able to detect (or exclude) effect sizes in the magnitude of 0.3 
in Cohen’s d with high probability, as it appears to be an appropriate choice to guide the 
interpretation of the cognitive function results. 
In addition, defining the magnitude of the MID using a measure of effect size, rather than a raw 
difference score has additional advantages:

Expressing the magnitude of an important difference in scale free units (Cohen’s d) allows 
models of clinically meaningful difference to be based on integration of outcomes from a 
broad set of studies whose characteristics are relevant to the current study (i.e. magnitude 
of change in cognition related to amyloid, magnitude of change occurring after heart 
failure, and magnitude of change related to cardiovascular disease).

Estimates of clinically meaningful difference can be referenced to the magnitude of 
cognitive decline detected from studies where compounds with accepted central nervous 
system adverse effects, at known doses are administered to older adults (e.g. scopolamine, 
alprazolam).
Sample size calculation was performed using N-Query 7.0.


Novartis
Page 54
SAP Final version 1.0
CLCZ696B2320
3.2
Sample size calculation for the PET imaging substudy
Approximately 300 complete patients (in 1:1 allocation ratio to LCZ696 and valsartan) will 
provide at least 80% probability that the 2-sided 95% CI excludes a between-treatment absolute 
difference of 0.01 (corresponding to an incremental 33% increase in LCZ696 vs. valsartan) in 
change from baseline in SUVr over 3 years if there is no expected difference between two 
treatments. This calculation is based on the assumptions that the mean change over 3 years from 
baseline in SUVr is 0.03 in the control group, the common standard deviation is 0.03 (estimated 
from ADNI data, Chen et al 2015). It is noted that the ADNI data presented in Chen’s paper are 
by patients’ cognitive status (normal, MCI, dementia) and for changes over two years. The 
assumptions used here are guestimates from the 2 year data in normal cognitive and MCI 
subjects. 
An absolute difference in SUV ratio of 0.01 was considered small as it represents a value that 
is lower than the rate of SUVr change that distinguishes between amyloid positive and negative 
patients (0.026 vs. 0.011). 
Sample size calculation was performed using N-Query 7.0.
3.3
Blinded sample size re-estimation
Approximately 520 patients will be randomized in order to provide overage to account for the 
information loss caused by an estimated 30% “drop-out” (including death, lost-to-follow-up, 
permanent discontinuation of study medication and start of treatments for AD or cognitive 
impairment) during 3 year period. In the PET imaging substudy approximately 430 patients will 
be randomized.
A loss of 30% of information is a crude estimate therefore it is planned to monitor the ‘dropout’ 
pattern as the trial is ongoing in order to provide a better prediction of the information loss for 
a given number of patients. The final number of patients randomized may be reduced if there is 
sufficient evidence that the information loss will be less than 30% and that the precision of the 
estimates of treatment effect (as described in the sample size section above), will be maintained.
4
Change to protocol specified analyses
Not applicable
5
Appendix
5.1
Imputation rules
5.1.1
AE date imputation
The missing or partially missing AE start or end dates will be handled/imputed using the 
Novartis ADaM Governance Board (AGB) global standard approach. Details will be provided
in the study Programming Datasets Specifications (PDS) document.


Novartis
Page 55
SAP Final version 1.0
CLCZ696B2320
5.1.2
Concomitant medication date imputation
The missing or partially missing concomitant medication start or end dates will be 
handled/imputed using the Novartis AGB global standard approach. Details will be provided in 
the study PDS document.
5.2
Statistical models
5.2.1
Primary analysis
See Section 2.5.2.
5.2.2
Key secondary analysis
Not applicable.
5.3
Rule of exclusion criteria of analysis sets 
Following tables present a sample of the rules for subject classification in the analysis sets based 
on protocol deviation specifications (Table 5-1) and non-protocol deviation classification 
criteria (Table 5-2). The PDs leading to exclusion of patients from analysis sets may be updated 
prospectively and will be finalized before DB lock.
Table 5-1
Protocol deviations leading to exclusion of subjects
Deviation ID
Description of Deviation
Exclusion in Analyses
INCL01
No study informed consent signature. 
Excluded from all analyses
INCL02
No sub-study informed consent 
signature. 
Excluded from PET imaging 
sub-study related analyses only
INCL10
No adequate functioning (e.g.: 
intellectual, motor, visual and 
auditory) to complete the study 
assessments
Excluded from per-protocol (PP)
analyses
EXCL19
MMSE score <24 at screening visit
Excluded from PP analyses
OTH21
MMSE score invalid or missing at 
screening visit
Excluded from PP analyses
EXCL20
Clinical diagnosis of Alzheimer’s 
disease or other dementia syndrome 
or any indication for or current 
treatment with cholinesterase 
inhibitors and/or another prescription 
AD treatment (e.g.memantine)
Excluded from PP analyses
EXCL21
History of medical or neurological 
condition likely to affect the 
participant’s cognition or Vitamin B12 
or folate deficiency at screening
Excluded from PP analyses
EXCL22
Inability to perform cognitive battery or 
other study evaluations based on 
significantly impaired motor or 
sensory skill
Excluded from PP analyses


Novartis
Page 56
SAP Final version 1.0
CLCZ696B2320
Deviation ID
Description of Deviation
Exclusion in Analyses
EXCL39
Patients who previously entered a 
LCZ696 study and had been 
randomized or enrolled into the active 
drug treatment epoch.
Excluded from PP analyses
OTH02
Site has been closed down for GCP 
reasons.
Excluded from analyses on FAS 
and PP
OTH09
Blind was broken locally
Excluded from PP analyses
OTH08
Patient was misrandomized (patient 
was randomized in error and no DB 
study medication taken).
Excluded from analyses on FAS 
and PP
Table 5-2
Subject classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
ENR
INCL01
LRS
INCL01
Not in ENR;
Did not take any dose of run-in LCZ696
VRS
INCL01
Not in ENR;
Did not take any dose of run-in valsartan
RAN
INCL01
Not randomized
FAS
INCL01, OTH02, OTH08
Not in RAN;
Mistakenly randomized and no double-blind 
study drug taken
PPS
INCL01, INCL10, EXCL19, 
EXCL20, EXCL21, EXCL22, 
EXCL39, OTH02, OTH08, 
OTH09, OTH21
Not in FAS;
Less than 30 months exposure to study 
medication or have less than 80% compliance 
on study medication averaged over treatment 
exposure duration
PPS2
INCL01, INCL10, EXCL19, 
EXCL20, EXCL21, EXCL22, 
EXCL39, OTH02, OTH08, 
OTH09, OTH21
Study medication exposure (in months)
multiplied by compliance on study treatment is 
less than 24
SAF
INCL01
No double-blind study drug taken
PET
INCL01, INCL02
5.4
Cerebrovascular disease burden scoring
Table 5-3
Cerebrovascular disease burden scoring
Component
Criteria
Score