Clinical trial NCT04666298
Conditions: Hypercholesterolemia Heterozygous Familial Hypercholesterolemia
Keywords: inclisiran siRNA dyslipidemia PCSK9 Hypercholesterolemia LDL-C
Sponsor: Novartis Pharmaceuticals
Start date: 2021-01-29; Completion date: 2022-10-19
Enrollment: 312 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a placebo-controlled, double-blind, randomized trial in Japanese participants with history of coronary artery disease (CAD) or participants categorized in 'high risk' by JAS 2017 guideline, or Japanese participants with heterozygous familial hypercholesterolemia (HeFH) and elevated Low-density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of statin(s) to evaluate the efficacy, safety, tolerability, and PK of subcutaneous inclisiran injection(s).

Detailed description:
The expected duration of the participants' involvement in the study was approximately 374 days which included screening (up to 14 days), Day 1 study drug administration, two additional injections on Day 90 and Day 270, and the follow-up period to Day 360.

The primary analysis was conducted after all participants had finished Day 180 visit assessments or discontinued before Day 180 visit.

After the primary analysis, double-blind treatment period were maintained to Day 360, although specific sponsor members (except for blinded monitors) were unblinded for the regulatory submission in Japan.

Arms: arm 1: Subcutaneous injection arm 2: Subcutaneous injection arm 3: Subcutaneous injection arm 4: Subcutaneous injection
Interventions: intervention 1: Inclisiran sodium intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneously injected on Day 1, 90 and 270. intervention 2: Subcutaneously injected on Day 1, 90, and 270.

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 1 ....................................................................................................................13
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Objectives and endpoints...................................................................................................20
2.1
Primary estimands .................................................................................................21
2.2
Secondary estimands .............................................................................................22
3
Study design ......................................................................................................................22
4
Rationale............................................................................................................................24
4.1
Rationale for study design .....................................................................................24
4.1.1
Rationale for choice of background therapy.........................................24
4.2
Rationale for dose/regimen and duration of treatment ..........................................24
4.3
Rationale for choice of control drugs (comparator/placebo).................................25
4.4
Purpose and timing of interim analyses.................................................................25
4.5
Risks and benefits..................................................................................................26
5
Study Population ...............................................................................................................26
5.1
Inclusion criteria ....................................................................................................26
5.2
Exclusion criteria...................................................................................................27
6
Treatment...........................................................................................................................29
6.1
Study treatment......................................................................................................29
6.1.1
Investigational and control drugs..........................................................29
6.1.2
Additional study treatments ..................................................................30
6.1.3
Treatment arms/group ...........................................................................30
6.1.4
Treatment duration................................................................................30
6.2
Other treatment(s)..................................................................................................30
6.2.1
Concomitant therapy.............................................................................30
6.2.2
Prohibited medication ...........................................................................31
6.3
Participant numbering, treatment assignment, randomization ..............................31
6.3.1
Participant numbering...........................................................................31


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6.3.2
Treatment assignment, randomization ..................................................31
6.4
Treatment blinding.................................................................................................32
6.5
Dose escalation and dose modification..................................................................33
6.5.1
Dose modifications................................................................................33
6.5.2
Follow-up for toxicities.........................................................................34
6.6
Additional treatment guidance...............................................................................36
6.6.1
Treatment compliance...........................................................................36
6.6.2
Recommended treatment of adverse events..........................................36
6.6.3
Emergency breaking of assigned treatment code..................................36
6.7
Preparation and dispensation.................................................................................37
6.7.1
Handling of study treatment and additional treatment..........................37
6.7.2
Instruction for prescribing and taking study treatment .........................37
7
Informed consent procedures ............................................................................................38
8
Visit schedule and assessments .........................................................................................39
8.1
Screening ...............................................................................................................43
8.1.1
Information to be collected on screening failures.................................43
8.2
Participant demographics/other baseline characteristics .......................................43
8.3
Efficacy..................................................................................................................43
8.3.1
LDL-C...................................................................................................44
8.3.2
Other efficacy biomarkers.....................................................................44
8.3.3
Appropriateness of efficacy assessments..............................................44
8.4
Safety.....................................................................................................................44
8.4.1
Laboratory evaluations..........................................................................45
8.4.2
Electrocardiogram (ECG) .....................................................................46
8.4.3
Pregnancy..............................................................................................47
8.4.4
Other safety evaluations........................................................................47
8.4.5
Appropriateness of safety measurements..............................................48
8.5
Additional assessments..........................................................................................48
48
9
Study discontinuation and completion ..............................................................................49
9.1
Discontinuation and completion............................................................................49
9.1.1
Study treatment discontinuation and study discontinuation..................49
9.1.2
Withdrawal of informed consent...........................................................50
9.1.3
Lost to follow-up...................................................................................51
9.1.4
Early study termination by the sponsor.................................................51
9.2
Study completion and post-study treatment ..........................................................51


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10 Safety monitoring and reporting........................................................................................51
10.1
Definition of adverse events and reporting requirements......................................51
10.1.1
Adverse events ......................................................................................51
10.1.2
Serious adverse events ..........................................................................53
10.1.3
SAE reporting........................................................................................54
10.1.4
Pregnancy reporting ..............................................................................55
10.1.5
Reporting of study treatment errors including misuse/abuse................55
10.2
Additional Safety Monitoring................................................................................56
10.2.1
Liver safety monitoring.........................................................................56
10.2.2
Renal safety monitoring........................................................................56
10.2.3
Data Monitoring Committee .................................................................57
11 Data Collection and Database management......................................................................57
11.1
Data collection.......................................................................................................57
11.2
Database management and quality control............................................................57
11.3
Site monitoring ......................................................................................................58
12 Data analysis and statistical methods ................................................................................59
12.1
Analysis sets ..........................................................................................................59
12.2
Participant demographics and other baseline characteristics.................................59
12.3
Treatments .............................................................................................................59
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................60
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................60
12.4.2
Statistical model, hypothesis, and method of analysis..........................60
12.4.3
Handling of remaining intercurrent events of primary estimand..........60
12.4.4
Handling of missing values not related to intercurrent event ...............61
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................61
12.4.6
Supplementary analysis.........................................................................61
12.4.7
Supportive analyses...............................................................................61
12.5
Analysis of secondary endpoints/estimands..........................................................61
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................61
12.5.2
Safety endpoints....................................................................................62
63
12.5.4
Biomarkers............................................................................................64
64
64
12.7
Interim analyses.....................................................................................................64
12.8
Sample size calculation..........................................................................................64


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12.8.1
Primary endpoint(s)...............................................................................64
12.8.2
Secondary endpoint(s)...........................................................................65
13 Ethical considerations and administrative procedures ......................................................65
13.1
Regulatory and ethical compliance........................................................................65
13.2
Responsibilities of the investigator and IRB/IEC..................................................65
13.3
Publication of study protocol and results...............................................................65
13.4
Quality Control and Quality Assurance.................................................................66
14 Protocol adherence ............................................................................................................66
14.1
Protocol amendments.............................................................................................66
15 References .........................................................................................................................68
16 Appendices ........................................................................................................................70
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................70
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ..........................................................................................................71
16.3
Appendix 3: Flowchart Using the Suita Score to Establish LDL-C 
Management Targets, from the Perspective of CAD Prevention (JAS 2017 
guideline) ...............................................................................................................73
16.4
Appendix 4: Diagnostic Criteria for Heterozygous FH in adults (15 years of 
age or older)...........................................................................................................74
16.5
Appendix 5: Sampson Criteria for Diagnosing Anaphylaxis ................................75
16.6
Appendix 6: Recommended Neurological Examination.......................................75
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 3-1
Dosing regimens....................................................................................23
Table 6-1
Investigational and control drug............................................................29
Table 6-2
Prohibited medication ...........................................................................31
Table 6-3
Blinding levels ......................................................................................33
Table 6-4
Guidance on specific clinical and diagnostic assessments which 
can be performed to rule out possible alternative causes of 
observed LFT abnormalities .................................................................35
Table 8-1
Assessment Schedule ............................................................................40
Table 8-2
Safety assessment..................................................................................45
Table 8-3
Clinical Laboratory Assessments..........................................................45
Table 8-4
Assessment Table for ADA ..................................................................47
49
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................55


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Table 16-1
Clinically notable vital signs.................................................................70
Table 16-2
Clinically notable laboratory abnormalities for selected tests ..............70
Table 16-3
Liver event and laboratory trigger definitions ......................................71
Table 16-4
Follow up requirements for liver laboratory triggers with liver 
symptoms ..............................................................................................71
Table 16-5
Follow up requirements for liver laboratory triggers............................72
Table 16-6
Diagnostic criteria for heterozygous FH in adults (15 years of age 
or older).................................................................................................74
Table 16-7
Grade Strength ......................................................................................76
Table 16-8
Reflex responses....................................................................................77
List of figures
Figure 3-1
Study design..........................................................................................23
Figure 16-1
Flowchart Using the Suita Score to Establish LDL-C Management 
Targets, from the Perspective of CAD Prevention................................73
Figure 16-2
Model for Predicting CAD Onset Using the Suita Score......................74


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List of abbreviations
ACC
American College of Cardiology
ACS
Acute coronary syndrome
ADA
Anti-drug antibodies
AE
Adverse Event
AHA
American Heart Association
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANA
antinuclear antibody
Apo-A1
apolipoprotein A1
Apo-B
apolipoprotein B
APTT
Activated partial thromboplastin time
ASCVD
Atherosclerotic cardiovascular disease
ASMA
anti-smooth muscle antibody
AST
Aspartate Aminotransferase
BP
blood pressure
BUN
Blood Urea Nitrogen
CAD
Coronary artery disease
CD
carbohydrate-deficient
CD-ROM
Compact Disc – Read Only Memory
CHF
chronic heart failure
CK
Creatine Kinase
CKD
Chronic kidney disease
CMO&PS 
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
COVID-19
Coronavirus disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
Cardiovascular
CVD
Cardiovascular disease
DDE
Direct Data Entry
DILI
Drug-induced liver injury
DMC
Data monitoring committee
EAS
European Atherosclerosis Society
EBV
Epstein-Barr virus
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EMA
Europeans Medicines Agency
ERCP
Endoscopic retrograde cholangiopancreatography
eSAE
Electronic Serious Adverse Event
ESC
European Society of Cardiology
FH
Familial hypercholesterolemia


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GalNAc
N-Acetylgalactosamine
GCP
Good Clinical Practice
GCS
Global Clinical Supply
G-CSF
Granulocyte-colony stimulating factor
GGT
Gamma-glutamyl transferase
GLDH
glutamate dehydrogenase
h
Hour
HAV
Hepatitis A Virus
HbA1c
Hemoglobin A1c
HBc
Hepatitis B core
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HDL-C
high-density lipoprotein cholesterol
HeFH
heterozygous familial hypercholesterolemia
HEV
Hepatitis E Virus
HIV
Human immunodeficiency virus
HoFH
Homozygous familial hypercholesterolemia
hsCRP
high sensitivity C-reactive protein
HSV
Herpes Simplex Virus
IA
Interim analysis
IAS
International Atherosclerosis Society
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IFN
Interferon
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL
Interleukin
IN
Investigator Notification
INR
International Normalized Ratio
IP-10
Interferon-gamma-inducible protein 10
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISR
injection site reaction
IUD
intrauterine device
IUS
intrauterine system
JAS
LDH
Japan Atherosclerosis Society
Lactate dehydrogenase
LDL
Low-density lipoprotein
LDL-C
Low-density lipoprotein cholesterol
LDLR
Low-density lipoprotein receptor


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LFT
Liver function test 
LLN
lower limit of normal
LMT
lipid-modifying therapies
Lp(a)
lipoprotein a
MAR
missing at random
MCH
Mean cell hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
MI
myocardial infarction
mL
milliliter(s)
MMRM
Mixed Model with Repeated Measurement
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
NLA
National Lipid Association
NYHA
New York Heart Association
PAD
Peripheral artery disease
PCR
Protein-creatinine ratio
PCS
potentially clinically significant
PCSK9
Proprotein convertase subtilisin/kexin type 9
PD
Pharmacodynamic(s)
PT
prothrombin time
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RBC
red blood cell(s)
RISC
RNA-induced silencing complex
RNA
Ribonucleic acid
s.c.
subcutaneous
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
siRNA
small interfering ribonucleic acid
SMQ
Standardized MedDRA Query
SoC
Standard of Care
SOP
Standard Operation Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TNF-α
Tumor necrosis factor-alpha
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UTI
Urinary Tract Infection
VLDL-C
very low-density lipoprotein cholesterol


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


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy)
Assessment
A procedure used to generate data required by the study
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care
Enrollment
Point/time of participant entry into the study at which informed consent must be obtained 
Estimand
A precise description of the treatment effect reflecting the clinical question posed by the 
trial objective. It summarizes at a population-level what the outcomes would be in the 
same patients under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable.
Inclisiran
In this protocol, the dose is shown with inclisiran sodium unless otherwise 
specified. Inclisiran is also referred to as KJX839.
300 mg inclisiran sodium is equivalent to 284 mg inclisiran.
200 mg inclisiran sodium is equivalent to 189 mg inclisiran.
100 mg inclisiran sodium is equivalent to 94.5 mg inclisiran.
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple dose 
part, or a part in participants with established disease and in those with newly-diagnosed 
disease
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized participant
Screen Failure
A participant who did not meet one or more criteria that were required for participation in 
the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource


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Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also be 
the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not want to 
participate in the study any longer and does not allow any further collection of personal 
data 




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
Section 10.1.4: To align with the pregnancy follow-up informed consent form, a small 
adjustment was made to the length of the follow-up period in case of a pregnancy: “until 
one year after birth” is replaced by “until one year after the baby was due to be born”.

Section 12.5.2: Minor changes were made in the output method.
Other minor corrections/clarifications were made where applicable. Changes to specific 
sections of the protocol are shown in the track changes version of the protocol using strike 
through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 




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Key Inclusion 
criteria
● Male or female participants ≥ 20 years of age.
● Participants with history of CAD or participants categorized in ‘high risk’ by JAS 
2017 guideline (diabetes, CKD, non-cardiogenic cerebral infarction, PAD or 
combination of other risk factors and categorized in ‘high risk’ assessed by Suita 
Score), or participants with HeFH diagnosed by JAS 2017 guideline.
● As per the JAS 2017 guideline, participants should meet serum LDL-C value at 
screening as follow: 
● Serum LDL-C ≥70 mg/dL for participants with history of CAD with additional risk 
factors such as HeFH, acute coronary syndrome (ACS) or diabetes complicated by 
other risk factors (non-cardiogenic cerebral infarction, PAD, CKD, metabolic 
syndrome, overlap of major risk factors, smoking)
● Serum LDL-C ≥100 mg/dL for participants with history of CAD without additional 
risk factors or HeFH participants without CAD history
● Serum LDL-C ≥ 120 mg/dL for participants categorized in ‘high risk’
● Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
● Estimated glomerular filtration rate (eGFR) calculated with the revised equations for 
eGFR in Japan (Matsuo et al 2009) >30 ml/min/1.73 m2 at screening.
● Participants on statins should be receiving a maximally tolerated dose. Maximum 
tolerated dose is defined as the maximum dose of statin that can be taken on a 
regular basis without intolerable adverse events (AE). Intolerance to any dose of any 
statin must be documented as historical AEs attributed to the statin in question in the 
source documentation and an appropriate electronic Case Report Form (eCRF).
●Participants not receiving statins must have documented evidence of intolerance to 
at least one statin.
● For all participants, the lipid-lowering therapy should have remained stable (stable 
dose and no medication change) for ≥ 30 days before screening with no planned 
medication/ dose change until Day 180
Key Exclusion 
criteria
● Participants diagnosed with homozygous familial hypercholesterolemia (HoFH).
● Any uncontrolled or serious disease, or any medical or surgical condition, that may 
either interfere with participation in the clinical study, and/or put the participant at 
significant risk (according to investigator’s judgment) if he/she participates in the 
clinical study.
● New York Heart Association (NYHA) class IV heart failure or last known left 
ventricular ejection fraction <25%.
● Cardiac arrhythmia within 3 months prior to randomization that is not controlled by 
medication or via ablation.
● Major adverse cardiovascular event within 3 months prior to randomization.
● Uncontrolled hypertension: systolic blood pressure >160 mmHg or diastolic blood 
pressure >100 mmHg prior to randomization despite antihypertensive therapy.
● Active liver disease defined as any known current infectious, neoplastic, or 
metabolic pathology of the liver or unexplained elevations in alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), >3x the upper limit of normal (ULN), or total 
bilirubin >2x ULN at screening confirmed by a repeat abnormal measurement at least 
1 week apart.
● Severe concomitant non-cardiovascular disease that carries the risk of reducing life 
expectancy to less than 2 years.
● Treatment (within 90 days of screening) with monoclonal antibodies directed 
towards PCSK9.
Study treatment
Study treatment will be administered as a single s.c. injection of one of below arms on 
Day 1, Day 90 and Day 270.
● 300 mg inclisiran sodium (equivalent to 284 mg inclisiran)
● 200 mg inclisiran sodium (equivalent to 189 mg inclisiran)
● 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran)
● Placebo
Inclisiran is also referred to as KJX839. 
Treatment of interest
The randomized treatment (inclisiran or placebo) with individualized, optimal standard 
of Care (SoC) lipid-lowering treatment. The dose of the permitted lipid-lowering 
medications must have remained stable for ≥30 days before screening with no 




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1
Introduction
1.1
Background
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
worldwide, resulting in over 17 million deaths annually (WHO 2017). Cardiovascular (CV) 
disease is the leading cause of mortality in Japan as well (MHLW 2018). Elevated low-density 
lipoprotein cholesterol (LDL-C) is a major risk factor for the development of CVD 
(Grundy et al 2004, Go et al 2014). Lowering LDL-C has been shown to reduce the risk of 
death, heart attack or stroke and within the range of effects achieved so far, the clinical risk 
reduction is linearly proportional to the absolute LDL-C reduction (Baigent et al 2005, 
Castilla-Guerra et al 2016).
The Japan Atherosclerosis Society (JAS) 2017 guidelines (Kinoshita et al 2018) recommend 
statins as first-line pharmacotherapy for lowering LDL-C, with consideration of non-statin 
lipid-modifying therapies (LMT) such as ezetimibe and/or bile acid sequestrants either as add-
on to statins or as monotherapy where statins may not be appropriate. This guideline is similar 
to other major guidelines across the world such as the American College of 
Cardiology/American 
Heart 
Association 
(ACC/AHA), 
European 
Society 
of 
Cardiology/European Atherosclerosis Society (ESC/EAS), National Lipid Association (NLA), 
and the International Atherosclerosis Society (IAS).
Approximately 100 million people worldwide are treated with lipid-lowering therapies, 
predominantly statins, to reduce LDL-C and the associated risk of death, nonfatal myocardial 
infarction (MI) and nonfatal stroke or associated events (Casula et al 2012). Despite the 
availability of statins alone or in combination with other lipid-lowering medications, many 
patients remain above the LDL-C control target (Jones et al 2012, Jameson et al 2014, 
Barkas et al 2015, Fitzgerald et al 2017). This is particularly true in participants with pre-
existing CHD and/or diabetes or a history of familial hypercholesterolemia (FH), who are at the 
highest risk and require the most intensive management (Davidson et al 2005). 
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the serine protease family, 
plays a key role in controlling the levels of low density lipoprotein receptors (LDLRs) on the 
surface of hepatocytes (Khvorova 2017). PCSK9 is expressed and secreted into the bloodstream 
predominantly by the liver, binds LDLR both intracellularly and extracellularly and promotes 
the lysosomal degradation of these receptors in hepatocytes, (Lakoski et al 2009, 
Mousavi et al 2009) thereby increasing the circulating LDL-C levels.
Recently developed and approved PCSK9-blocking monoclonal antibodies reduce PCSK9 and 
lower LDL-C levels, and were also shown to significantly reduced the risk of CV events 
(Sabatine et al 2017, Schwartz et al 2018).
Small interfering ribonucleic acids (siRNAs) selectively and catalytically silence the translation 
of their complimentary target messenger RNAs (mRNAs) in a sequence specific manner 
through the formation of effector RNA-induced silencing complexes (RISCs), utilizing a highly 
specific endogenous mechanism for regulating gene expression (Ray et al 2019). Inclisiran is a 
chemically modified double-stranded small interfering RNA, conjugated on the sense strand 
with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In 
hepatocytes, the antisense strand is incorporated in the RISC and directs catalytic breakdown 




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This study will be conducted in compliance with Good Clinical Practices (GCP) including the 
Declaration of Helsinki and all applicable regulatory requirements.
2
Objectives and endpoints
This study is designed to evaluate the efficacy, safety, tolerability 
of 
subcutaneous inclisiran injection(s) in Japanese participants.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
● To demonstrate superiority of inclisiran 
treatment at different dose levels (100 mg, 200 
mg, and 300 mg) to placebo on LDL-C levels 
at Day 180
● Percentage change in LDL-C from baseline to Day 180
Secondary objective(s)
Endpoint(s) for secondary objective(s)
● To evaluate the effect of inclisiran until Day 
180 on the following:
● PCSK9 levels over time
● Percentage change in PCSK9 levels from baseline to Days 
14, 30, 60, 90, 104, 120, 150, and 180
● LDL-C levels over time
● Percentage change in LDL-C from baseline to Days 14, 30, 
60, 90, 104, 120, and 150
● Absolute change in LDL-C from baseline to Day 180
● Proportion of participants in each group with LDL-C greater 
than 80% of the baseline value at Day 180
● Proportion of participants in each group with greater or 
equal to 50% LDL-C reduction from baseline at Days 14, 30, 
60, 90, 104, 120, 150, and 180
● Other lipids, lipoproteins, apolipoproteins 
(total cholesterol, triglycerides, HDL-C, non-
HDL-C, VLDL-C, Apo-A1, Apo-B, and Lp(a))
● Percentage change in other lipids, lipoproteins, 
apolipoproteins from baseline to Days 14, 30, 60, 90, 104, 
120, 150, and 180
● Proportion of participants achieving lipid 
control target pre-specified by JAS 2017 
guidelines
● Proportion of participants in each group who attain lipid 
control target pre-specified by JAS 2017 guideline for their 
level of cardiovascular risk at Day 180
● Individual responsiveness to different 
doses
● Individual responsiveness defined as the number of 
participants reaching on treatment LDL-C levels of <25 
mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 14, 
30, 60, 90, 104, 120, 150, and 180
● To evaluate the safety and tolerability profile 
of inclisiran
● Incidence, severity and relationship to study drug of TEAEs 
and Serious Adverse Events (SAEs); anti-drug antibodies 
(ADA) measurement










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In the prior Phase I study, maximum reductions in LDL-C and PCSK9 levels with inclisiran 
were achieved with single s.c. doses of 300 mg inclisiran sodium, with no additional meaningful 
benefit observed at higher doses. In the multiple dose phase, maximal LDL-C reductions were 
also observed on inclisiran sodium doses of 300 mg.
Based on the results of the Phase I study, the Phase II Dose Finding Study (ORION-1) tested 
the efficacy of a single dose (200 mg, 300 mg, or 500 mg) or two doses (100mg, 200mg or 
300mg) of inclisiran sodium 90 days apart. All inclisiran sodium single and double-dose groups 
reduced LDL-C and PCSK9 levels significantly at Day 180 in a dose dependent manner up to 
300 mg. The 300 mg dose of inclisiran sodium was the lowest dose that provided maximal 
efficacy for both LDL-C lowering and PCSK9 inhibition. This was the dose selected for the 
confirmatory Phase III program. Doses up to 900 mg (3-fold the therapeutic dose) have been 
studied in Phase I study. No dose limiting safety events were observed up to the highest dose 
tested.
Three large pivotal phase III studies in adult participants with ASCVD, ASCVD risk equivalent, 
and/or HeFH demonstrated that 300 mg inclisiran sodium s.c. on Day 1, Day 90 and every 6 
months thereafter, the highest dose regimen used in the present study, resulted in statistically 
significant placebo-adjusted percentage reductions in LDL-C from baseline at Day 510 of 
49.5% to 57.6%, with time-adjusted average reductions (time-adjusted percent change in LDL-
C levels from baseline after Day 90 and up to Day 540) of 44.3% to 53.8% sustained over 18 
months. This dose and regimen also showed good tolerability of inclisiran sodium, with a safety 
profile similar to placebo, except for a higher incidence of AEs at the injection site with 
inclisiran. Injection site reactions (ISRs) were generally mild and self limiting. No participant 
populations were identified that required an inclisiran dose adjustment. .
This current study is designed to demonstrate the optimal dose in Japanese participants is the 
same as (or different from) non-Japanese participants. The four treatment arms are therefore the 
same as those evaluated in the multiple dose assessments in the ORION-1 dose finding study 
in non-Japanese participants, namely inclisiran sodium 300mg, 200mg, 100mg, and placebo  
 and confirmation of an optimal dose for Japanese 
participants.
The primary endpoint will be evaluated at Day 180, however treatment will continue to Day 
270 with a final assessment at Day 360. The rationale for the 1 year duration is to provide an 
assessment of long term safety in Japanese participants. It fulfills the Japanese regulatory 
requirement that the clinical safety data for 1 year should be included in clinical data package.
4.3
Rationale for choice of control drugs (comparator/placebo)
This study is a placebo controlled study. Placebo is used to control for potential bias in the 
evaluation of efficacy and safety of the drug. The design, including the placebo comparator, is 
similar to the Phase II Dose Finding Study in non-Japanese participants (ORION-1) t
 
4.4
Purpose and timing of interim analyses
There is no interim analysis (IA) planned.




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cardiogenic cerebral infarction, PAD, CKD, metabolic syndrome, overlap of major 
risk factors, smoking)

Serum LDL-C ≥100 mg/dL for participants with history of CAD without additional 
risk factors or HeFH participants without CAD history

Serum LDL-C ≥ 120 mg/dL for participants categorized in ‘high risk’
5. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
6. Estimated glomerular filtration rate (eGFR) calculated with the revised equations for 
eGFR in Japan (Matsuo et al 2009) >30 ml/min/1.73 m2 at screening.
7. Participants on statins should be receiving a maximally tolerated dose. Maximum tolerated 
dose is defined as the maximum dose of statin that can be taken on a regular basis without 
intolerable adverse events (AE). Intolerance to any dose of any statin must be documented 
as historical AEs attributed to the statin in question in the source documentation and 
appropriate electronic Case Report Form (eCRF).
8. Participants not receiving statins must have documented evidence of intolerance to at least 
one statin.
9. For all participants, the lipid-lowering therapy should have remained stable (stable dose 
and no medication change) for ≥ 30 days before screening with no planned medication/ 
dose change until Day 180.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Use of other investigational drugs within 5 half-lives of enrollment within 30 days (e.g. 
small molecules) / or until the expected pharmacodynamic effect has returned to baseline 
(e.g. biologics), whichever is longer; or longer if required by local regulations.
2. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes.
3. Participants diagnosed with homozygous familial hypercholesterolemia (HoFH).
4. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study, and/or put the participant at significant 
risk (according to investigator’s judgment) if he/she participates in the clinical study.
5. An underlying known disease, or surgical, physical, or medical condition that, in the 
opinion of the investigator (or delegate) might interfere with interpretation of the clinical 
study results.
6. New York Heart Association (NYHA) class IV heart failure or last known left ventricular 
ejection fraction <25%.
7. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by 
medication or via ablation.
8. Major adverse cardiovascular event within 3 months prior to randomization.
9. Uncontrolled hypertension: systolic blood pressure >160 mmHg or diastolic blood 
pressure >100 mmHg prior to randomization despite antihypertensive therapy.
10. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or unexplained elevations in alanine aminotransferase (ALT), 


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aspartate aminotransferase (AST), >3x the upper limit of normal (ULN), or total bilirubin 
>2x ULN at screening confirmed by a repeat abnormal measurement at least 1 week apart. 
The repeat test should be done and confirmed before the randomization.
11. Severe concomitant non-cardiovascular disease that carries the risk of reducing life 
expectancy to less than 2 years.
12. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, or if 
diagnosed between screening visit and randomization visit regardless of whether there is 
evidence of local recurrence or metastases
13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) pregnancy test
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
study treatment. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant

Barrier methods of contraception: Condom or Occlusive cap (e.g. diaphragm or 
cervical/vault caps).

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS).

In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential.

If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
15. Known history of alcohol and/or drug abuse within the last 5 years.




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Investigational/ 
Control Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global or 
local)
Placebo
Solution for 
Injection
Subcutaneous 
injection
Open label supply 
in vials; blinding at 
site by unblinded 
site personnel
Sponsor (global)
Inclisiran is also referred to as KJX839
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Participants will be assigned at Day 1 (Baseline) to one of the following 4 treatment 
arms/groups.
1. 300 mg inclisiran sodium (equivalent to 284 mg inclisiran), n=100
2. 200 mg inclisiran sodium (equivalent to 189 mg inclisiran), n=100
3. 100 mg inclisiran sodium (equivalent to 94.5 mg inclisiran), n=54
4. Placebo, n=54
Inclisiran is also referred to as KJX839.
6.1.4
Treatment duration
The expected duration of the participants’ involvement in the study will be approximately 374 
days which includes screening (up to 14 days), Day 1 study drug administration, two additional 
injections on Day 90 and Day 270, and the follow-up period to Day 360.
Participants may be discontinued from treatment earlier due to safety reasons and/or at the 
discretion of the investigator or the participant. They will continue to be followed up in the 
study unless informed consent is withdrawn (Section 9.1.1 and Section 9.1.2).
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
The following medications/treatments are permitted during the study:

Hormone replacement therapy


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
Lipid-lowering medications; participants on lipid-lowering medications (such as statins 
and/or ezetimibe) should be on a stable dose for ≥30 days before screening with no 
planned medication or dose change until Day 180

Prescription medications prescribed to treat pre-existing medical conditions such as 
diabetes and hypertension

Prescription or non-prescription medications, when necessary to treat an AE, and at the 
discretion of the investigator
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed.
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
*Newly added therapies including dietary 
supplements used to lower LDL-C (e.g., 
statins, ezetimibe, lomitapide, probucol, 
niacin, bile acid absorption inhibitors)
After the screening 
until Day 180
● Participant in screening phase: 
Participant should be screening failure.
● Participant in treatment phase: Study 
treatment should be discontinued.
Monoclonal antibodies for PCSK9 and 
LDL-C apheresis treatment
Throughout the study 
period
● Participant in screening phase: 
Participant should be screening failure.
● Participant in treatment phase: Study 
treatment should be discontinued.
* The lipid-lowering therapy should have remained stable (stable dose and no medication change) for 
≥ 30 days before screening and until Day 180.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigational site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the informed consent form, the participant is assigned to the next 
sequential Participant No. available.
6.3.2
Treatment assignment, randomization
At Day 1 (baseline), all eligible participants 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 participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 




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The randomization codes associated with participants from whom
 ADA samples are 
taken will be disclosed to bioanalysts who will keep 
 ADA results confidential until the 
primary analysis database lock at Day 180.
Any
 ADA and results from lipid/lipoprotein/PCSK9 measurements after the first 
administration of study drug until the final database lock will be blinded for participants, 
investigator staff, persons performing the assessments and blinded monitors, while they will be 
unblinded to the sponsor members (except for blinded monitors) after the primary analysis 
database lock at Day 180.
After Day 180, investigators will be notified by the central laboratory in case a LDL-C value 
has increased by more than 50% or 30 mg/dL compared with the value at Baseline.
Unblinding will occur in the case of participant emergencies and at the conclusion of the study.
Table 6-3
Blinding levels
Role
Time of Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single participant 
unblinded)
Primary 
Analysis at 
Day 180
Participant
B
B
UI
B
Blinded site staff (blinded 
investigators/ blinded nurses)
B
B
UI
B
Unblinded site staff (unblinded 
investigators/ unblinded nurses/ 
unblinded pharmacist)
B
UI
UI
UI
Blinded monitors
B
B
UI
B
Drug Supply and Randomization 
office
UI
UI
UI
UI
Unblinded sponsor staff (e.g. 
bioanalysts, unblinded monitors)
B
UI
UI
UI
Trial Statistician/ Trial programmer/ 
data analyst
B
B
UI
UI
Independent DMC and 
independent statistician and 
programmer
B
UI
UI
UI
All other sponsor staff not identified 
above
B
B
UI
UI
B Remains blinded
UI Allowed to be unblinded on individual participant level
6.5
Dose escalation and dose modification
Investigational study treatment dose adjustments are not permitted.
6.5.1
Dose modifications
Study drug administration should be temporarily interrupted or permanently discontinued in 
participants with:


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1. Intolerable AEs, or if the investigator believes that continuing dosing will be detrimental 
to the participant’s mental or physical health. This includes severe or serious reactions at 
the injection site and any anaphylactic type reactions.
2. Liver laboratory values meeting the study drug interruption criteria listed in Table 16-4
and Table 16-5.
3. Unexplained creatine kinase (CK) values >5 x ULN confirmed by repeat test when the CK 
elevation is associated with muscle pain, muscle tenderness and/or muscle weakness, or 
new onset renal dysfunction.
Study treatment may be restarted at the discretion of the investigator, if the reason for 
discontinuation has resolved.
The dose interruptions must be recorded on an appropriate eCRF.
6.5.2
Follow-up for toxicities
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI, and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities.
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below:

For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN

For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT > 2 x baseline] OR [AST or ALT >300 U/L] whichever occurs first combined with 
[total bilirubin > 2 x baseline AND > 2.0 x ULN
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), prothrombin time 
(PT)/International Normalized Ratio (INR), alkaline phosphatase (ALP), albumin, and CK.
Perform relevant examinations (Ultrasound or Magnetic resonance imaging (MRI), Endoscopic 
retrograde cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause 
of cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis).


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Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 
may be less specific than ALP as a marker of cholestatic injury, since GGT can also be elevated 
by enzyme induction or by ethanol consumption. It is more sensitive than ALP for detecting 
bile duct injury (https://livertox.nih.gov/rucam.html).
Table 6-4 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed liver function test (LFT) 
abnormalities.
Table 6-4
Guidance on specific clinical and diagnostic assessments which can 
be performed to rule out possible alternative causes of observed LFT 
abnormalities
Disease
Assesment
Hepatitis A, B, C, E
● IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
● IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
● ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
● Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
● Ultrasound or MRI
Hypoxic/ischemic hepatopathy
● Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI.
Biliary tract disease
● Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
● Caeruloplasmin
Hemochromatosis
● Ferritin, transferrin
Alpha-1-antitrypsin deficiency
● Alpha-1-antitrypsin
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; CVD / ischemic hepatitis – ECG, prior 
hypotensive episodes; T1D / glycogenic hepatitis).
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented.


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6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by informing the participant that compliance is 
necessary for the participant’s safety and the validity of the study. The investigator should also 
instruct the participant to adhere closely to the scheduled study visits. Study treatment will not 
be dispensed to the participant but will be administered at designated study visits at the study 
site by unblinded qualified personnel. Study drug administration information should be 
captured within each designated visit on an appropriate eCRF. The unblinded site personnel or 
designee must also maintain an inventory record of study drug (inclisiran/placebo) received and 
administered.
6.6.2
Recommended treatment of adverse events
AE should be treated according to local practice and guidelines, and is at the discretion of the 
investigator and treating physician.
Medication used to treat AEs must be recorded on appropriate eCRF page(s).
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Blinding codes may also be broken after a participant discontinues treatment 
due to disease progression if deemed essential to allow the investigator to select the participant’s 
next treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study participant 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 participant, he/she must provide the requested participant identifying 
information and confirm the necessity to break the treatment code for the participant. The 
investigator will then receive details of the investigational drug treatment for the specified 
participant and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

name (if available)

participant number
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
After an emergency unblinding, study drug should be permanently discontinued. The 
participant will continue to be followed up in the study unless informed consent is withdrawn 
(Section 9.1.1 and Section 9.1.2).


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6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
Unblinded site personnel will identify the study medication kits to dispense to the participant 
by contacting the IRT and obtaining the medication number(s). The study medication has a 2-
part label (base plus tear-off label), which immediately before dispensing the medication kit to 
the unblinded investigator/nurse, the unblinded pharmacist will detach the outer part of the label 
from the packaging and affix it to the source document.
6.7.1
Handling of study treatment and additional treatment
Study treatment must be received by a unblinded site personnel (unblinded pharmacist or a 
designated unblinded person) at the study site, handled and stored safely and properly and kept 
in a secured location to which only the unblinded site personnel 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 CO Quality Assurance.
The unblinded pharmacist or qualified designee will prepare the investigational product to be 
administered to the participant on that day. The procedure for preparing investigational product 
is provided in the Pharmacy Manual.
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 participant except for the medication number.
The unblinded site personnel 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 unblinded monitors during site visits or remotely and at the completion of the 
trial.
At the conclusion of the study, and as appropriate during the course of the study, the unblinded 
site personnel will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis unblinded monitor or to the Novartis address 
provided in the investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
Participants will be administered a single s.c. injection of 100 mg, 200 mg or 300 mg inclisiran 
sodium or placebo at predefined time points as described in the Assessment Schedule 
(Section 8.1.1). Study drug injection will be administered by unblinded investigators or nurse. 
The site of injection is the abdomen, alternating sides for each injection. The arm and thigh are 
other locations for injections. Injections should not be done into areas of active skin disease or 
injury such as sunburns, skin rashes, inflammation, tattoos or skin infections. Detailed 
instructions for study drug administration are found in the Pharmacy Manual.
AE at the injection site must be reported as described in Section 8.4.4.2.




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
As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule or 
as close to the designated day/time as possible. (Every effort should be done to keep the visit 
window within ± 7 days after Day 1/Baseline as much as possible.) Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, adverse events and 
concomitant medications should be recorded on the eCRF.
Participants will have to comply with the following restrictions during the study:

Fasted for at least 10 hours for all visits for fasting lipids and glucose blood samples

Blood samples for steroid hormones should be collected at the same morning time 
throughout the study due to diurnal variation.

Blood donation will not be allowed at any time during the study

Must refrain from unaccustomed strenuous physical exercise for 48 hours before the 
screening and any study visit until the follow-up has been completed
During the Coronavirus disease 2019 (COVID-19) pandemic that limits or prevents on-site 
study visits, the collection of samples may be modified by Novartis and will be communicated 
to the Investigator.








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8.1
Screening
Screening
Screening procedures (Table 8-1) will be performed within 2 weeks prior to randomization to 
assess the eligibility only after the ICF has been signed.
In the case where liver function value(s) at screening is outside of the range specified in the 
exclusion criteria 10, the assessment may be repeated once at least 1 week apart and prior to 
randomization. If the repeat value remains outside of the specified ranges, the participant is not 
eligible for the study.
Participants may be re-screened only once, and no study-related re-screening procedure should 
be performed prior to written re-consent by the participant.
8.1.1
Information to be collected on screening failures
Participants who sign an ICF and subsequently found to be ineligible prior to randomization 
will be considered a screen failure. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a SAE during the screening phase (see SAE section for reporting 
details). If the participant fails to be randomized, the IRT must be notified within 2 days of the 
screen fail that the participant was not randomized.
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate eCRF.
8.2
Participant demographics/other baseline characteristics
Participant demographic and baseline characteristic data to be collected on all participants 
include: age, sex, race, ethnicity, relevant medical history/current medical condition present 
before informed consent was signed (where possible, diagnoses and not symptoms will be 
recorded), HeFH (yes/no), statin intolerance (if applicable), prior/concomitant lipid-lowering 
therapy, as well as relevant laboratory tests.
Investigators will have the discretion to record abnormal test findings as medical history in an 
appropriate eCRF whenever in their judgment, the test abnormality occurred prior to the 
informed consent signature.
Participant race and ethnicity are collected and analyzed to confirm the inclusion of Japanese 
participants as required by Health Authorities.
8.3
Efficacy
Specimens will be obtained at the time points in the Assessment Schedule (Table 8-1). 
Parameters to be assessed will include: total cholesterol, triglycerides, LDL-C, high-density 
lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein cholesterol 


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(VLDL-C), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), lipoprotein a (Lp(a)), and 
PCSK9.
All efficacy assessments are biomarkers analyzed at a central laboratory.
Participants will be in a fasted state at least 10 hours for all efficacy laboratory assessments. 
Details regarding the collection, processing, shipping and storage of the samples will be 
provided in a Laboratory Manual.
After randomization (Day 1) until the primary analysis database lock at Day 180, the results of 
efficacy laboratory assessments mentioned above will be blinded to participants, investigator 
staff, persons performing the assessments and the sponsor members.
Unblinding of the sponsor members and other parties (as needed) will occur after the primary 
analysis database lock at Day 180. However, participants, investigator staff and persons 
performing the assessment will remain blinded to the results of efficacy laboratory assessments 
until final database lock.
After Day 180, investigators will be notified by the central laboratory in case a LDL-C value 
has increased by more than 50% or 30 mg/dL compared with the value at baseline.
8.3.1
LDL-C
The primary efficacy assessment will be LDL-C. Blood samples for LDL-C will be collected at 
the time points in the Assessment Schedule (Table 8-1), including screening to confirm the 
eligibility
8.3.2
Other efficacy biomarkers
Other efficacy assessments will include:

Total cholesterol, triglycerides, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-B, Lp(a), 
and PCSK9
Samples for these additional efficacy biomarkers will be collected based on the Assessment
Schedule (Table 8-1). At screening, the sample only for triglycerides will be collected to 
confirm the eligibility.
Plasma samples will be analyzed using a validated enzyme linked immunosorbent assay to 
determine PCSK9 protein concentration. Full details of the analytical methods used will be 
described in a separate bioanalytical report.
8.3.3
Appropriateness of efficacy assessments
Efficacy assessments of this study are aligned with Phase II Dose Finding Study in non-
Japanese participants (ORION-1)
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.


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During the COVID-19 pandemic that limits or prevents on-site study visits regular phone or 
virtual calls will occur for safety monitoring and discussion of the participant´s health status 
until the participant can again visit the site.
Table 8-2
Safety assessment
Assessment
Specification
Physical exam
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular, and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed consent 
must be recorded on the appropriate eCRF that captures medical history. Significant 
findings made after signing informed consent which meet the definition of an AE must be 
recorded as an adverse event.
A short physical examination will include the examination of general appearance and 
vital signs as well as other examinations based on Investigator discretion.In case more 
detailed neurological examination is required as per the investigator's discretion, the full 
neurological examination in Section 16.6 can be referred.
Vital signs
Vital signs include blood pressure and pulse measurements. After the participant has been 
sitting for five minutes, with back supported and both feet placed on the floor, systolic and 
diastolic blood pressure (BP) will be measured three times using an automated validated 
device, e.g. OMRON, with an appropriately sized cuff. The repeat sitting measurements 
will be made at 1 - 2 minute intervals and the mean of the three measurements will be 
used. In case the cuff sizes available are not large enough for the participant's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
Clinically notable vital signs are defined in Table 16-1.
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. Height will be used to calculate body mass 
index.
8.4.1
Laboratory evaluations
Specimens will be obtained at the time points in the Assessment Schedule (Table 8-1).
Central laboratory will be used for analysis of all specimens collected, with the exception of 
urine pregnancy tests and urine dipstick tests, which will be done locally (using testing materials 
supplied by the central laboratory). Serum pregnancy tests at screening will be done by the 
central laboratory. Details on the collections, shipment of samples and reporting of results by 
the central laboratory are provided to investigators in a Laboratory Manual.
Note: Efficacy laboratory assessments (e.g., LDL-C and PCSK9) are described in Section 8.3.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Clinically notable laboratory findings are defined in Section 16.1.
Table 8-3
Clinical Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean cell hemoglobin (MCH), Mean corpuscular 
hemoglobin concentration (MCHC), MCV, Platelets, Red blood cells (RBC), White 
blood cells (WBC), Differential (% of Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils)




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place for clinically significant ECG findings throughout the study and especially at baseline 
before administration of study treatment.
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.3
Pregnancy
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
A positive urine pregnancy test requires immediate interruption of study drug until serum 
pregnancy test is performed and found to be negative.
A positive urine pregnancy test should be confirmed with a serum pregnancy test. Local 
pregnancy test and associated results will not be collected on eCRF.
8.4.4
Other safety evaluations
8.4.4.1
Anti-drug antibody in blood
Additional sample for analysis of the induction of antibodies will be collected at the time points 
in the Assessment Schedule (Table 8-1) and Table 8-4.
Instructions to be followed regarding sample collection, numbering, processing and shipment 
are outlined in a Laboratory Manual.
Table 8-4
Assessment Table for ADA
Visit Name
Day
Time (hour)*
ADA Sample number
Dose reference ID
V1
Day 1
Predose (-1h)
201
1
V3
Day 30
0h
202
1
V5
Day 90
Predose (-1h)
203
2
V9
Day 180
0h
204
2
V11
Day 270
Predose (-1h)
205
3
TD/ EOS
Day 360
0h
206
3
* Time (hour): This is used for internal system. For Day 1, Day 90 and Day 270, the sample will be 
collected anytime prior to injection (predose).
8.4.4.2
Other safety evaluations
Assessment of Cardiovascular Events
Information on CV events such as CV death, resuscitated cardiac arrest, non-fatal MI, and non-
fatal stroke (ischemic and hemorrhagic) will be collected as AE data.
Injection site reactions
Injection site reactions (ISR) should be monitored at each visit from the Randomization (Day 
1) visit onwards (Table 8-1) and through additional contacts with the participant between visits 
as needed. ISR including individual signs or symptoms at the injection site following study 
treatment administration should be recorded on an appropriate eCRF page. Every effort should 
be made to follow up with the participant until resolution of the ISR.






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Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

AE/ SAE
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

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
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
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 participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.


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Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. 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 participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision.
All treated participants should have a safety follow-up call conducted 30 days after the last 
study visit or 90 days after the last administration of study drug, whichever is longer. The 
information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the participant should be recorded in the source documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 


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investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer 
to Section 10.1.2):
1. The severity grade.

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. Its outcome (i.e. not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal or unknown)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.


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Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 16.1.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the participant’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above


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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 participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. (Table 10-1)
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 90 days after the last study visit (or 180 days after the 
last administration of study drug, whichever is longer) must be reported to Novartis safety 
within 24 hours of learning of its occurrence. Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site.
SAE reporting time frames are as follows:
1. Screen Failures: SAEs occurring after the participant has provided informed consent until 
the time the participant is deemed a Screen Failure must be reported to Novartis.
2. Randomized Participants: SAEs collected between time participant signs ICF until 90 days 
after the last study visit (or 180 days after the last administration of study drug, whichever 
is longer) must be reported to Novartis.
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.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety (CMO 
& PS) Department associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.


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Any SAEs experienced after the 90 days after the last study visit (or 180 days after the last 
administration of study drug, whichever is longer) should only be reported to Novartis Safety 
if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant 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 until one year after the baby was due to be 
born 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 should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.


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10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant 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.
Please refer to Table 16-3 in Appendix 2 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-3 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-4. Repeat 
liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and GGT) to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate eCRF.

If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF.
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Any one of the following: 

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR

New onset dipstick proteinuria ≥ 3+, OR

New onset dipstick hematuria ≥ 3+ (after excluding menstruation, urinary tract 
infection (UTI), extreme exercise, or trauma)


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Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.
10.2.3
Data Monitoring Committee
This study will include a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The DMC will assess at defined intervals the progress of a clinical trial, safety data, 
and critical efficacy variables and recommend to the sponsor whether to continue, modify, or 
terminate a trial.
It is anticipated that the first review occurs after the first 40 randomized participants have 
reached the Visit 3 (Day 30). Thereafter, the DMC will review safety data regularly based on 
the DMC charter until the end of the trial.
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 


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Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis representative will review the protocol and data capture requirements (i.e. eSource 
DDE or eCRFs) with the investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant 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 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.




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Other concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The analysis set used for the primary efficacy analysis will be the FAS.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary estimand is defined in Section 2.1. The corresponding endpoint, i.e. primary 
analysis variable, is the percentage change in LDL-C from baseline to Day 180. The treatment 
assessment (summary measure) of the primary estimand is the difference in mean percentage 
change from baseline to Day 180 between different inclisiran sodium dose groups and the 
placebo group.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary objective of this study is to evaluate the effect of inclisiran compared to placebo 
in reducing the percentage change from baseline in LDL-C to Day 180 in Japanese participants 
with CAD, categorized as 'high risk' by JAS 2017 guidelines, or with HeFH. The global 
statistical hypotheses that will be tested are as follows:

H0: μi-μ0 = 0 for i=1,2,3 versus Ha: μi-μ0 <0 for at least i=1,2,3
Where μ0 is the mean percentage change in LDL-C from baseline to Day 180 in placebo group, 
and μ1, μ2, μ3 are the mean percentage changes in LDL-C from baseline to Day 180 in inclisiran 
sodium 100mg, 200mg and 300mg group respectively.
An MMRM (Mixed-effect Model with Repeated Measurement) will be used as the primary 
analysis model, with treatment group, visits, interaction between visits and treatment groups, 
baseline LDL-C and current use of statins or other lipid-modifying therapies as fixed effects.
The significance level of the hypothesis test is 0.025 using one-sided test. To control the overall 
type-one error rate, Dunnett's test (one step) will be used on the above statistical model to 
provide adjusted p-values. In addition, point estimate and 95% confidence interval a will be 
presented for the difference between inclisiran and placebo groups. Also the p-value (before 
and after multiplicity adjustment) will also be provided. 
The primary objective will be achieved if the null hypothesis is rejected.
Full details on the model will be provided in the SAP.
12.4.3
Handling of remaining intercurrent events of primary estimand
The other potential intercurrent events could be death, which considering its expected small 
number of occurrences with the short follow-up period planned and being consistent with the 
approach in the other phase III studies, will be treated the same way as for the other missing 
data.


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12.4.4
Handling of missing values not related to intercurrent event
The primary MMRM model implicitly imputes missing data under a missing at random (MAR) 
assumption.
12.4.5
Sensitivity analyses for primary endpoint/estimand
The following sensitivity analysis will be performed for the primary estimand, to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis: 

MMRM analysis with multiple imputation using a control-based pattern mixture model
The control-based pattern mixture model will be used to explore the possibility of missing data 
being missing not at random. This approach will utilize placebo data for monotone missing 
inclisiran treatment data.
Full details for sensitivity analyses will be provided in the SAP.
12.4.6
Supplementary analysis
No supplementary analyses are planned. 
12.4.7
Supportive analyses
No supportive analyses are planned. 
12.5
Analysis of secondary endpoints/estimands
The key secondary efficacy endpoints of this study are the following:

Percentage change in PCSK9 from baseline to Day 180

Absolute change in LDL-C from baseline to Day 180
The key secondary efficacy endpoints will be analyzed using the same methods as for the 
primary efficacy endpoint.
Descriptive statistics on percentage change from baseline in LDL-C, PCSK9, and in other lipids, 
lipoproteins, apolipoproteins will include number of participants (n), mean, standard deviation, 
median and interquartile range [first and third quartiles], minimum and maximum. Frequencies 
and percentages will be calculated for the categorical variables. Percentages are based on the 
number of participants in the analysis set for whom there are non-missing data.
The two-sided 95% confidence interval for difference will be provided for continuous variables. 
Odds ratio and 95% confidence interval will be provided for binary variables. Nominal p-values 
will be provided when applicable.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
The other secondary efficacy objectives of this study are to evaluate the effect of inclisiran on 
the following:

Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 90, 104, 120, and 
150


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
Percentage change in LDL-C from baseline to Days 14, 30, 60, 90, 104, 120, and 150

Proportion of participants in each group with LDL-C greater than 80% of the baseline 
value at Day 180

Percentage change in other lipids, lipoproteins, apolipoproteins from baseline to Days 14, 
30, 60, 90, 104, 120, 150, and 180

Proportion of participants in each group with greater or equal to 50% LDL-C reduction 
from baseline at Days 14, 30, 60, 90, 104, 120, 150, and 180

Individual responsiveness defined as the number of participants reaching on treatment 
LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 14, 30, 60, 
90, 104, 120, 150, and 180

Proportion of participants in each group who attain Japanese lipid modification targets for 
their level of cardiovascular risk at Day 180
For other secondary endpoints, only the descriptive statistics by treatment group will be 
presented.
12.5.2
Safety endpoints
The safety objectives of this study are to evaluate the safety and tolerability profile of inclisiran. 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only treatment-emergent events (events started after 
the first dose of study medication or events present prior to start of double-blind treatment but 
increased in severity based on preferred term) with the exception of baseline data which will 
also be summarized where appropriate (e.g. change from baseline summaries). In addition, a 
separate summary for death including on treatment and post treatment deaths will be provided. 
In particular, summary tables for AEs will summarize only treatment emergent AEs.
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
The MedDRA dictionary will be used for coding AEs. An AE (classified as preferred term) 
occurring during the double-blind treatment period will be counted as a TEAE either if it is not 
present at baseline or if it is present at baseline but increased in severity during the treatment 
period.
The number (and percentage) of participants with TEAEs (events started after the first dose of 
study medication or events present prior to start of double-blind treatment but increased in 
severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity

by treatment, primary system organ class and preferred term for treatment emergent AEs 
leading to study drug discontinuation

by treatment, primary system organ class and preferred term for treatment emergent AEs 
related to study drug.








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


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be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Baigent C, Keech A, Kearney PM, et al (2005) Efficacy and safety of cholesterol-lowering 
treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials 
of statins. Lancet; 366:1267-78.
Barkas F, Liberopoulos EN, Kostapanos MS, et al (2015) Lipid target achievement among 
patients with very high and high cardiovascular risk in a lipid clinic. Angiology; 66:346-53.
Castilla-Guerra L, Del Carmen Fernandez-Moreno M, Colmenero-Camacho MA (2016) 
Statins in Stroke Prevention: Present and Future. Curr Pharm Des; 22:4638-44.
Casula M, Tragni E, Catapano AL (2012) Adherence to lipid-lowering treatment: the patient 
perspective. Patient Prefer Adherence; 6:805-14.
Davidson MH, Maki KC, Pearson TA, et al (2005) Results of the National Cholesterol 
Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) 
II survey and implications for treatment under the recent NCEP Writing Group 
recommendations. Am J Cardiol; 96:556-63.
Fitzgerald K, White S, Borodovsky A, et al (2017) A Highly Durable RNAi Therapeutic 
Inhibitor of PCSK9. N Engl J Med; 376:41-51.
Go AS, Mozaffarian D, Roger VL, et al (2014) Executive summary: heart disease and stroke 
statistics--2014 update: a report from the American Heart Association. Circulation; 129:399-
410.
Grundy SM, Cleeman JI, Merz CN, et al (2004) Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll 
Cardiol; 44:720-32.
Jameson K, Zhang Q, Zhao C, et al (2014) Total and low-density lipoprotein cholesterol in 
high-risk patients treated with atorvastatin monotherapy in the United Kingdom: analysis of a 
primary-care database. Curr Med Res Opin; 30:655-65.
Jones PH, Nair R, Thakker KM (2012) Prevalence of dyslipidemia and lipid goal attainment 
in statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc; 
1:e001800.
Khvorova A (2017) Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering 
Drugs. N Engl J Med; 376:4-7.
Kinoshita M, Yokote K, Arai H, et al (2018) Japan Atherosclerosis Society (JAS) Guidelines 
for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J Atheroscler Thromb; 
25:846-984.
Lakoski SG, Lagace TA, Cohen JC, et al (2009) Genetic and metabolic determinants of 
plasma PCSK9 levels. J Clin Endocrinol Metab; 94:2537-43.
Mann DM, Woodward M, Muntner P, et al (2010) Predictors of nonadherence to statins: a 
systematic review and meta-analysis. Ann Pharmacother; 44:1410-21.


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Matsuo S, Imai E, Horio M, et al (2009) Revised equations for estimated GFR from serum 
creatinine in Japan. Am J Kidney Dis; 53:982-92.
Ministry of Health, Labour and Welfare (2018) Summary of Vital Statistics. Accessed from: 
https://www.mhlw.go.jp/english/database/db-hw/populate/dl/E03.pdf Accessed on: 2018
Mousavi SA, Berge KE, Leren TP (2009) The unique role of proprotein convertase 
subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med; 266:507-19.
Poluzzi E, Strahinja P, Lanzoni M, et al (2008) Adherence to statin therapy and patients' 
cardiovascular risk: a pharmacoepidemiological study in Italy. Eur J Clin Pharmacol; 64:425-
32.
Raal FJ, Kallend D, Ray KK, et al (2020) Inclisiran for the Treatment of Heterozygous 
Familial Hypercholesterolemia. N Engl J Med; 382:1520-30.
Ray KK, Stoekenbroek RM, Kallend D, et al (2019) Effect of 1 or 2 Doses of Inclisiran on 
Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 
Randomized Clinical Trial. JAMA Cardiol; 4:1067-75.
Ray KK, Wright RS, Kallend D, et al (2020) Two Phase 3 Trials of Inclisiran in Patients with 
Elevated LDL Cholesterol. N Engl J Med; 382:1507-19.
Sabatine MS, Giugliano RP, Keech AC, et al (2017) Evolocumab and Clinical Outcomes in 
Patients with Cardiovascular Disease. N Engl J Med; 376:1713-22.
Sampson HA, Munoz-Furlong A, Bock SA, et al (2005) Symposium on the definition and 
management of anaphylaxis: summary report. J Allergy Clin Immunol; 115:584-91.
Sampson HA, Munoz-Furlong A, Campbell RL, et al (2006) Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol; 117:391-7.
Schwartz GG, Steg PG, Szarek M, et al (2018) Alirocumab and Cardiovascular Outcomes 
after Acute Coronary Syndrome. N Engl J Med; 379:2097-107.
WHO (2017) World Health Organization Cardiovascular Diseases. Accessed from: 
https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) 
Accessed on: 17 May 2017.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Vital signs range deviations are defined in Table 16-1:
Table 16-1
Clinically notable vital signs
Vital sign
Notable abnormalities
Pulse (beats/min)
either ≥120 + increase ≥25* or > 130
either ≤50 + decrease ≥30* or < 40
BP (mmHg)
systolic
either ≥180 + increase≥30* or > 200
either ≤90 + decrease≥30* or < 75
diastolic
either ≥105 + increase≥20* or > 115
either ≤50 + decrease≥20* or < 40
* Refers to post-BL value as compared to BL value
Notable laboratory values are defined in Table 16-2:
Table 16-2
Clinically notable laboratory abnormalities for selected tests
Parameters
Criteria
Hematology
Hemoglobin
≤ 10 g/dL
Hematocrit
≤ 0.8 × LLN
WBC (total)
≤ 2.8 ×103 / μL, ≥ 16 ×103 / μL
Platelet count
≤ 75 ×103 / μL, ≥ 700 ×103 / μL
HbA1c
≥ 6.5% and ≥0.5% change from baseline
Clinically chemistry
Creatinine
> 2 mg/dL
CK
> 1 and ≤ 3 × ULN
CK
> 3 and ≤ 5 × ULN
CK
> 5 and ≤ 10 × ULN
CK
> 10 × ULN
ALT
> 1 and ≤ 3 × ULN
ALT
> 3 and ≤ 5 × ULN
ALT
> 5 × ULN
AST
> 1 and ≤ 3 × ULN
AST
> 3 and ≤ 5 × ULN
AST
> 5 × ULN
Total bilirubin
> 2 × ULN
ALP
> 2 × ULN


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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-3
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total 
bilirubin normal at baseline:
● ALT or AST > 5 × ULN
● ALP > 2 × ULN (in the absence of known bone pathology)
● Total bilirubin > 3 × ULN (in the absence of known Gilbert syndrome)
● ALT or AST > 3 × ULN and INR > 1.5
● Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and Total 
bilirubin > 2 × ULN [mainly conjugated fraction] without notable increase in ALP 
to > 2 × ULN)
● Any clinical event of jaundice (or equivalent term)
● ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal 
pain, nausea, or vomiting, or rash with eosinophilia
● Any adverse event potentially indicative of a liver toxicity*
If ALT or AST abnormal at 
baseline:
● ALT or AST > 2x baseline or > 300 U/L (whichever occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: upper limit of 
normal
Table 16-4
Follow up requirements for liver laboratory triggers with liver 
symptoms
ALT or AST
TBL
Liver Symptoms
Action
ALT or AST increase without bilirubin increase:
If normal at baseline:
ALT or AST > 3 x ULN
Normal
For patients with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
● No change to study 
treatment
● Measure ALT, AST, ALP, 
GGT, TBL, direct and indirect 
bilirubin, PT/INR, albumin, CK, 
and GLDH in 48-72 hours.
● Follow-up for symptoms.
If elevated at baseline:
ALT or AST > 2 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
If normal at baseline:
ALT or AST > 5 x ULN for 
more than two weeks
Normal
For patients with 
Gilbert’s syndrome: 
No change in 
baseline TBL
None
● Interrupt study drug
● Measure ALT, AST, ALP, 
GGT, TBL, direct and indirect 
bilirubin, PT/INR, albumin, CK, 
and GLDH in 48-72 hours.
● Follow-up for symptoms.
● Initiate close monitoring and 
workup for competing 
etiologies.
● Study drug can be restarted 
only if another etiology is 
identiﬁed and liver enzymes 
return to baseline.
If elevated at baseline:
ALT or AST > 3 x baseline
or > 300 U/L (whichever 
occurs ﬁrst) for more than two 
weeks
If normal at baseline:
ALT or AST > 8 x ULN
Normal
None
ALT or AST increase with bilirubin increase:
If normal at baseline:
ALT or AST > 3 x ULN
TBL > 2 x ULN (or 
INR > 1.5)
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin
None
If elevated at baseline:
ALT or AST > 2 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
If normal at baseline:
ALT or AST > 3 x ULN
Normal or elevated


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ALT or AST
TBL
Liver Symptoms
Action
If elevated at baseline:
ALT or AST > 2 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain
Table 16-5
Follow up requirements for liver laboratory triggers
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
>1.5 – 3.0 ULN
● Maintain treatment
● Repeat LFTs within 48-72 hours
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the 
absence of known 
Gilbert syndrome)
● Interrupt treatment
● Repeat LFT within 48-72 hours
● Hospitalize if clinically appropriate
● Establish causality
● Record the AE and contributing factors 
(e.g. conmeds, med hx, lab) in the 
appropriate CRF
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 10 x ULN
● Discontinue the study treatment 
immediately
● Hospitalize the participant
● Establish causality
● Record the AE and contributing 
factors(e.g. conmeds, med hx, lab)in the 
appropriate CRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*
● Consider study treatment interruption or 
discontinuation
● Hospitalization if clinically appropriate
● Establish causality
● Record the AE and contributing 
factors(e.g., conmeds, med hx, lab)in the 
appropriate CRF
Investigator discretion
aResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


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16.3
Appendix 3: Flowchart Using the Suita Score to Establish LDL-C 
Management Targets, from the Perspective of CAD Prevention 
(JAS 2017 guideline)
Figure 16-1
Flowchart Using the Suita Score to Establish LDL-C Management 
Targets, from the Perspective of CAD Prevention

The Suita score is calculated based on Figure 16-2.

Note: For patients diagnosed with FH and those diagnosed with familial type III hyperlipidemia, do 
not use this chart.


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Figure 16-2
Model for Predicting CAD Onset Using the Suita Score
*Ex-smokers should be regarded as nonsmokers. Note that the risk of CAD decreases by almost half 1 
year after smoking cessation and drops to the same level as in nonsmokers after 15 years of smoking 
cessation.
**The current values are used even if the patient is currently undergoing treatment or not. However, 
counsel the patient while keeping in mind that patients undergoing treatment for hypertension have a 
higher risk of CAD than whose who have the same blood pressure value without undergoing 
treatment.
Note: The advantages and dis-advantages of lipid management in patients aged < 40 years of age are 
at the discretion of the attending physician; however, if lipid management is to be carried out, then the 
Suita score absolute risk for 35-44 years of age group is used.
Source: JAS 2017 guideline (Kinoshita et al 2018)
16.4
Appendix 4: Diagnostic Criteria for Heterozygous FH in adults 
(15 years of age or older)
Table 16-6
Diagnostic criteria for heterozygous FH in adults (15 years of age or 
older)
● Hyper-LDL-cholesterolemia (an untreated LDL-C level ≥ 180 mg/dL)
● Tendon xanthomas (thickening of tendons on dorsal side of the hands, elbows, knees or Achilles tendon 
hypertrophy) or xanthoma tuberosum
● Family history of FH or premature CAD (within the patient's second-degree relatives)

The diagnosis should be made after excluding secondary dyslipidemia.

If a patient meets two or more of the above-mentioned criteria, the condition should be diagnosed 
as FH. In case of suspected heterozygous FH, making a diagnosis using genetic testing is 
desirable.

Xanthelasma is not included in xanthoma tuberosum.

Achilles tendon hypertrophy is diagnosed if the Achilles tendon thickness is ≥ 9 mm on X-ray 
imaging.


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
An LDL-C level of ≥ 250 mg/dL strongly suggests FH.

If a patient is already receiving drug therapy, the lipid level that led to treatment should be used as 
the reference for diagnosis.

Premature CAD is defined as the occurrence of CAD in men < 55 years of age or women < 65 
years of age, respectively.

If FH is diagnosed, it is preferable to also examine the patient's family members.

These diagnostic criteria also apply to HoFH.
Source: JAS 2017 guideline (Kinoshita et al 2018)
16.5
Appendix 5: Sampson Criteria for Diagnosing Anaphylaxis
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced PEF, 
hypoxemia
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, painful abdominal cramps, vomiting)
3. Reduced blood pressure after exposure to a known allergen for that patient (minutes to several 
hours):
a. Infants and children: low systolic blood pressure (age specific) or > 30% decrease in 
systolic blood pressure*
b. Adults: systolic blood pressure <90 mmHg or >30% decrease from that person’s baseline
*Low systolic blood pressure for children is age specific and defined as: <70 mmHg for age 
1 month to 1 year; <70 mmHg + [2 x age] for age 1 to years; <90 mmHg for age 11 to 17 years.
Source: Sampson et al 2005 and Sampson et al 2006
16.6
Appendix 6: Recommended Neurological Examination
MOTOR FUNCTION
When assessing motor function, from a neurological perspective, the assessment should focus 
on arm and leg movement. You should consider the following:
1. Muscle size


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2. Muscle tone
3. Muscle strength
4. Involuntary movements
5. Posture, gait
Symmetry is the most important consideration when identifying focal findings. Compare one 
side of the body to the other when performing your assessment.
Limb assessment of a conscious patient usually involves a grading of strength.
Table 16-7
Grade Strength
Grade 
strength
Description
5
Full range of motion against gravity and resistance; normal muscle strength
4
Full range of motion against gravity and a moderate amount of resistance; slight weakness
3
Full range of motion against gravity only, moderate muscle weakness
2
Full range of motion when gravity is eliminated, severe weakness
1
A weak muscle contraction is palpated, but no movement is noted, very severe weakness
0
Complete paralysis
NB: In a conscious patient, the single best test to quickly identify motor weakness is the “drift 
test”. Have the patient hold their arms outward at 90 degrees from the body. With palms up, 
have the patient close their eyes and hold the arms for a couple of minutes. “Drifting” will 
occur if one side is weak.
Lower Extremities
Assess the patient in a supine position. Ask him/her to separate both legs to test for hip 
abduction. Then ask the patient to bring the legs back together to test for hip adduction. Sit the 
patient on the side of the bed to assess knee flexion and extension. Ask the patient to flex and 
extend the knee. If able to do this, apply resistance as these movements are repeated. Test 
plantar and dorsiflexion by having the patient push down against your hand with their foot and 
then pull up against your hand with their foot. Remember to compare the left side to the right 
side.
Upper Extremities
Assess ability to flex elbow (biceps) and straighten (triceps). Assess ability to raise shoulders 
and return to a resting position. Assess wrist flexion and extension. Test each function with 
resistance. For focused upper extremity assessment, assess each digit for flexion, extension and 
lateral movement.
SENSORY FUNCTION 
When assessing sensory function remember that there are three main pathways for sensation, 
and they should be compared bilaterally:
1. Pain and temperature sensation.
2. Position sense (proprioception).
3. Light touch.


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Pain can be assessed using a sterile pin. Light touch can be assessed with a cotton wisp. To test 
proprioception, grasp the patient's index finger from the middle joint and move it side to side 
and up and down. Have the patient identify the direction of movement. Repeat this using the 
great toe.
Sensory Tests:
A number of tests for lesions of the sensory cortex can be done. Examples include the following:

Stereognosis: The ability to recognize an object by feel. Place a common object in the 
persons hand and ask them to identify the object.

Graphesthesis: “Draw” a number in the palm of the person’s hand and ask them to 
identify the number.

Two-Point Discrimination: Simultaneously apply two pin pricks to the skin surface. 
Continually repeat the test while bringing the two pins closer together, until the individual 
can no longer identify two separate stimuli. The finger tips are the most sensitive location 
for recognizing two point differences while the upper arms, thighs and back are the least 
sensitive.

Extinction: Touch the same spot on both sides of the body at the same time (eg, the left 
and right forearms. Ask the individual to describe how many spots are being touched. 
Normally, both sides are felt; with sensory lesions the individual will sense only one.

Point Locations: Touch the surface of the skin and remove the stimulus quickly. Ask the 
individual to touch the spot where the sensation was felt. Sensory lesions can impair 
accurate identification, even if they retain their sensation of light touch.
TONE and REFLEXES
Upper motor neuron problems (brain and spinal cord) are associated with increased tone. Lower 
motor neuron problems are associated with decreased tone.
Look at the muscles on each side of the body in pairs. Assess for symmetry of bulk.
Evaluation of the stretch reflexes assesses the intactness of the spinal reflex arc at various spinal 
cord levels. The limb should be relaxed while applying a short and snappy blow with a reflex 
hammer. Hold the hammer loosely in a relaxed manner, making a wrist action. Allow the 
hammer to bounce.
Table 16-8
Reflex responses
Reflex responses
Description
0
No response
1+
Diminished, low normal
2+
Average, normal
3+
Brisker than normal
4+
Very brisk, hyperactive
Lower motor neuron disease is associated with 0 or 1+, upper motor neuron disease is associated with 
3+ or 4+.
Biceps Reflex (C5 – C6)


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Support the forearm on the examiners forearm. Place your thumb on the bicep tendon (located 
in the front of the bend of the elbow; midline to the anticubital fossa). Tap on your thumb to 
stimulate a response.
Triceps Reflex (C7-C8)
Have the individual bend their elbow while pointing their arm downward at 90 degrees. Support 
the upper arm so that the arm hangs loosely and “goes dead”. Tap on the triceps tendon located 
just above the elbow bend (funny bone).
Brachioradialis Reflex (C5-C6):
Hold the person’s thumb so that the forearm relaxes. Strike the forearm about 2-3 cm above the 
radial styloid process (located along the thumb side of the wrist, about 2-3 cm above the round 
bone at the bend of the wrist). Normally, the forearm with flex and supinate.
Quadriceps Reflex (Knee jerk) L2 – L4
Allow the lower legs to dangle freely. Place one hand on the quadriceps. Strike just below the 
knee cap. The lower leg normally will extend and the quadriceps will contract.
If the patient is supine: Stand on one side of the bed. Place the examiners forearm under the 
thigh closest to the examiner, lifting the leg up. Reach under the thigh and place the hand on 
the thigh of the opposite leg, just above the knee cap. Tap the knee closest to the examiner, (the 
one that has been lifted up with the examiners forearm).
Achilles Reflex (ankle jerks) L5 – S2:
Flex the knee and externally rotate the hip. Dorsiflex the foot and strike the Achilles tendon of 
the heel. In conscious patients, kneeling on a chair can help to relax the foot.
Heel Lift
While the patient is supine, bend the knee and support the leg under the thigh. Have the leg “go 
dead”. Briskly jerk the leg to lift the heel of the bed. Normally, the leg will remain relaxed and 
the heel will slide upward; increased tone will cause the heel and leg to stiffen and lift off the 
bed.
Babinski Response:
Dorsiflexion of the great toe with fanning of remaining toes is a positive Babinski response. 
This indicates upper motor neuron disease. It is normal in infants.
CEREBELLAR FUNCTION
The cerebellum is responsible for muscle coordination and balance on the same side. To test 
cerebellar function use the following tests:
1. Finger to finger test: have the patient touch their index finger to your index finger (repeat 
several times).
2. Finger to nose test: perform with eyes open and then eyes closed.
3. Tandem walking: heel to toe on a straight line.
4. Romberg test: stand with feet together and arms at their sides. Have patient close his/her 
eyes and maintain this position for 10 seconds. If the patient begins to sway, have them 


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open their eyes. If swaying continues, the test is “positive” or suggestive of cerebellum 
problems.
Dizziness that occurs in response to position changes is usually blood pressure initiated. If the 
patient sways during a Romberg test, but stops when the eyes are opened, the problem is 
probably visual or CN VIII (vestibular).

SAP_001.pdf: 


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2
S A P 
K J X 8 3 9 A 1 1 2 0 1
D o c u m e nt Hi st or y – C h a n g e s c o m p ar e d t o pr e vi o u s fi n al v er si o n of S A P
D at e  
Ti m e 
p oi nt
R e a s o n 
f or 
u p d at e
O ut c o m e f or u p d at e
S e cti o n a n d titl e i m p a ct e d 
( C urr e nt)
0 7-
Dec-
2 0 2 0
Pri or t o 
D B l oc k
Creati o n 
of 
fi nal 
versi o n
N/ A – First versi o n
N A
1 4-
Fe b- 
2 0 2 2
Pri or t o 
D B l oc k
•   
U p date d pri mar y a nal ysis c ut-
off at Da y 1 8 0
•   
A d de d data a nal ysis a p pr oac h 
f or L D L- C a n d V L D L- C
•   
A d de d f orest 
pl ots f or t he 
s u b gr o u p a nal yses. 
C orrecte d 
i ne q ualit y si g n ( Baseli ne L D L- C 
a n d P C S K 9)
•   
U p date d 
t he  
a nal yses  
of 
scree ne d partici pa nts
•   
U p date d  
de m o gra p hic  
a n d 
baseli ne 
c haracteristics 
a n d 
a d de d 
ne w 
cate g ories 
a n d 
me dical hist ories.
•  
Re m o ve d 
ne w 
or 
c ha n ge d 
c o nc o mita nt    
me dicati o ns 
s u m mar y
•   
A d de d fi g ures of pri mar y a n d 
ke y sec o n dar y e n d p oi nts.
•   
A d de d L D L- C testi n g ha n dli n g
•   
A d de d o ver vie w s u m mar y a n d 
re m o ve d s u m maries u p t o Da y 
9 0
•   
U p date d  
A E SI 
a n d 
a d de d 
re p orte d I njecti o n Site reacti o n 
T E A Es a n d re m o ve d s u m mar y 
u p t o Da y 9 0.
•  
Re m o ve d s u m mar y of Creati ne 
Ki nase/ Creati ne criteria.
•   
A d de d cate g ories f or t he ti me t o 
ne w- o nset dia betes.
•  
2. 1 Data a nal ysis ge neral 
i nf or mati o n
•  
2. 1. 1 Ge neral defi niti o ns
•  
2. 2. 1   
S u b gr o u p  
of 
i nterest
•  
2. 3 Dis p ositi o n
•  
2. 3. 1 De m o gra p hic a n d 
ot her    
baseli ne 
c haracteristics
•  
2. 4. 2 Pri or, c o nc o mita nt 
a n d p ost t hera pies
•  
2. 5. 3   
Ha n dli n g   
of 
missi n g val ues
•  
2. 6. 2    
Statistical 
h y p ot hesis, 
m o del, a n d 
met h o d of a nal ysis
•  
2. 8. 1 A d verse e ve nts.
•  
2. 8. 1. 1 
A d verse e ve nts 
of s pecial i nterest
•  
2. 8. 3 La b orat or y data






N o v arti s
F or b u si n e s s u s e o nl y
P a g e 5
S A P 
K J X 8 3 9 A 1 1 2 0 1
T a bl e of c o nt e nt s
Ta ble of c o nte nts.................................................................................................................. 5
List of a b bre viati o ns ............................................................................................................ 7
1 
I ntr o d ucti o n.......................................................................................................................... 8
1. 1   
St u d y desi g n............................................................................................................. 8
1. 2   
St u d y o bjecti ves a n d e n d p oi nts.............................................................................. 1 0
1. 3   
Pri mar y esti ma n ds.................................................................................................. 1 1
1. 4   
Sec o n dar y esti ma n ds.............................................................................................. 1 2
2 
Statistical met h o ds............................................................................................................. 1 3
2. 1    
Data a nal ysis ge neral i nf or mati o n.......................................................................... 1 3
2. 1. 1    
Ge neral defi niti o ns ................................................................................ 1 3
2. 2    
A nal ysis sets........................................................................................................... 1 4
2. 2. 1   
S u b gr o u p of i nterest .............................................................................. 1 4
2. 3    
Dis p ositi o n, de m o gra p hics a n d ot her baseli ne c haracteristics............................... 1 5
2. 3. 1    
De m o gra p hics a n d ot her baseli ne c haracteristics.................................. 1 6
2. 4   
Treat me nts (st u d y treat me nt, resc ue me dicati o n, c o nc o mita nt t hera pies, 
c o m plia nce)............................................................................................................ 1 7
2. 4. 1   
St u d y treat me nt / c o m plia nce................................................................ 1 7
2. 4. 2   
Pri or, c o nc o mita nt a n d p ost t hera pies ................................................... 1 7
2. 5    
A nal ysis of t he pri mar y o bjecti ve.......................................................................... 1 8
2. 5. 1   
Pri mar y e n d p oi nt................................................................................... 1 8
2. 5. 2   
Statistical h y p ot hesis, m o del, a n d met h o d of a nal ysis.......................... 1 8
2. 5. 3    
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns....................... 1 9
2. 5. 4   
S u p p orti ve/ Se nsiti vit y a nal yses............................................................. 1 9
2. 6    
A nal ysis of t he ke y sec o n dar y o bjecti ve................................................................ 1 9
2. 6. 1    
Ke y sec o n dar y e n d p oi nt........................................................................ 1 9
2. 6. 2   
Statistical h y p ot hesis, m o del, a n d met h o d of a nal ysis.......................... 2 0
2. 6. 3    
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns....................... 2 0
2. 7    
A nal ysis of ot her sec o n dar y efficac y o bjecti ve(s)................................................. 2 0
2. 7. 1   
Sec o n dar y e n d p oi nts.............................................................................. 2 0
2. 7. 2   
Statistical h y p ot hesis, m o del, a n d met h o d of a nal ysis.......................... 2 0
2. 7. 3    
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns....................... 2 1
2. 8   
Safet y a nal yses....................................................................................................... 2 1
2. 8. 1    
A d verse e ve nts ( A Es)............................................................................ 2 1
2. 8. 2    
Deat hs.................................................................................................... 2 3
2. 8. 3   
La b orat or y data...................................................................................... 2 3
2. 8. 4    
Dia betes assess me nt.............................................................................. 2 4


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 6
S A P 
K J X 8 3 9 A 1 1 2 0 1
2. 8. 5   
E C G a n d car diac i ma gi n g data.............................................................. 2 7
2. 8. 6    
Vital si g ns.............................................................................................. 2 7
2 7
2. 1 0 
I m m u n o ge nicit y..................................................................................................... 2 8
2 8
2. 1 2 
I nteri m a nal ysis...................................................................................................... 2 8
3 
Sa m ple size calc ulati o n...................................................................................................... 2 9
4  
C ha n ge t o pr ot oc ol s pecifie d a nal yses............................................................................... 2 9
5   
A p pe n di x............................................................................................................................ 2 9
5. 1   
I m p utati o n r ules..................................................................................................... 2 9
5. 1. 1    
A E date i m p utati o n................................................................................ 2 9
5. 1. 2   
C o nc o mita nt me dicati o n date i m p utati o n.............................................. 3 1
5. 2    
A Es c o di n g/ gra di n g................................................................................................ 3 2
5. 2. 1   
Searc h criteria f or ot her safet y t o pics: M A C E....................................... 3 2
5. 3   
La b orat or y para meters deri vati o ns......................................................................... 3 3
5. 4   
Statistical m o dels................................................................................................... 3 6
5. 4. 1   
Pri mar y a nal ysis.................................................................................... 3 6
5. 4. 2    
M ulti ple i m p utati o n (c o ntr ol- base d patter n i m p utati o n) f or missi n g 
data ........................................................................................................ 3 7
5. 4. 3    
Ke y sec o n dar y a nal ysis ......................................................................... 3 7
5. 5   
Res p o n der defi niti o n.............................................................................................. 3 8
5. 6   
R ule of e xcl usi o n criteria of a nal ysis sets.............................................................. 3 9
6  
Refere nce........................................................................................................................... 3 9


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 7
S A P 
K J X 8 3 9 A 1 1 2 0 1
Li st of a b br e vi ati o n s
A D A
A nti- dr u g A nti b o di e s
A E
A d v er s e e v e nt
A T C
A n at o mi c al T h er a p e uti c Cl a s sifi c ati o n
C A D
C or o n ar y Art er y Di s e a s e 
C K D
C hr o ni c Ki d n e y Di s e a s e
C R S
C a s e R etri e v al S h e et
C S R
Cli ni c al St u d y r e p ort
C V
C o effi ci e nt of V ari ati o n
D M
Di a b et e s M ellit u s
D M C
D at a M o nit ori n g C o m mitt e e 
E C G
El e ctr o c ar di o gr a m
E O S
E n d of St u d y
F A S
F ull A n al y si s S et
e C R F
El e ctr o ni c C a s e R e p ort F or m
H e F H
H et er o z y g o u s F a mili al H y p er c h ol e st er ol e mi a
J A S
J a p a n At h er o s cl er o si s S o ci et y
L F T
Li v er F u n cti o n T e st
L M T
Li pi d- M o dif yi n g T h er a pi e s
M A R
Mi s si n g at R a n d o m
M e d D R A  
M e di c al Di cti o n ar y f or Dr u g R e g ul at or y Aff air s
M M R M
Mi x e d M o d el wit h R e p e at e d M e a s ur e m e nt
M N A R
Mi s si n g N ot at R a n d o m
P A D
P eri p h er al Art er y Di s e a s e
P M M
P att er n Mi xt ur e M o d el
R A N
R a n d o mi z e d S et
R A P
R e p ort a n d A n al y si s Pr o c e s s
S A E
S eri o u s A d v er s e E v e nt
S A P
St ati sti c al A n al y si s Pl a n
S M Q
St a n d ar d M e d D R A Q u er y
S O C
S y st e m Or g a n Cl a s s
T E A E
Tr e at m e nt- e m er g e nt a d v er s e e v e nt
T F L s
T a bl e s, Fi g ur e s, Li sti n g s
W H O
W orl d H e alt h Or g a ni z ati o n










N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 2
S A P 
K J X 8 3 9 A 1 1 2 0 1
partici pa nts wit h hi g h car di o vasc ular ris k a n d ele vate d L D L- C des pite ma xi m u m t olerate d d ose 
of stati n, re gar dless of treat me nt disc o nti n uati o ns f or a n y reas o n a n d re gar dless of c ha n ge i n t he 
d ose of all o we d c o nc o mita nt me dicati o n.
T he j ustificati o n f or t he pri mar y esti ma n d is t hat it will ca pt ure b ot h t he effect of t he st u d y dr u g 
a n d t he effect of a d diti o nal me dicati o ns, mirr ori n g t he c o n diti o ns i n cli nical practice. F urt her 
details ca n be f o u n d i n Secti o n 2. 5 .
T he pri mar y esti ma n d is descri be d b y t he f oll o wi n g attri b utes:
1.
P o p ulati o n: Ja pa nese partici pa nts wit h hist or y of c or o nar y arter y disease ( C A D) or 
partici pa nts cate g orize d i n ' hi g h ris k' b y J A S 2 0 1 7 g ui deli ne ( dia betes, c hr o nic ki d ne y 
disease ( C K D), n o n-car di o ge nic cere bral i nfarcti o n, peri p heral arter y disease ( P A D) or 
c o m bi nati o n of ot her ris k fact ors a n d cate g orize d i n ' hi g h ris k' assesse d b y S uita Sc ore), or 
Ja pa nese partici pa nts wit h He F H des pite ma xi m u m t olerate d d ose of stati n. F urt her details 
a b o ut t he p o p ulati o n are pr o vi de d i n t he pr ot oc ol.
2.
E n d p oi nt: perce nta ge c ha n ge fr o m baseli ne t o Da y 1 8 0 i n L D L- C le vels
3.
Treat me nt of i nterest: t he ra n d o mize d treat me nt (t he i n vesti gati o nal treat me nt of i nclisira n 
at differe nt d ose le vels or t he c o ntr ol treat me nt place b o) wit h t he o pti mal S o C li pi d-
l o weri n g t hera p y. T he t y pe a n d d ose of t he c o nc o mita nt li pi d-l o weri n g t hera p y m ust 
re mai n sta ble u ntil Da y 1 8 0. F urt her details a b o ut t he i n vesti gati o nal treat me nt a n d c o ntr ol 
treat me nt are pr o vi de d i n t he pr ot oc ol.
4.  i nterc urre nt e ve nts :
•
Treat me nt disc o nti n uati o ns f or a n y reas o n: i g n ore (treat me nt p olic y strate g y)
•
U nf oresee n c ha n ge i n t he d ose of all o we d c o nc o mita nt me dicati o ns: i g n ore (treat me nt 
p olic y strate g y)
T he s u m mar y meas ure: differe nce bet wee n differe nt I nclisira n d ose gr o u ps a n d t he place b o 
gr o u p i n perce nta ge c ha n ge i n L D L- C le vels fr o m baseli ne t o Da y 1 8 0.
1. 4   
S e c o n d ar y e sti m a n d s
Sec o n dar y esti ma n ds c orres p o n di n g t o ke y sec o n dar y efficac y e n d p oi nts are defi ne d si milarl y 
t o t he pri mar y esti ma n d. T hese e n d p oi nts, a n d t he c orres p o n di n g s u m mar y meas ures, are liste d 
bel o w. P o p ulati o n, treat me nt of i nterest a n d i nterc urre nt e ve nts are defi ne d si milarl y as f or t he 
pri mar y esti ma n d. 
•
E n d p oi nt: Perce nta ge c ha n ge i n P C S K 9 fr o m baseli ne t o Da y 1 8 0; t he s u m mar y meas ure: 
differe nce bet wee n differe nt i nclisira n d ose gr o u ps a n d t he place b o gr o u p i n perce nta ge 
c ha n ge i n P C S K 9 fr o m baseli ne t o Da y 1 8 0
•
E n d p oi nt: A bs ol ute c ha n ge i n L D L- C fr o m baseli ne t o Da y 1 8 0; t he s u m mar y meas ure: 
differe nce bet wee n differe nt i nclisira n d ose gr o u ps a n d t he place b o gr o u p i n a bs ol ute 
c ha n ge i n L D L- C le vels fr o m baseli ne t o Da y 1 8 0


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 3
S A P 
K J X 8 3 9 A 1 1 2 0 1
2   
St ati sti c al m et h o d s
2. 1    
D at a a n al y si s g e n er al i nf or m ati o n
Data will be a nal yze d b y N o vartis acc or di n g t o t he data a nal ysis Secti o n 1 2 of t he st u d y pr ot oc ol 
w hic h is a vaila ble i n A p pe n di x 1 6. 1. 1 of t he C S R. I m p orta nt i nf or mati o n is gi ve n i n t he 
f oll o wi n g secti o ns a n d details are pr o vi de d, as a p plica ble, i n A p pe n di x 1 6. 1. 9 of t he C S R.
S A S will be use d f or ge nerati n g st u d y o ut p uts use d f or cli nical re p orts. T he m ost rece nt versi o n 
of S A S a vaila ble i n t he statistical pr o gra m mi n g e n vir o n me nt of N o vartis will be use d f or t he 
a nal ysis.
U nless ot her wise state d, s u m mar y ta bles/fi g ures/listi n gs will be o n all partici pa nts i ncl u de d i n 
t he st u d y a nal ysis set u n der c o nsi derati o n. Data will be s u m marize d wit h res pect t o 
de m o gra p hic a n d baseli ne disease c haracteristics, efficac y, a n d safet y assess me nts. Cate g orical 
varia bles will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us varia bles, n ( n o n-
missi n g o bser vati o ns), mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be 
prese nte d. T he a nal ysis will be c o n d ucte d o n all partici pa nt data at t he ti me of t he pri mar y 
a nal ysis a n d t he e n d of t he st u d y trial. 
T he pri mar y a nal ysis will be c o n d ucte d after all partici pa nts ha ve fi nis he d t he Da y 1 8 0 visit 
assess me nts or disc o nti n ue d bef ore Da y 1 8 0 visit. T he pri mar y a nal ysis will be perf or me d usi n g 
all data c ollecte d i n t he data base u p t o  t he Da y 1 8 0 visit date. All data wit h a n assess me nt date 
or e ve nt start date (e. g. start date of a n a d verse e ve nt) pri or t o or o n t he  Da y 1 8 0 visit date will 
be i ncl u de d i n t he a nal ysis. A n y data c ollecte d be y o n d t he  Da y 1 8 0 visit  date  will n ot be 
i ncl u de d i n t he a nal ysis a n d will n ot be use d f or a n y deri vati o ns. All e ve nts wit h start date 
bef ore or o n t he Da y 1 8 0 visit  date a n d e n d date after t he Da y 1 8 0 visit  date will be re p orte d 
as ‘ o n g oi n g’. T he sa me r ule will be a p plie d t o e ve nts starti n g bef ore or o n t he Da y 1 8 0 visit  
date a n d n ot ha vi n g a d oc u me nte d e n d date. T his a p pr oac h a p plies, i n partic ular, t o a d verse 
e ve nt a n d c o nc o mita nt me dicati o n a n d si g nifica nt n o n- dr u g t hera pies (s ur gical a n d me dical 
pr oce d ures) re p orts. F or t hese e ve nts, t he e n d date will n ot be i m p ute d a n d t heref ore will n ot 
a p pear i n t he listi n gs.
At t he e n d of t he st u d y ( E O S), a fi nal a nal ysis of all data c ollecte d will be perf or me d w he n all 
partici pa nts ha ve c o m plete d t heir last visit i n t he st u d y.
T he stratificati o n fact ors L D L- C cate g or y at scree ni n g a n d c urre nt use of stati ns or ot her li pi d-
m o dif yi n g t hera pies,
will be i ncl u de d i n s u b gr o u p a nal ysis 
w here a p pr o priate. 
A d diti o nal a nal ysis ma y be c o n d ucte d t o e val uate t he i m pact of C O VI D- 1 9 pa n de mic o n 
partici pa nts fi nis hi n g or disc o nti n ui n g t he Da y 1 8 0 visit assess me nts a n d c o m pleti n g or 
disc o nti n ui n g t he E n d of St u d y visit. .
2. 1. 1    
G e n er al d efi niti o n s 
T he scree ni n g peri o d will be u p t o 1 4 da ys. T he treat me nt peri o d will be 3 6 0 da ys.
St u d y dr u g refers t o t he i n vesti gati o nal dr u g i nclisira n s o di u m a n d place b o.




N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 5
S A P 
K J X 8 3 9 A 1 1 2 0 1
T he s u b gr o u ps are liste d i n Ta ble 2. 2 .
T a bl e 2. 2  S u b gr o u p a n al y si s a n d c at e g ori e s
N u m ber 
S u b gr o u p 
C ate g ories 
1  
Se x
Fe male, Male
2  
A ge 
< 6 5, ≥6 5
3  
B MI
< 2 5,  ≥2 5
4  
Baseli ne ( Da y 1) stati n use  
Yes or N o
5
Baseli ne Li pi d m o dif yi n g t hera p y 
A n y stati n or Ot her L M T b ut n o stati n or 
N o ne
6
Baseli ne L D L- C
≤ or > baseli ne me dia n
7
Baseli ne P C S K 9
≤ or > baseli ne me dia n
8  
e G F R
< 6 0, ≥6 0 
9  
C A D hist or y
Yes or N o
1 0  
He F H
Yes or N o
1 1  
D M hist or y 
Yes or N o
1 2  
H y perte nsi o n hist or y
Yes or N o
1 3  
C urre nt s m o ker
Yes or N o
S u b gr o u p a nal ysis of all treat me nt e mer ge nt a d verse e ve nts ( T E A E) will als o be perf or me d b y 
treat me nt, S O C a n d P T o n Safet y set. T he n u m ber (a n d perce nta ge) of partici pa nts wit h T E A Es 
will be pr o vi de d f or eac h cate g ories of s u b gr o u ps w hic h is t he sa me as Ta ble 2. 2 .
2. 3    
Di s p o siti o n, d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s
T he n u m ber of scree ne d partici pa nts w h o c o m plete d scree ni n g a n d t he n u m ber of scree ne d 
partici pa nts w h o disc o nti n ue d pri or t o scree ni n g p hase c o m pleti o n will be gi ve n i n t he S C R.  
T he n u m ber a n d perce nta ge of partici pa nts i n t he R A N w h o are c o m plete d/ disc o nti n ue d bef ore 
t he Da y 1 8 0 visit, a n d t he reas o n f or disc o nti n uati o n will be prese nte d b y treat me nt gr o u p. T he 
d urati o n ( da ys) of t he partici pa nts’ i n v ol ve me nt i n t he st u d y bef ore Da y 1 8 0 visit will be 
s u m marize d i n t he R A N. F or t he fi nal a nal ysis at t he e n d of t he st u d y, t he n u m ber a n d 
perce nta ge of partici pa nts i n t he R A N w h o c o m plete d/ disc o nti n ue d bef ore t he Da y 3 6 0 visit, 
a n d t he reas o n f or disc o nti n uati o n will als o be prese nte d b y treat me nt gr o u p. T he d urati o n ( da ys) 
of t he partici pa nts’ i n v ol ve me nt i n t he st u d y bef ore Da y 3 6 0 visit will be s u m marize d i n t he 
R A N. Patie nt dis p ositi o n will be liste d, i ncl u di n g t he reas o ns f or disc o nti n uati o n.
T he n u m ber of partici pa nts wit h pr ot oc ol de viati o ns will be ta b ulate d b y cate g or y (e. g., 
selecti o n criteria n ot met, partici pa nts n ot wit h dra w n as per pr ot oc ol, treat me nt de viati o n, 


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 6
S A P 
K J X 8 3 9 A 1 1 2 0 1
pr o hi bite d c o nc o mita nt me dicati o n, ot her) f or t he F A S set. Pr ot oc ol de viati o n will be liste d f or 
t he S C R.
2. 3. 1    
D e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s
De m o gra p hic a n d ot her baseli ne data i ncl u di n g disease c haracteristics will be s u m marize d 
descri pti vel y b y treat me nt gr o u p f or t he F A S set.
Cate g orical data of t he f oll o wi n g varia bles will be prese nte d as fre q ue ncies a n d perce nta ges. 
• 
Se x: Fe male or Male
• 
Race: Asia n, S u bcate g or y ( Asia n):Ja pa nese
• 
S m o ki n g stat us: N o or Yes, S u bcate g or y ( Yes): Usa ge of T o bacc o: C urre nt or F or mer
F or t he f oll o wi n g c o nti n u o us varia bles, n ( n o n- missi n g o bser vati o ns), mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d. F or selecte d para meters, 2 5t h a n d 7 5t h 
perce ntiles will als o be prese nte d .
• 
A ge
• 
A ge gr o u p: < 6 5 years or ≥6 5 years
• 
Hei g ht
• 
Wei g ht
• 
B MI
• 
B MI gr o u p: < 2 5 k g/ m 2 or ≥2 5 k g/ m 2
• 
Baseli ne li pi d para meters ( L D L- C, P C S K 9, T C, T G, H D L- C, n o n- H D L- C, V L D L- C, A p o-
A 1, A p o- B, a n d L p(a))
• 
Scree ni n g L D L- C
• 
Baseli ne vital ( S B P, D B P, P ulse)
• 
Baseli ne e G F R
I n a d diti o n, t he f oll o wi n g cate g orizati o ns of c o nti n u o us varia bles will be d o ne as fre q ue ncies 
a n d perce nta ges.
• 
Scree ni n g L D L- C gr o u p: < 1 3 0 m g/ d L or ≥1 3 0 m g/ d L
• 
Baseli ne e G F R gr o u p: < 6 0 m L/ mi n/ 1. 7 3 m 2 or ≥6 0 m L/ mi n/ 1. 7 3 m 2
• 
L D L- C tar get b y J A S 2 0 1 7: < 7 0 m g/ d L, < 1 0 0 m g/ d L, < 1 2 0 m g/ d L
N ote: T he cate g ories of L D L- C tar get b y J A S 2 0 1 7 are as f oll o ws.
< 7 0 m g/ d L: Partici pa nt wit h hist or y of C A D wit h a d diti o nal ris k fact ors s uc h as He F H, A C S 
or dia betes c o m plicate d b y ot her ris k fact ors.
< 1 0 0 m g/ d L: Partici pa nt wit h hist or y of C A D wit h o ut a d diti o nal ris k fact ors or He F H 
partici pa nt wit h o ut C A D hist or y.


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 7
S A P 
K J X 8 3 9 A 1 1 2 0 1
< 1 2 0 m g/ d L: Partici pa nt cate g orize d i n hi g h ris k.
A n d t he f oll o wi n g h y perc h olester ole mia relate d 
me dical hist ories a n d c urre nt 
me dical 
c o n diti o ns at baseli ne a n d ot her me dical hist ories a n d c urre nt c o n diti o ns will be s u m marize d.
• 
Heter oz y g o us fa milial h y perc h olester ole mia, C or o nar y arter y disease, Dia betes mellit us, 
Arterial h y perte nsi o n, Fa mil y hist or y of C or o nar y arter y disease,
D ysli pi de mia/ H y perli pi de mia/ H y perc h olester ole mia ( N o n-fa milial h y perc h olester ole mia): 
Yes or N o
• 
Bac k gr o u n d li pi d-l o weri n g t hera p y at Scree ni n g/ Da y 1: Yes or N o
• 
Bac k gr o u n d stati n at Da y 1: Yes or N o
• 
Stati n i nt olera nce ( partial or c o m plete): Yes or N o
2. 4   
Tr e at m e nt s ( st u d y tr e at m e nt, r e s c u e m e di c ati o n, c o n c o mit a nt 
t h er a pi e s, c o m pli a n c e)
T he Safet y Set will be use d f or t he a nal yses bel o w.
2. 4. 1   
St u d y tr e at m e nt / c o m pli a n c e
T he n u m ber of partici pa nts d ose d at eac h d osi n g visit, n u m ber of partici pa nts b y n u m ber of 
i njecti o ns, d urati o n of e x p os ure will be s u m marize d b y treat me nt gr o u p usi n g t he safet y set. 
Listi n g will be pr o vi de d.
D urati o n of e x p os ure will be calc ulate d as : mi ni m u m of ( Date of last d ose of treat me nt – Date 
of first d ose of treat me nt + 1 8 0, Date of last k n o w n visit – Date of first d ose of treat me nt). F or 
pri mar y a nal ysis, d urati o n of e x p os ure will be tr u ncate d at data c ut- off date.
Patie nt- year of e x p os ure will be calc ulate d as t he s u m of t he d urati o ns of e x p os ure f or all 
s u bjects i n eac h treat me nt gr o u p di vi de d b y 3 6 5. 2 5..
T he partici pa nts w h o will disc o nti n ue t he treat me nt pre mat urel y bef ore disc o nti n ui n g t he 
treat me nt peri o d will be s u m marize d b y treat me nt gr o u p, i ncl u di n g t he reas o n f or treat me nt 
disc o nti n uati o n. Listi n g will als o be pr o vi de d.
2. 4. 2   
Pri or, c o n c o mit a nt a n d p o st t h er a pi e s
Pri or me dicati o ns are defi ne d as treat me nts ta ke n a n d st o p pe d pri or t o first d ose of st u d y 
treat me nt. A n y me dicati o n gi ve n at least o nce bet wee n t he da y of first d ose of ra n d o mize d st u d y 
treat me nt a n d t he date of t he last st u d y visit will be a c o nc o mita nt me dicati o n, i ncl u di n g t h ose 
w hic h were starte d pre- baseli ne a n d c o nti n ue d i nt o t he peri o d w here st u d y treat me nt is 
a d mi nistere d.
Li pi d- m o dif yi n g t hera p y use a n d t he baseli ne/ Ra n d o mizati o n visit ( Da y 1) will be s u m marize d 
b y treat me nt gr o u p. T he cate g ories of li pi d- m o dif yi n g t hera p y use are as f oll o ws.
•
L M T a n d N o L M T
•
Stati ns ( Yes, N o)


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 8
S A P 
K J X 8 3 9 A 1 1 2 0 1
•
Ezeti mi be ( Yes, N o)
•
Stati ns o nl y a n d n o ot her L M T, ot her L M T, ot her L M T o nl y ( N o stati n). 
F or Stati n ( Yes), it is f urt her s u b-cate g orize d b y t he i nte nsit y ( hi g h, m o derate, l o w) defi ne d i n 
t he ta ble bel o w. 
T a bl e 2- 4    
Hi g h/ M o d er at e/ L o w i nt e n sit y st ati n t h er a p y 
Hi g h i nt e n sit y
M o d er at e i nt e n sit y  
L o w i nt e n sit y
St ati n n a m e a n d 
d o s e/ d a y
At or v a st ati n 4 0 m g
R o s u v a st ati n 2 0 m g
At or v a st ati n ≥1 0 a n d < 
4 0 m g
R o s u v a st ati n ≥5 a n d < 
2 0 m g
Si m v a st ati n 2 0 m g
Pit a v a st ati n 1- 4 m g
At or v a st ati n < 1 0 m g
R o s u v a st ati n < 5 m g
Si m v a st ati n ≤ 1 0 m g
Pr a v a st ati n ≤ 2 0 m g
Fl u v a st ati n ≤ 6 0 m g
R e s p e cti n g r ef er e n c e 2 0 1 8 A H A/ A C A cl a s sifi c ati o n b ut t a ki n g i nt o a c c o u nt t h e e v e nt u alit y t h at s o m e 
st u d y s u bj e ct s m a y b e o n d o s e s f alli n g b et w e e n t h e c o n s e n s u s c at e g ori e s.
Ne w or c ha n ge d li pi d- m o dif yi n g t hera p y after baseli ne usi n g t he sa me cate g ories as a b o ve will 
be s u m marize d b y treat me nt gr o u p.
Pri or me dicati o ns a n d ot her c o nc o mita nt me dicati o ns will be s u m marize d b y treat me nt gr o u p 
acc or di n g t o t he A nat o mical T hera pe utic C he mical ( A T C) classificati o n s yste m. Si g nifica nt 
n o n- dr u g t hera pies (s ur gical a n d me dical pr oce d ures) will be s u m marize d b y treat me nt gr o u p, 
acc or di n g t o t he S O C a n d P T i n t he Me d D R A dicti o nar y.
2. 5    
A n al y si s of t h e pri m ar y o bj e cti v e
T he a nal ysis f or t he pri mar y o bjecti ve will be perf or me d w he n all partici pa nts c o m plete d t he 
Da y 1 8 0 visit.
2. 5. 1   
Pri m ar y e n d p oi nt
T he a nal ysis set use d f or t he pri mar y efficac y a nal ysis will be t he F A S.
T he pri mar y esti ma n d is defi ne d i n Secti o n 1. 3 . T he c orres p o n di n g e n d p oi nt, i.e. pri mar y 
a nal ysis varia ble, is t he perce nta ge c ha n ge i n L D L- C  fr o m baseli ne t o Da y 1 8 0. T he treat me nt 
effect (s u m mar y meas ure) of t he pri mar y esti ma n d is t he differe nce i n mea n perce nta ge c ha n ge 
fr o m baseli ne t o Da y 1 8 0 bet wee n differe nt i nclisira n s o di u m d ose gr o u ps a n d t he place b o 
gr o u p.
2. 5. 2   
St ati sti c al h y p ot h e si s, m o d el, a n d m et h o d of a n al y si s
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he effect of i nclisira n c o m pare d t o place b o 
i n ter ms of perce nta ge c ha n ge fr o m baseli ne i n L D L- C t o Da y 1 8 0. T he gl o bal statistical 
h y p ot heses t hat will be teste d are as f oll o ws:
•
H 0: μi- μ 0 = 0 f or i = 1, 2, 3 vers us Ha: μi- μ 0 < 0 f or at least i = 1, 2, 3
W here μ 0  is t he mea n perce nta ge c ha n ge i n L D L- C fr o m baseli ne t o Da y 1 8 0 i n place b o gr o u p, 
a n d μ 1,  μ 2,  μ 3  are t he mea n perce nta ge c ha n ges i n L D L- C fr o m baseli ne t o Da y 1 8 0 i n i nclisira n 
s o di u m 1 0 0 m g, 2 0 0 m g a n d 3 0 0 m g gr o u p res pecti vel y.


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 1 9
S A P 
K J X 8 3 9 A 1 1 2 0 1
A n M M R M ( Mi xe d-effect M o del wit h Re peate d Meas ure me nt) will be use d as t he pri mar y 
a nal ysis m o del, wit h treat me nt gr o u p, visits, i nteracti o n bet wee n visits a n d treat me nt gr o u ps 
a n d c urre nt use of stati ns or ot her li pi d- m o dif yi n g t hera pies as fi xe d effects a n d baseli ne L D L- C 
as a c o nti n u o us c o variate. F urt her details ca n be f o u n d i n Secti o n 5. 4. 1 .
T he si g nifica nce le vel of t he h y p ot hesis test is 0. 0 2 5 usi n g o ne-si de d test. T o c o ntr ol t he o verall 
t y pe- o ne err or rate, D u n nett's test ( o ne ste p) will be use d o n t he a b o ve statistical m o del t o 
pr o vi de a dj uste d p- val ues. I n a d diti o n, p oi nt esti mate a n d 9 5 % c o nfi de nce i nter val will be 
prese nte d f or t he differe nce bet wee n i nclisira n a n d place b o gr o u ps. Als o t he p- val ue ( bef ore 
a n d after m ulti plicit y a dj ust me nt) will als o be pr o vi de d. 
T he pri mar y o bjecti ve will be ac hie ve d if t he n ull h y p ot hesis is rejecte d.
2. 5. 3    
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
T he 
M M R M m o del i m plicitl y i m p utes missi n g data u n der a missi n g at ra n d o m ( M A R) 
ass u m pti o n a n d res ults are vali d u n der t his M A R ass u m pti o n. Patie nts w h o ha ve at least o ne 
p ost- baseli ne are i ncl u de d i n t he M M R M a nal ysis. T his i ncl u des n ot o nl y t he patie nts w h o ha ve 
c o m plete d Da y 1 8 0 visit, b ut als o t h ose w h o disc o nti n ue fr o m st u d y treat me nt earl y (alt h o u g h 
o nl y a ble t o c o ntri b ute t o a partial ti me pr ofile). T his is u n der t he ass u m pti o n t hat dr o p o uts 
w o ul d f oll o w t he si milar data patter n li ke ot her patie nts w h o c o m plete t he treat me nt peri o d i n 
t he sa me treat me nt gr o u p, as if t he y ha d n ot disc o nti n ue d fr o m t he st u d y treat me nt.  
Patie nts w h o disc o nti n ue fr o m st u d y treat me nt earl y will re mai n i n t he st u d y a n d f oll o w t he 
pr oce d ures descri be d i n pr ot oc ol Secti o n 9. 1. All c ollecte d data after disc o nti n uati o n fr o m st u d y 
treat me nt will be use d i n t he a nal ysis base d o n t he treat me nt p olic y strate g y i n Secti o n 1. 3 .
T he ot her p ote ntial i nterc urre nt e ve nts c o ul d be deat h, w hic h c o nsi deri n g its e x pecte d s mall 
n u m ber of occ urre nces wit h t he s h ort f oll o w- u p peri o d pla n ne d a n d bei n g c o nsiste nt wit h t he 
a p pr oac h i n t he ot her p hase II a n d III st u dies, will be treate d t he sa me wa y as f or t he ot her 
missi n g data.
2. 5. 4   
S u p p orti v e/ S e n siti vit y a n al y s e s
T he f oll o wi n g se nsiti vit y a nal ysis will be perf or me d f or t he pri mar y esti ma n d, t o assess t he 
r o b ust ness of t he esti mati o n i n t he prese nce of de viati o ns fr o m t he ass u m pti o ns s pecifie d i n t he 
pri mar y a nal ysis: 
•
M M R M a nal ysis wit h m ulti ple i m p utati o n usi n g a c o ntr ol- base d patter n mi xt ure m o del 
( P M M)
T he c o ntr ol- base d patter n mi xt ure m o del ( P M M) will be use d t o e x pl ore t he p ossi bilit y of 
missi n g data bei n g missi n g n ot at ra n d o m. T his a p pr oac h will utilize place b o data f or m o n ot o ne 
missi n g i nclisira n treat me nt data. T he details are descri be d i n Secti o n 5. 4. 2 .
2. 6    
A n al y si s of t h e k e y s e c o n d ar y o bj e cti v e
2. 6. 1    
K e y s e c o n d ar y e n d p oi nt
T he ke y sec o n dar y efficac y e n d p oi nts of t his st u d y are  t he f oll o wi n g:
•
Perce nta ge c ha n ge i n P C S K 9 fr o m baseli ne t o Da y 1 8 0


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2 0
S A P 
K J X 8 3 9 A 1 1 2 0 1
•
A bs ol ute c ha n ge i n L D L- C fr o m baseli ne t o Da y 1 8 0
2. 6. 2   
St ati sti c al h y p ot h e si s, m o d el, a n d m et h o d of a n al y si s
T he ke y sec o n dar y efficac y e n d p oi nts will be a nal yze d usi n g t he sa me met h o ds as f or t he 
pri mar y efficac y e n d p oi nt.
Descri pti ve statistics o n perce nta ge c ha n ge fr o m baseli ne i n L D L- C a n d P C S K 9 a n d a bs ol ute 
c ha n ge fr o m baseli ne i n L D L- C will i ncl u de n u m ber of partici pa nts ( n), mea n, sta n dar d 
de viati o n, me dia n a n d i nter q uartile ra n ge [first a n d t hir d q uartiles], mi ni m u m a n d ma xi m u m. 
T he t w o-si de d 9 5 % c o nfi de nce i nter val f or differe nce will be pr o vi de d f or c o nti n u o us varia bles. 
N o mi nal p- val ues will be pr o vi de d w he n a p plica ble.
F or dis pla yi n g t he res ults, fi g ures of L D L- C a n d P C S K 9 (a bs ol ute mea n b y visit, perce nta ge 
c ha n ge fr o m baseli ne b y visit, a bs ol ute mea n c ha n ge fr o m baseli ne b y visit) a n d waterfall pl ot 
of L D L- C ( perce nta ge c ha n ge a n d a bs ol ute c ha n ge fr o m Baseli ne t o Da y 1 8 0) will be use d.
2. 6. 3    
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
Sa me a p pr oac h as f or pri mar y a nal ysis will be a p plie d.
2. 7    
A n al y si s of ot h er s e c o n d ar y effi c a c y o bj e cti v e( s)
2. 7. 1   
S e c o n d ar y e n d p oi nt s
T he ot her sec o n dar y efficac y o bjecti ves  of t his st u d y are t o e val uate t he effect of i nclisira n o n 
t he f oll o wi n g:
•
Perce nta ge c ha n ge i n P C S K 9 le vels fr o m baseli ne t o Da ys 1 4, 3 0, 6 0, 9 0, 1 0 4, 1 2 0, a n d 
1 5 0
•
Perce nta ge c ha n ge i n L D L- C fr o m baseli ne t o Da ys 1 4, 3 0, 6 0, 9 0, 1 0 4, 1 2 0, a n d 1 5 0
•
Pr o p orti o n of partici pa nts i n eac h gr o u p wit h L D L- C greater t ha n 8 0 % of t he baseli ne 
val ue at Da y 1 8 0 ( A p pe n di x 5. 5 )
•
Perce nta ge c ha n ge i n ot her li pi ds, li p o pr otei ns, a p oli p o pr otei ns fr o m baseli ne t o Da ys 1 4, 
3 0, 6 0, 9 0, 1 0 4, 1 2 0, 1 5 0, a n d 1 8 0
•
Pr o p orti o n of partici pa nts i n eac h gr o u p wit h greater or e q ual t o 5 0 % L D L- C re d ucti o n 
fr o m baseli ne at Da ys 1 4, 3 0, 6 0, 9 0, 1 0 4, 1 2 0, 1 5 0, a n d 1 8 0
•
I n di vi d ual res p o nsi ve ness defi ne d as t he n u m ber of partici pa nts reac hi n g L D L- C le vels of 
< 2 5 m g/ d L, < 5 0 m g/ d L, < 7 0 m g/ d L, a n d < 1 0 0 m g/ d L at Da ys 1 4, 3 0, 6 0, 9 0, 1 0 4, 1 2 0, 
1 5 0, a n d 1 8 0
•
Pr o p orti o n of partici pa nts i n eac h gr o u p w h o attai n Ja pa nese li pi d m o dificati o n tar gets 
s pecifie d b y J A S- 2 0 1 7 a n d J A S- 2 0 2 2 g ui deli nes (A p pe n di x 5. 5 ) f or t heir le vel of 
car di o vasc ular ris k at Da y 1 8 0
2. 7. 2   
St ati sti c al h y p ot h e si s, m o d el, a n d m et h o d of a n al y si s
•
F or ot her sec o n dar y e n d p oi nts, o nl y t he descri pti ve statistics b y treat me nt gr o u p will be 
prese nte d. T he t w o-si de d 9 5 % c o nfi de nce i nter val f or t he pr o p orti o n will be pr o vi de d 
usi n g t he e xact met h o d of Cl o p per a n d Pears o n.


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2 1
S A P 
K J X 8 3 9 A 1 1 2 0 1
2. 7. 3    
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
Missi n g val ues f or ot her para meters will n ot be i m p ute d. Disc o nti n uati o ns are treate d t he sa me 
as f or t he pri mar y a nal ysis. 
2. 8   
S af et y a n al y s e s
T he safet y o bjecti ves of t his st u d y are t o e val uate t he safet y a n d t olera bilit y pr ofile of i nclisira n. 
F or all safet y a nal yses, t he safet y set will be use d. All listi n gs a n d ta bles will be prese nte d b y 
treat me nt gr o u p. 
Safet y s u m maries (ta bles, fi g ures) i ncl u de o nl y treat me nt-e mer ge nt e ve nts (e ve nts starte d after 
t he first d ose of st u d y me dicati o n or e ve nts prese nt pri or t o start of d o u ble- bli n d treat me nt b ut 
i ncrease d i n se verit y base d o n preferre d ter m) wit h t he e xce pti o n of baseli ne data w hic h will 
als o be s u m marize d w here a p pr o priate (e. g. c ha n ge fr o m baseli ne s u m maries). I n a d diti o n, a 
se parate s u m mar y f or deat h i ncl u di n g o n treat me nt a n d p ost treat me nt deat hs will be pr o vi de d. 
I n partic ular, s u m mar y ta bles f or A Es will s u m marize o nl y treat me nt e mer ge nt A Es.
T he pri mar y a nal ysis after all partici pa nts disc o nti n ue d bef ore Da y 1 8 0 visit or ha ve fi nis he d 
Da y 1 8 0 visit assess me nts will be c o n d ucte d.
2. 8. 1    
A d v er s e e v e nt s ( A E s)
All i nf or mati o n o btai ne d o n a d verse e ve nts will be dis pla ye d b y treat me nt gr o u p a n d partici pa nt.
T he Me d D R A dicti o nar y will be use d f or c o di n g A Es. A n A E (classifie d as preferre d ter m) 
occ urri n g d uri n g t he d o u ble- bli n d treat me nt peri o d will be c o u nte d as a T E A E eit her if it is n ot 
prese nt at baseli ne or if it is prese nt at baseli ne b ut i ncrease d i n se verit y d uri n g t he treat me nt 
peri o d.
T he n u m ber (a n d perce nta ge) of partici pa nts wit h T E A Es (e ve nts starte d after t he first d ose of 
st u d y me dicati o n or e ve nts prese nt pri or t o start of d o u ble- bli n d treat me nt b ut i ncrease d i n 
se verit y base d o n preferre d ter m) will be s u m marize d i n t he f oll o wi n g wa ys:
•
b y treat me nt, pri mar y s yste m or ga n class a n d preferre d ter m.
•
b y treat me nt, pri mar y s yste m or ga n class, preferre d ter m a n d ma xi m u m se verit y
•
b y treat me nt, pri mar y s yste m or ga n class a n d preferre d ter m f or treat me nt e mer ge nt A Es 
lea di n g t o st u d y dr u g disc o nti n uati o n
•
b y treat me nt, pri mar y s yste m or ga n class a n d preferre d ter m f or treat me nt e mer ge nt A Es 
relate d t o st u d y dr u g.
Se parate s u m maries will be pr o vi de d f or deat h a n d seri o us a d verse e ve nts ( S A Es). T he 
o ver vie w s u m mar y ta ble ( T E A Es, Se vere 
A Es, S A Es, Fatal S A Es, 
A Es lea di n g t o 
disc o nti n uati o n a n d res pecti ve treat me nt-relate d) will be pr o vi de d.
A partici pa nt wit h m ulti ple a d verse e ve nts wit hi n a pri mar y s yste m or ga n class is o nl y c o u nte d 
o nce t o war ds t he t otal of t he pri mar y s yste m or ga n class.
Listi n gs will als o be ge nerate d f or deat hs, S A Es, T E A Es a n d A Es lea di n g t o disc o nti n uati o n.
A E re p orti n g f or C T. g o v


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2 2
S A P 
K J X 8 3 9 A 1 1 2 0 1
F or t he le gal re q uire me nt of Cli nical Trials. g o v, t w o re q uire d ta bles o n T E A Es w hic h are n ot 
seri o us a d verse e ve nts wit h a n i nci de nce greater t ha n 5 % ( 5 % was selecte d pri or t o data base 
l oc k) a n d o n seri o us T E A Es will be pr o vi de d b y s yste m or ga n class a n d preferre d ter m o n t he 
safet y set p o p ulati o n.
If f or a sa me patie nt, se veral c o nsec uti ve A Es (irres pecti ve of st u d y treat me nt ca usalit y, 
seri o us ness a n d se verit y) occ urre d wit h t he sa me S O C a n d P T:
•
a si n gle occ urre nce will be c o u nte d if t here is  ≤ 1 da y ga p bet wee n t he e n d date of t he 
prece di n g A E a n d t he start date of t he c o nsec uti ve A E
•
m ore t ha n o ne occ urre nce will be c o u nte d if t here is > 1 da y ga p bet wee n t he e n d date 
of t he prece di n g A E a n d t he start date of t he c o nsec uti ve A E
T he n u m ber of deat hs res ulti n g fr o m S A Es irres pecti ve of st u d y treat me nt relati o ns hi p will be 
pr o vi de d b y S O C a n d P T.
T hese s u m maries will be pr o vi de d o nl y after f ull st u d y c o m pleti o n.
2. 8. 1. 1  
A d v er s e e v e nt s of s p e ci al i nt er e st / gr o u pi n g of A E s
I n or der t o s u p p ort t he a d diti o nal assess me nt of a d verse e ve nts, a d verse e ve nts of s pecial 
i nterest a n d ot her safet y t o pics will be s u m marize d b y treat me nt gr o u p, i ncl u di n g t he n u m ber 
(a n d pr o p orti o n) of partici pa nts. I n a d diti o n, t he a d verse e ve nts of s pecial i nterest will als o be 
s u m marize d b y seri o us ness a n d se verit y, a n d ot her safet y t o pics will be s u m marize d b y 
seri o us ness. A d verse e ve nts of s pecial i nterest a n d ot her safet y t o pics use d i n t his a nal ysis are 
s pecifie d as f oll o ws. T he searc h criteria i ncl u di n g s u bcate g oires will be defi ne d i n detail i n a n 
e xter nal file acc or di n g t o t he latest versi o n of e C R S at t he D B L. T his i ncl u des Me d D R A versi o n 
a n d N o vartis Me d D R A Q uer y ( N M Q) dicti o nar y date. H o we ver, f or maj or car di o vasc ular 
e ve nts ( M A C E), t he o utc o me data (fatal/ n o n-fatal) will als o be use d, t he details is pr o vi de d i n 
A p pe n di x 5. 2.
A d verse e ve nts of S pecial I nterest
• 
I njecti o n Site Reacti o n
• 
He pat ot o xicit y _ He patic e ve nts
• 
Ne w o nset dia betes or w orse ni n g of dia betes mellit us
Ot her safet y t o pics
• 
Re nal e ve nts
• 
H y perse nsiti vit y reacti o ns
• 
Ne ur ol o gical e ve nts
• 
Ne ur oc o g niti ve dis or ders
• 
O p ht hal m ol o gical e ve nts
• 
Maj or car di o vasc ular e ve nts ( M A C E)


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2 3
S A P 
K J X 8 3 9 A 1 1 2 0 1
T he e C R S safet y defi niti o ns use d t o i de ntif y A Es of s pecial i nterest a n d ot her safet y t o pics will 
be pr o vi de d as a listi n g.
T he n u m ber a n d perce nta ge of partici pa nts w h o ha d i njecti o n site reacti o ns (si g n a n d s y m pt o m) 
will be s u m marize d a n d liste d.
Listi n g of partici pa nts wit h a d verse e ve nt of s pecial i nterest a n d ot her safet y t o pics will be 
pr o vi de d.
2. 8. 2    
D e at h s
O verall deat hs will be s u m marize d a n d liste d.
2. 8. 3   
L a b or at or y d at a
La b orat or y val ues will be s u m marize d b y treat me nt gr o u p, i ncl u di n g c ha n ges fr o m baseli ne at 
eac h ti me p oi nt. Fre q ue nc y ta ble of res ults f or cate g orical la b orat or y para meters will be 
prese nte d b y visit a n d ti me p oi nt.
S hift ta bles usi n g t he l o w, n or mal, or hi g h classificati o n (e xce pt f or e G F R a n d H b A 1c) will be 
use d t o c o m pare baseli ne t o t he w orst o n-treat me nt val ue b y treat me nt gr o u p. All data c ollecte d 
after first d ose of d o u ble- bli n d treat me nt, fr o m sc he d ule d, u nsc he d ule d a n d pre mat ure 
disc o nti n uati o n visits will be use d.
T he f oll o wi n g ra n ges will be use d f or e G F R a n d H b A 1c
•  
F or e G F R, t he cate g ories will be Se vere = < 3 0 m L/ mi n/ 1. 7 3 m 2; M o derate = ≥ 3 0 t o < 6 0 
m L/ mi n/ 1. 7 3 m 2; Mil d = ≥ 6 0 t o < 9 0 m L/ mi n/ 1. 7 3 m 2; a n d N or mal = ≥9 0  m L/ mi n/ 1. 7 3 m 2.
• 
F or H b A 1c, t he cate g ories will be < 5. 7 %, ≥5. 7 % t o < 6. 5 %, a n d ≥6. 5 %.
T he s hift ta ble deali n g wit h t he fasti n g gl uc ose para meter will re q uire t he la b sa m ple t o be ta ke n 
w hile fasti n g. Sa m ples ta ke n w hile t he partici pa nt was n ot fasti n g will n ot be a nal yze d.
F or selecte d la b orat or y tests, t he n u m ber a n d perce nta ge of patie nts meeti n g t he cli nicall y 
n ota ble criteria at a n y ti me, c o nsi deri n g all data c ollecte d after first d ose of d o u ble- bli n d 
treat me nt, fr o m sc he d ule d, u nsc he d ule d a n d pre mat ure disc o nti n uati o n visits, 
will be 
s u m marize d b y la b orat or y para meter a n d treat me nt gr o u p. N ota ble criteria are defi ne d i n 
A p pe n di x 5. 3 . Cli nicall y n ota ble criteria a n d n ota ble li ver criteria will be c o nsi dere d t o be met 
w he n b ot h of t he f oll o wi n g occ ur:
•  
P ost- baseli ne val ues meet t he t hres h ol ds liste d i n A p pe n di x 5. 3
•  
Baseli ne val ues or a n y pri or p ost- baseli ne val ues d o n ot meet t he t hres h ol ds liste d i n 
A p pe n di x 5. 3
F urt her m ore, t he n u m ber a n d perce nta ge of partici pa nts meeti n g n ota ble criteria i n li ver 
f u ncti o n test ( L F T) will be s u m marize d b y treat me nt gr o u p c o nsi deri n g o n-treat me nt data fr o m 
sc he d ule d, u nsc he d ule d a n d pre mat ure disc o nti n uati o n visits. L F T criteria are defi ne d i n 
A p pe n di x 5. 3 .
All la b orat or y data will be liste d b y treat me nt gr o u p, partici pa nt, a n d visit/ti me a n d if n or mal 
ra n ges are a vaila ble a b n or malities will be fla g ge d.


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2 4
S A P 
K J X 8 3 9 A 1 1 2 0 1
2. 8. 4    
Di a b et e s a s s e s s m e nt
Dia betes will be assesse d b y t he a nal ysis of: 
• 
T E A Es 
• 
c ha n ge i n gl uc ose-relate d la b orat or y val ues o ver ti me 
• 
S hifts fr o m baseli ne i n gl uc ose c o ntr ol cate g or y a n d,  
• 
I nci de nce of p ost- baseli ne ne w o nset of dia betes. 
N ote t hat dia betes relate d ta bles deali n g wit h t he fasti n g gl uc ose para meter will re q uire t he la b 
sa m ple t o be ta ke n w hile fasti n g.  Sa m ples ta ke n w hile t he partici pa nt was n ot fasti n g will n ot 
be a nal yze d. 
Di a betes T E A E
Ne w o nset/ w orse ni n g of dia betes will be i de ntifie d b y t he searc h criteria s pecifie d i n A p pe n di x 
5. 2 . T he a nal ysis will be perf or me d f or all partici pa nts a n d t he n b y baseli ne dia betes stat us.  A 
partici pa nt will be i de ntifie d as bei n g dia betic at baseli ne if t he tar gete d me dical hist or y n otes 
t hat t he partici pa nt is dia betic or t he baseli ne H b A 1c val ue is ≥ 6. 5 %. T his s u m mar y will be 
pr o vi de d b y treat me nt gr o u p.
C h a n ge i n Gl uc ose-rel ate d L a b or at or y V al ues o ver Ti me
T his a nal ysis o nl y utilizes la b orat or y data (fasti n g gl uc ose a n d H b A 1c).  T he c ha n ge fr o m 
baseli ne t o t he last o n-treat me nt o bser vati o n a n d t he w orst o n-treat me nt o bser vati o n will be 
s u m marize d b y treat me nt gr o u p, se paratel y f or fasti n g gl uc ose a n d H b A 1c f or all partici pa nts 
a n d t he n b y baseli ne gl uc ose c o ntr ol stat us.  Baseli ne gl uc ose c o ntr ol stat us will be i de ntifie d 
se paratel y f or fasti n g gl uc ose a n d H b A 1c usi n g t he val ues pr o vi de d i n t he ta ble bel o w ( n ote 
t hat me dical hist or y will n ot be ta ke n i nt o acc o u nt f or t his a nal ysis). 
P ar a meter   
B aseli ne Gl uc ose C o ntr ol St at us   
B aseli ne L a b or at or y V al ues 
N or mal 
< 1 0 0 m g/ d L 
I m paire d  
≥1 0 0 t o < 1 2 6 m g/ d L 
 
Fasti n g Gl uc ose * 
Dia betes  
≥1 2 6 m g/ d L 
N or mal 
< 5. 7 % 
I m paire d 
≥5. 7 t o < 6. 5 % 
 
H b A 1c * * 
Dia betes  
≥6. 5 % 
* A vera ge of Scree ni n g a n d Da y 1 fasti n g gl uc ose val ues will be c o nsi dere d as baseli ne.  If o ne 
fasti n g gl uc ose val ue is missi n g ( Scree ni n g or Da y 1), t he assess me nt will be base d o n t he 
a vaila ble data.
* * Da y 1 assess me nt will be c o nsi dere d as baseli ne. If missi n g, t he n t he baseli ne will be base d 
o n assess me nt at scree ni n g visit.
S hifts fr o m B aseli ne i n Gl uc ose C o ntr ol C ate g or y  




N o v arti s
F or b u si n e s s u s e o nl y
P a g e 2 6
S A P 
K J X 8 3 9 A 1 1 2 0 1
Dia betes t o I m paire d   
Fasti n g gl uc ose ≥1 2 6 m g/ d L 
O R 
H b A 1c ≥6. 5 % 
Fasti n g gl uc ose ≥1 0 0 a n d < 1 2 6 
m g/ d L o n t w o c o nsec uti ve 
occasi o ns 
O R
H b A 1c ≥5. 7 a n d < 6. 5 %
Dia betes t o Dia betes 
( n o c ha n ge) 
Fasti n g gl uc ose ≥1 2 6 m g/ d L 
O R 
H b A 1c ≥6. 5 % 
Fasti n g gl uc ose ≥1 2 6 m g/ d L 
t w o c o nsec uti ve occasi o ns 
O R 
H b A 1c ≥6. 5 %
* N o c ha n ge ( N or mal t o N or mal, I m paire d t o I m paire d, a n d Dia betes t o Dia betes), w orse ne d 
( N or mal t o I m paire d, N or mal t o Dia betes, a n d I m paire d t o Dia betes), a n d I m pr o ve d (I m paire d 
t o N or mal, Dia betes t o I m paire d, a n d Dia betes t o N or mal) cate g ories will als o be s u m marize d. 
* * Baseli ne of fasti n g gl uc ose is defi ne d as a vera ge of Scree ni n g a n d Da y 1 assess me nt.  If o ne 
fasti n g gl uc ose val ue is missi n g ( Scree ni n g or Da y 1), t he baseli ne will be base d o n t he a vaila ble 
data. F or H b A 1c, Da y 1 assess me nt will be c o nsi dere d as baseli ne. 
* * * F or p ost- baseli ne cate g ories, if t he p ost- baseli ne t w o c o nsec uti ve fasti n g gl uc ose 
meas ure me nts fall i n se parate cate g ories, or if o nl y o ne p ost- baseli ne fasti n g gl uc ose 
meas ure me nt is a vaila ble, t he n t he p ost- baseli ne gl uc ose c o ntr ol cate g or y will be defi ne d 
base d o n t he H b A 1c meas ure me nt o nl y. If H b A 1c val ue is missi n g a n d t w o c o nsec uti ve fasti n g 
gl uc ose meas ure me nts fall i n se parate cate g ories, t he l o wer cate g or y will be use d t o deter mi ne 
t he p ost- baseli ne cate g or y. 
I nci de nce of P ost- b aseli ne Ne w- O nset of Di a betes
T he n u m ber of partici pa nts w h o s hift fr o m n o dia betes at baseli ne t o p ost- baseli ne ne w o nset 
of dia betes will be s u m marize d. 
T he partici pa nt wit h n o dia betes at baseli ne are t h ose w h o ha d n o me dical hist or y of dia betes 
i n t he tar gete d me dical hist or y C R F, ha d H b A 1c < 6. 5 %, a n d ha d fasti n g gl uc ose < 1 2 6 m g/ d L 
pri or t o t he st u d y treat me nt (t he baseli ne fasti n g gl uc ose is defi ne d as t he a vera ge of fasti n g 
gl uc ose val ues at Scree ni n g a n d Da y 1. If o ne of t he baseli ne fasti n g gl uc ose val ues is missi n g, 
t he assess me nt will be base d o n t he a vaila ble data).  
A 4-c o m p o ne nt a nal ysis will be utilize d t o detect t he p ost- baseli ne ne w o nset of dia betes.  T he 
4 c o m p o ne nts are pr o vi de d bel o w.
1.    
Dia betic T E A Es i de ntifie d b y t he S M Q searc h (see A p pe n di x 5. 2 ), or 
2.  
P ost- baseli ne fasti n g gl uc ose ≥1 2 6 m g/ d L o n t w o c o nsec uti ve occasi o ns, or 
3.   
I nitiati o n of a nti- dia betic me dicati o n at a n y ti me p ost- baseli ne, or 
4.  
At least o ne p ost- baseli ne H b A 1c ≥6. 5 %. 
T he n u m ber of partici pa nts w h o ha ve a n y of t he 4 c o m p o ne nts will be s u m marize d ( p ost-
baseli ne ne w- o nset of dia betes) b y treat me nt gr o u p.  








N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 0
S A P 
K J X 8 3 9 A 1 1 2 0 1
Y Y Y Y < T R T Y
( 2. a  )
B ef or e Tr e at m e nt 
St art
( 2. b  )
B ef or e Tr e at m e nt 
St art
( 2. b  )
B ef or e Tr e at m e nt 
St art
( 2. b  )
B ef or e Tr e at m e nt 
St art
Y Y Y Y = T R T Y
( 4. a  )
U n c ert ai n
( 4. b  )
B ef or e Tr e at m e nt 
St art
( 4. c  )
U n c ert ai n
( 4. c  )
Aft er Tr e at m e nt St art
Y Y Y Y > T R T Y
( 3. a  )
Aft er Tr e at m e nt St art
( 3. b  )
Aft er Tr e at m e nt St art
( 3. b  )
Aft er Tr e at m e nt St art
( 3. b  )
Aft er Tr e at m e nt St art
Bef ore i m p uti n g A E start date, fi n d t he A E start refere nce date. 
1. If t he (i m p ute d) A E e n d date is c o m plete a n d t he (i m p ute d) A E e n d date < treat me nt start 
date t he n A E start refere nce date = mi n(i nf or me d c o nse nt date, earliest visit date).
2.
Else A E start refere nce date = treat me nt start date
I m p ute A E start date - 
1. If t he A E start date year val ue is missi n g, t he date u ncertai nt y is t o o hi g h t o i m p ute a rati o nal 
date.  T heref ore, if t he A E year val ue is missi n g, t he i m p ute d A E start date is set t o N U L L.
2. If t he A E start date year val ue is less t ha n t he treat me nt start date year val ue, t he A E starte d 
bef ore treat me nt.  T heref ore:
a.
If A E m o nt h is missi n g, t he i m p ute d A E start date is set t o t he mi d- year p oi nt 
( 0 1J ul Y Y Y Y).
b.
Else if A E m o nt h is n ot missi n g, t he i m p ute d A E start date is set t o  t he mi d- m o nt h 
p oi nt ( 1 5 M O N Y Y Y Y).
3. If t he A E start date year val ue is greater t ha n t he treat me nt start date year val ue, t he A E 
starte d after treat me nt.  T heref ore:
a.
If t he A E m o nt h is missi n g, t he i m p ute d A E start date is set t o t he year start p oi nt 
( 0 1Ja n Y Y Y Y).
b.
Else if t he A E m o nt h is n ot missi n g, t he i m p ute d A E start date is set t o t he later of 
( m o nt h start p oi nt ( 0 1 M O N Y Y Y Y), A E start refere nce date + 1 da y).
4. If t he A E start date year val ue is e q ual t o t he treat me nt start date year val ue:
a. 
A n d t he A E m o nt h is missi n g t he i m p ute d A E start date is set t o t he A E refere nce 
start date + 1 da y.
b.
Else if t he A E m o nt h is less t ha n t he treat me nt start m o nt h, t he i m p ute d A E start 
date is set t o t he mi d- m o nt h p oi nt ( 1 5 M O N Y Y Y Y).
c.
Else if t he A E m o nt h is e q ual t o t he treat me nt start date m o nt h or greater t ha n t he 
treat me nt start date m o nt h, t he i m p ute d A E start date is set t o t he later of ( m o nt h 
start p oi nt ( 0 1 M O N Y Y Y Y), A E start refere nce date + 1 da y).
If c o m plete (i m p ute d) A E e n d date is a vaila ble a n d t he i m p ute d A E start date is greater t ha n t he 
(i m p ute d) A E e n d date, t he n i m p ute d A E start date s h o ul d be set t o t he (i m p ute d) A E e n d date.


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 1
S A P 
K J X 8 3 9 A 1 1 2 0 1
•
If t he A E e n d date m o nt h is missi n g, t he i m p ute d e n d date s h o ul d be set t o t he earliest 
of t he (f oll o w u p peri o d date, 3 1 D E C Y Y Y Y, date of deat h).
•
If t he A E e n d date da y is missi n g, t he i m p ute d e n d date s h o ul d be set t o t he earliest of 
t he (f oll o w u p peri o d date, last da y of t he m o nt h, date of deat h).
•
If A E year is missi n g or A E is o n g oi n g, t he e n d date will n ot be i m p ute d.
5. 1. 2    
C o n c o mit a nt m e di c ati o n d at e i m p ut ati o n
T he f oll o wi n g ta ble e x plai ns t he n otati o n use d i n t he l o gic matri x. Please n ote t hat  missi n g 
st art d ates will n ot be i m p ute d.
D a y
M o nt h
Y e ar
P arti al C M D St art D at e
N ot u s e d
M O N
Y Y Y Y
Tr e at m e nt St art D at e
N ot u s e d
T R T M
T R T Y
T h e f oll o wi n g m atri x e x pl ai n s t h e l o gi c b e hi n d t h e i m p ut ati o n.
M O N
MI S SI N G
M O N < T R T M
M O N = T R T M
M O N > T R T M
Y Y Y Y
MI S SI N G
 ( 1  )
U n c ert ai n
( 1 )
U n c ert ai n
( 1 )
U n c ert ai n
( 1 )
U n c ert ai n
Y Y Y Y < T R T Y
( 2. a)  ) 
B ef or e Tr e at m e nt St art
( 2. b)  )
B ef or e Tr e at m e nt St art
( 2. b)  )
B ef or e Tr e at m e nt St art
( 2. b)  )
B ef or e Tr e at m e nt St art
Y Y Y Y = T R T Y
( 4. a)  )
U n c ert ai n
( 4. b)  )
B ef or e Tr e at m e nt St art
( 4. a)  )
U n c ert ai n
( 4. c)  )
Aft er Tr e at m e nt St art
Y Y Y Y > T R T Y
( 3. a)  )
Aft er Tr e at m e nt St art
( 3. b)  )
Aft er Tr e at m e nt St art
( 3. b)  )
Aft er Tr e at m e nt St art
( 3. b)  )
Aft er Tr e at m e nt St art
1. If t he C M start date year val ue is missi n g, t he i m p ute d C M start date is set t o o ne da y 
pri or t o treat me nt start date. 
2. If t he C M start date year val ue is less t ha n t he treat me nt start date year val ue, t he C M 
starte d bef ore treat me nt.  T heref ore:
a) If t he C M m o nt h is missi n g, t he i m p ute d C M start date is set t o t he mi d- year 
p oi nt ( 0 1J ul Y Y Y Y).
b)
Else if t he C M m o nt h is n ot missi n g, t he i m p ute d C M start date is set t o t he mi d-
m o nt h p oi nt ( 1 5 M O N Y Y Y Y).
3. If t he C M start date year val ue is greater t ha n t he treat me nt start date year val ue, t he C M 
starte d after treat me nt. T heref ore:
a) If t he C M m o nt h is missi n g, t he i m p ute d C M start date is set t o t he year start 
p oi nt ( 0 1Ja n Y Y Y Y).


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 2
S A P 
K J X 8 3 9 A 1 1 2 0 1
b)
Else if t he C M m o nt h is n ot missi n g, t he i m p ute d C M start date is set t o t he 
m o nt h start p oi nt ( 0 1 M O N Y Y Y Y).
4. If t he C M start date year val ue is e q ual t o t he treat me nt start date year val ue:
a)
A n d t he C M m o nt h is missi n g or t he C M m o nt h is e q ual t o t he treat me nt start 
date m o nt h, t he n t he i m p ute d C M start date is set t o o ne da y pri or treat me nt start 
date.
b)
Else if t he C M m o nt h is less t ha n t he treat me nt start date m o nt h, t he i m p ute d 
C M start date is set t o t he mi d- m o nt h p oi nt ( 1 5 M O N Y Y Y Y).
c)
Else if t he C M m o nt h is greater t ha n t he treat me nt start date m o nt h, t he i m p ute d 
C M start date is set t o t he m o nt h start p oi nt ( 0 1 M O N Y Y Y Y).
If c o m plete (i m p ute d) C M e n d date is a vaila ble a n d t he i m p ute d C M start date is greater t ha n 
t he (i m p ute d) C M e n d date, t he n i m p ute d C M start date s h o ul d be set t o t he (i m p ute d) C M e n d 
date.
•
If C M e n d da y is missi n g a n d C M m o nt h/ year are n o n- missi n g t he n i m p ute C M da y as 
t he mi ni m u m of  dis p ositi o n date a n d t he last da y of t he m o nt h.
•
If C M e n d da y/ m o nt h are missi n g a n d C M year is n o n- missi n g t he n i m p ute C M da y as 
t he mi ni m u m of dis p ositi o n date a n d t he e n d of t he year ( 3 1 D E C Y Y Y Y).
•
O nl y i ncl u de if o n g oi n g rec or ds will n ot be i m p ute d.
•
If i m p ute d C M e n d date is less t ha n t he C M start date, use t he C M start date as t he 
i m p ute d C M e n d date.
A b o ve r ules a p pl y t o c o nc o mita nt s ur gical a n d me dical pr oce d ures as well. 
5. 1. 2. 1  
Pri or t h er a pi e s d at e i m p ut ati o n
Sa me i m p utati o n r ules as f or c o nc o mita nt me dicati o n date i m p utati o n. 
5. 1. 2. 2  
Ot h er i m p ut ati o n s
N ot a p plica ble.
5. 2    
A E s c o di n g/ gr a di n g
C o di n g of A E will be d o ne per Me d D R A dicti o nar y. 
5. 2. 1   
S e ar c h crit eri a f or ot h er s af et y t o pi c s: M A C E
T he searc h criteria of M A C E will be base d o n t he e C R S a n d t he f oll o wi n g o utc o me data 
(fatal/ n o n-fatal).
Maj or car di o vasc ular e ve nts ( M A C E) 
Car diac deat h 
•
Fatal S A Es i n Car diac dis or ders S O C   


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 3
S A P 
K J X 8 3 9 A 1 1 2 0 1
•
Fatal S A Es i n Ge neral dis or der S O C:  P Ts ‘ Deat h’, ‘ S u d de n car diac deat h’, 
‘ Car diac deat h’, ‘ A p pare nt deat h’
Car diac arrest
•
P T ‘ Car diac arrest’
N o n-fatal MI
•
M y ocar dial i nfarcti o n ( S M Q, br oa d a n d narr o w), n o nfatal e ve nts o nl y
Str o ke
•
Ce ntral Ner v o us S yste m he m orr ha ges a n d cere br o vasc ular acci de nts ( H L T), 
n o n-fatal e ve nts
5. 3   
L a b or at or y p ar a m et er s d eri v ati o n s
N ota ble la b orat or y val ues are defi ne d as f oll o ws.
T a bl e 5. 3- 1 Cli ni c all y n ot a bl e l a b or at or y a b n or m aliti e s f or s el e ct e d t e st s
P ar a m et er s
Crit eri a
H e m at ol o g y
H e m o gl o bi n
≤ 1 0 g/ d L
H e m at o crit
≤ 0. 8 × L L N
W B C (t ot al)
≤ 2. 8 × 1 0 3  / μ L, ≥ 1 6 × 1 03 / μ L
Pl at el et c o u nt
≤ 7 5 × 1 0 3  / μ L, ≥ 7 0 0 × 1 03 / μ L
H b A 1 c
≥ 6. 5 % a n d ≥0. 5 % c h a n g e fr o m b a s eli n e
Cli ni c all y c h e mi str y
Cr e ati ni n e
> 2 m g/ d L
C K
> 1 a n d ≤ 3 × U L N
C K
> 3 a n d ≤ 5 × U L N
C K
> 5 a n d ≤ 1 0 × U L N
C K
> 1 0 × U L N
A L T
> 1 a n d ≤ 3 × U L N
A L T
> 3 a n d ≤ 5 × U L N
A L T
> 5 a n d ≤ 1 0 × U L N
A L T
> 1 0 × U L N
A S T
> 1 a n d ≤ 3 × U L N
A S T
> 3 a n d ≤ 5 × U L N
A S T
> 5 a n d ≤ 1 0 × U L N
A S T
> 1 0 × U L N


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 4
S A P 
K J X 8 3 9 A 1 1 2 0 1
P ar a m et er s
Crit eri a
T ot al bilir u bi n
> 2 × U L N
A L P
> 2 × U L N
 


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 5
S A P 
K J X 8 3 9 A 1 1 2 0 1
T a bl e 5. 3- 2 N ot a bl e li v er f u n cti o n t e st v al u e s
Crit eri o n
A L T > 3 x t h e u p p er li mit of n or m al r a n g e ( U L N)
A L T > 5 x U L N
A L T > 8 x U L N
A L T > 1 0 x U L N
A L T > 2 0 x U L N
A S T > 3 x U L N
A S T > 5 x U L N
A S T > 8 x U L N
A S T > 1 0 x U L N
A S T > 2 0 x U L N
A L T or A S T > 3 x U L N
A L T or A S T > 5 x U L N
A L T or A S T > 8 x U L N
A L T or A S T > 1 0 x U L N
A L T or A S T > 2 0 x U L N
T ot al bilir u bi n > 1 x U L N
T ot al bilir u bi n > 1. 5 x U L N
T ot al bilir u bi n > 2 x U L N
T ot al bilir u bi n > 3 x U L N
T B L > 2 x U L N & D B L > U L N
T B L > 2 x U L N & D B L > 1. 5 x U L N
T B L > 2 x U L N & D B L > 2 x U L N
A L P > 1. 5 x U L N
A L P > 2 x U L N
A L P > 3 x U L N
A L P > 5 x U L N
A L T or A S T > 3 x U L N a n d t ot al bilir u bi n > 1. 5 x U L N
A L T or A S T > 3 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L T or A S T > 5 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L T or A S T > 8 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L T or A S T > 1 0 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L T or A S T > 2 0 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L P > 3 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L P > 5 x U L N a n d t ot al bilir u bi n > 2 x U L N
A L T or A S T > 3 x U L N a n d T ot al Bilir u bi n > 2 x U L N a n d A L P < 2 x U L N ( H y' s l a w)
A L T = al a ni n e a mi n otr a n sf er a s e, A S T = a s p art at e a mi n otr a n sf er a s e, A L P = al k ali n e p h o s p h at a s e, 
D B L = Dir e ct bilir u bi n






N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 8
S A P 
K J X 8 3 9 A 1 1 2 0 1
5. 5    
R e s p o n d er d efi niti o n
T he f oll o wi n g ta ble e x plai ns Ja pa nese li pi d m o dificati o n tar gets acc or di n g t o partici pa nt's 
bac k gr o u n d ris k cate g ories as per t he J A S 2 0 1 7 g ui deli ne.
Partici pa nt's bac k gr o u n d ris k cate g ories as per t he J A S 
2 0 1 7 g ui deli ne
L D L- C tar gets
Partici pa nt wit h hist or y of C A D wit h a d diti o nal ris k 
fact ors s uc h as He F H, A C S or dia betes c o m plicate d 
b y ot her ris k fact ors
Ser u m L D L- C < 7 0 m g/ d L
Partici pa nt wit h hist or y of C A D wit h o ut a d diti o nal 
ris k fact ors or He F H partici pa nt wit h o ut C A D hist or y
Ser u m L D L- C < 1 0 0 m g/ d L
Partici pa nt cate g orize d i n ' hi g h ris k'
Ser u m L D L- C < 1 2 0 m g/ d L
T he f oll o wi n g ta ble e x plai ns Ja pa nese li pi d m o dificati o n tar gets acc or di n g t o partici pa nt's 
bac k gr o u n d ris k cate g ories as per t he J A S 2 0 2 2 g ui deli ne.
Partici pa nt's bac k gr o u n d ris k 
cate g ories as per t he J A S 
2 0 2 2 g ui deli ne
A d diti o nal bac k gr o u n d cate g ories as per 
t he J A S 2 0 2 2 g ui deli ne
L D L- C tar gets
M H of C A D ，F H ，D M
[ Pr o gra m mi n g n ote]
C A D: C or o nar y arter y disease ( Occ urre nce = Yes)
F H: Heter oz y g o us fa milial h y perc h olester ole mia 
( O n g oi n g = Yes)
D M Dia betes mellit us ( Occ urre nce = Yes)
Ser u m L D L- C < 7 0 
m g/ d L 
Partici pa nts wit h a me dical 
hist or y ( M H) of cere bral 
I nfarcti o n ( Occ urre nce = Yes) 
e xcl u di n g lac u nar i nfarcti o n
E xce pt f or t he a b o ve, 
Ser u m L D L- C < 1 0 0 
m g/ d L 
M H of D M
Ser u m L D L- C < 7 0 
m g/ d L
Partici pa nts ot her t ha n t he 
a b o ve a n d were classifie d as 
tar get val ue Ser u m L D L- C 
≥1 0 0 m g/ d L at baseli ne
a n d
Partici pa nts wit h M H of C A D
E xce pt f or t he a b o ve,
Ser u m L D L- C < 1 0 0 
m g/ d L
Partici pa nts ot her t ha n t he 
a b o ve a n d were classifie d as 
tar get val ue Ser u m L D L- C 
≥7 0 m g/ d L at baseli ne
Ser u m L D L- C < 7 0 
m g/ d L
He F H ( M H of He F H) 
partici pa nts ot her t ha n t he 
a b o ve
N o M H of cere bral I nfarcti o n e xcl u di n g 
lac u nar i nfarcti o n or 
N o M H of C A D
Ser u m L D L- C < 1 0 0 
m g/ d L


N o v arti s
F or b u si n e s s u s e o nl y
P a g e 3 9
S A P 
K J X 8 3 9 A 1 1 2 0 1
D M ( M H of D M) partici pa nts 
ot her t ha n t he a b o ve
S m o ki n g ( C urre nt) 
[ Pr o gra m mi n g n ote]
c urre nt s m o ki n g stat us cate g or y = C urre nt 
or 
Reti n o pat h y ( o n g oi n g)
[ Pr o gra m mi n g n ote]
P T = Dia betic reti n o pat h y & O n g oi n g = Yes 
or
Ne p hr o pat h y ( o n g oi n g):
[ Pr o gra m mi n g n ote]
P T = Dia betic ne p hr o pat h y & O n g oi n g = Yes
P T = Ne p hr otic s y n dr o me & O n g oi n g = Yes
or 
Ne ur o pat h y ( o n g oi n g):
[ Pr o gra m mi n g n ote]
P T = Dia betic ne ur o pat h y & O n g oi n g = Yes 
P T = peri p heral ne ur o pat h y & O n g oi n g = Yes
or 
P A D ( o n g oi n g):
[ Pr o gra m mi n g n ote]
P T = Peri p heral arterial occ ul usi ve disease & O n g oi n g = Yes 
P T ＝peri p heral arter y occl usi o n & O n g oi n g = Yes
Ser u m L D L- C < 1 0 0 
m g/ d L
Partici pa nts ot her t ha n t he 
a b o ve
Ser u m L D L- C < 1 2 0 
m g/ d L
T he f oll o wi n g calc ulati o ns are defi ne d t o deter mi ne w het her a s u bject has > 8 0 % of baseli ne at 
Da y 1 8 0,
1. T hres h ol d = 8 0 % * ( L D L- C at Baseli ne - L D L- C at Da y 1 8 0) + L D L- C at Da y 1 8 0.
2. If t he s u bject’s L D L- C val ue is greater t ha n t he t hres h ol d s pecifie d a b o ve, or t he s u bject’s 
L D L- C val ue is greater t ha n or e q ual t o t he L D L- C at Baseli ne, t he s u bject is c o nsi dere d t o 
ha ve > 8 0 % of baseli ne.
5. 6    
R ul e of e x cl u si o n crit eri a of a n al y si s s et s 
T he pr ot oc ol de viati o ns ( P D) a n d ot her criteria lea di n g t o c o m plete e xcl usi o n fr o m a nal yses 
sets will be i ncl u de d i n t his secti o n a n d will be fi nalize d bef ore st u d y D B L.
6    
R ef er e n c e