Conditions: Hypercholesterolemia
Keywords: inclisiran ezetimibe LDL-C monotherapy primary hypercholesterolemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 350
Healthy volunteers: no

Brief summary:
CKJX839D12304 was a research study to determine if the study treatment, called inclisiran, in comparison to placebo and ezetimibe effectively reduces Low-Density Lipoprotein Cholesterol (LDL-C) as measured by percentage change from baseline to Day 150. This study was conducted in eligible participants with primary hypercholesterolemia not receiving any lipid-lowering therapy (LLT), with a 10-year Atherosclerotic Cardiovascular Disease (ASCVD) risk of less than 7.5%.

Detailed description:
This study was a randomized, double-blind, placebo- and active comparator-controlled, multicenter study in 350 adult participants with primary hypercholesterolemia not receiving any LLT with a 10-year ASCVD risk score of less than 7.5%. This study evaluated the efficacy and safety of inclisiran sodium 300 mg, administered as a monotherapy in comparison to ezetimibe and placebo.

The study consisted of:

* a screening period of up to 14 days;
* a double-blind treatment period of 150+/- 5 days during which participants were randomly assigned to either the inclisiran arm, the ezetimibe arm or the placebo arm in a 2:1:1 ratio; and
* a safety follow-up / End of Study visit conducted 30+5 days after the Day 150 visit.

The overall study duration was approximately 190 days.

Arms:
arm 1: Inclisiran s.c and Placebo p.o arm 2: Placebo s.c. and Ezetimibe p.o. arm 3: Placebo s.c. and Placebo p.o.

Interventions: intervention 1: Inclisiran intervention 2: Ezetimibe intervention 3: Matching Placebo for Inclisiran intervention 4: Matching Placebo for Ezetimibe
Intervention descriptions: intervention 1: 284 mg (equivalent to 300 mg inclisiran sodium) subcutaneous injection given on Day 1 and Day 90 intervention 2: 10 mg over-encapsulated tablet taken once a day from Day 1 through Day 149 intervention 3: 0mg placebo injection solution for subcutaneous injection on Day 1 and Day 90 intervention 4: 0mg over-encapsulated placebo tablet taken once a day from Day 1 through Day 149

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
KJX839/Inclisiran 
Clinical Trial Protocol CKJX839D12304 / NCT05763875
A Double-blind, Randomized, Placebo- and Active-
Comparator Controlled Study to Evaluate the Efficacy of 
Inclisiran as Monotherapy in Patients with Primary 
Hypercholesterolemia Not Receiving Lipid-Lowering 
Therapy (VictORION-Mono) 
Document type: 
Amended Protocol Version (Clean) 
EUDRACT number: 
2022-001109-29 
Version number: 
V01 (Amended Protocol) 
Clinical Trial Phase: 
III 
Release date: 
08-Feb-2023 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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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 ............................................................................................................... 10 
Amendment 1 (08-Feb-2023) ............................................................................................ 13 
Protocol summary .............................................................................................................. 17 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
1.2 
Purpose .................................................................................................................. 21 
2 
Objectives, endpoints and estimands ................................................................................. 22 
2.1 
Primary estimands ................................................................................................. 22 
2.2 
Secondary estimands ............................................................................................. 23 
3 
Study design ...................................................................................................................... 24 
3.1 
Off-site procedures ................................................................................................ 24 
3.1.1 
Responsibility of Investigators .............................................................. 25 
3.1.2 
Responsibility of OHPs ......................................................................... 25 
3.1.3 
Telemedicine ......................................................................................... 25 
3.2 
Screening ............................................................................................................... 26 
3.3 
Double-blind treatment .......................................................................................... 26 
3.4 
Safety Follow-up/EOS ........................................................................................... 27 
4 
Rationale ............................................................................................................................ 27 
4.1 
Rationale for study design ..................................................................................... 27 
4.1.1 
Rationale for choice of background therapy ......................................... 27 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 28 
4.3 
Rationale for choice of control drugs (comparator/placebo) ................................. 28 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 28 
4.5 
Risks and benefits .................................................................................................. 29 
4.6 
Rationale for planned off-site procedures .............................................................. 30 
4.7 
Rationale for Public Health Emergency mitigation procedures ............................ 30 
5 
Study Population ............................................................................................................... 30 
5.1 
Inclusion criteria .................................................................................................... 30 
5.2 
Exclusion criteria ................................................................................................... 31 
6 
Treatment ........................................................................................................................... 33 
6.1 
Study treatment ...................................................................................................... 33 


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6.1.1 
Investigational and control drugs .......................................................... 33 
6.1.2 
Additional study treatments .................................................................. 33 
6.1.3 
Treatment arms/group ........................................................................... 33 
6.1.4 
Treatment duration ................................................................................ 34 
6.2 
Other treatment(s) .................................................................................................. 34 
6.2.1 
Concomitant therapy ............................................................................. 34 
6.2.2 
Prohibited medication ........................................................................... 35 
6.3 
Preparation and dispensation ................................................................................. 36 
6.3.1 
Handling of study treatment and other treatment .................................. 37 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 38 
6.4 
Participant numbering, treatment assignment, randomization .............................. 39 
6.4.1 
Participant numbering ........................................................................... 39 
6.4.2 
Treatment assignment, randomization .................................................. 39 
6.5 
Treatment blinding ................................................................................................ 39 
6.6 
Dose escalation and dose modification.................................................................. 40 
6.6.1 
Definitions of dose limiting toxicities (DLTs) ...................................... 40 
6.6.2 
Dose modifications ................................................................................ 40 
6.6.3 
Follow-up for toxicities ......................................................................... 40 
6.7 
Additional treatment guidance ............................................................................... 42 
6.7.1 
Treatment compliance ........................................................................... 42 
6.7.2 
Recommended treatment of adverse events .......................................... 42 
6.7.3 
Emergency breaking of assigned treatment code .................................. 42 
7 
Informed consent procedures ............................................................................................ 43 
8 
Visit schedule and assessments ......................................................................................... 44 
8.1 
Screening ............................................................................................................... 50 
8.1.1 
Information to be collected on screening failures ................................. 50 
8.2 
Participant demographics/other baseline characteristics ....................................... 50 
8.3 
Efficacy .................................................................................................................. 51 
8.3.1 
LDL-C ................................................................................................... 51 
8.3.2 
Additional efficacy assessments ........................................................... 51 
8.3.3 
Appropriateness of efficacy assessments .............................................. 51 
8.4 
Safety ..................................................................................................................... 52 
8.4.1 
Laboratory evaluations .......................................................................... 52 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 54 
8.4.3 
Pregnancy and assessments of fertility ................................................. 54 
8.4.4 
Appropriateness of safety measurements .............................................. 55 


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8.5 
Additional assessments .......................................................................................... 55 
8.5.1 
Trial Feedback Questionnaire ............................................................... 55 
 
 ............................................................................................ 55 
8.5.3 
Lifestyle instructions ............................................................................. 55 
9 
Discontinuation and completion ........................................................................................ 56 
9.1 
Discontinuation from study treatment and from study .......................................... 56 
9.1.1 
Discontinuation from study treatment ................................................... 56 
9.1.2 
Discontinuation from study ................................................................... 57 
9.1.3 
Lost to follow-up ................................................................................... 57 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 57 
9.3 
Study completion and post-study treatment .......................................................... 58 
9.4 
Early study termination by the sponsor ................................................................. 59 
10 Safety monitoring, reporting and committees ................................................................... 59 
10.1 
Definition of adverse events and reporting requirements ...................................... 59 
10.1.1 
Adverse events ...................................................................................... 59 
10.1.2 
Serious adverse events .......................................................................... 61 
10.1.3 
SAE reporting........................................................................................ 62 
10.1.4 
Pregnancy reporting .............................................................................. 63 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 63 
10.2 
Additional Safety Monitoring ................................................................................ 64 
10.2.1 
Liver safety monitoring ......................................................................... 64 
10.2.2 
Renal safety monitoring ........................................................................ 64 
10.3 
Committees ............................................................................................................ 65 
11 Data Collection and Database management ...................................................................... 65 
11.1 
Data collection ....................................................................................................... 65 
11.2 
Database management and quality control ............................................................ 65 
11.3 
Site monitoring ...................................................................................................... 66 
12 Data analysis and statistical methods ................................................................................ 66 
12.1 
Analysis sets .......................................................................................................... 66 
12.2 
Participant demographics and other baseline characteristics ................................. 67 
12.3 
Treatments ............................................................................................................. 68 
12.4 
Analysis supporting primary objectives ................................................................ 68 
12.4.1 
Definition of primary endpoint(s) ......................................................... 68 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 69 
12.4.3 
Handling of intercurrent events of primary estimands .......................... 70 
12.4.4 
Handling of missing values not related to intercurrent event ............... 71 


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12.4.5 
Sensitivity analyses ............................................................................... 71 
12.4.6 
Supplementary analysis ......................................................................... 71 
12.5 
Analysis supporting secondary objectives ............................................................. 71 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 71 
12.5.2 
Safety endpoints .................................................................................... 73 
 
 ............................................................................................ 74 
 
 ......................................................................... 74 
12.7 
Interim analyses ..................................................................................................... 74 
12.8 
Sample size calculation.......................................................................................... 75 
12.8.1 
Primary endpoint(s) ............................................................................... 75 
12.8.2 
Secondary endpoint(s) ........................................................................... 75 
13 Ethical considerations and administrative procedures ...................................................... 75 
13.1 
Regulatory and ethical compliance ........................................................................ 75 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 75 
13.3 
Publication of study protocol and results............................................................... 76 
13.4 
Quality Control and Quality Assurance ................................................................. 76 
13.5 
Participant Engagement ......................................................................................... 77 
13.6 
Data Protection ...................................................................................................... 77 
14 Protocol adherence ............................................................................................................ 77 
14.1 
Protocol amendments............................................................................................. 78 
15 References ......................................................................................................................... 79 
16 Appendices ........................................................................................................................ 81 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 81 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 82 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 84 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Investigational and control drug ............................................................ 33 
Table 6-2 
Medication allowed under certain conditions ....................................... 35 
Table 6-3 
Prohibited medication ........................................................................... 36 
Table 6-4 
Dose and treatment schedule ................................................................. 38 
Table 6-5 
Guidance on clinical and diagnostic assessments to rule out 
alternative causes of observed LFT abnormalities ................................ 41 
Table 8-1 
Assessment Schedule ............................................................................ 46 


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Table 8-2 
Safety assessments ................................................................................ 52 
Table 8-3 
Safety Laboratory Assessments ............................................................ 53 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 63 
Table 16-1 
Liver laboratory trigger definitions ....................................................... 82 
Table 16-2 
Follow-up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 82 
Table 16-3 
Follow-up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia or elevated ALP .................................................... 83 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 24 
Figure 12-1 
Testing procedure for primary and secondary endpoints ...................... 73 
 


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List of abbreviations 
ACC 
American College of Cardiology 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AHA 
American Heart Association 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANCOVA 
Analysis of covariance 
Apo A-1 
Apolipoprotein A-1 
Apo B 
Apolipoprotein B 
APTT 
Activated Partial Thromboplastin time 
ASCVD 
Atherosclerotic Cardiovascular Disease 
ASMA 
Anti-smooth muscle antibody 
ASO 
Antisense Oligonucleotide 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CD-transferrin 
Carbohydrate-deficient transferrin 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
cm 
centimeter(s) 
CMO&PS  
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CO 
Country Organization 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTIS 
Clinical Trials Information System (European Medicines Agency) 
CTT 
Clinical Trial Team 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DHA 
Docosahexaenoic acid 
DILI 
Drug-Induced Liver Injury 
dL 
deciliter(s) 
DNA 
Deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
EC 
European Commission 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
EPA 
Eicosapentaenoic acid 


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ERCP 
Endoscopic retrograde cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
FSH 
Follicle Stimulating Hormone 
GalNAc 
N-Acetylgalactosamine 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
HAV 
Hepatitis A Virus 
HbA1c 
Glycated hemoglobin (hemoglobin A1c) 
HBc 
Hepatitis B core antigen 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL-C 
High-Density Lipoprotein Cholesterol 
HeFH 
Heterozygous Familial Hypercholesterolemia 
HEV 
Hepatitis E Virus 
HSV 
Herpes simplex virus 
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 
Ig 
Immunoglobulin 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
kg 
kilogram(s) 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LDLR 
Low Density Lipoprotein Receptor 
LFT 
Liver function test  
LLT 
Lipid-Lowering Therapy 
Lp(a) 
Lipoprotein (a) 
LPLV 
Last participant last visit 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCP 
Multiple Comparison Procedure 
MCV 
Mean Corpuscular Volume 


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MDRD 
Modification of diet in renal disease 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
mmol 
millimol(s) 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
non-HDL-C 
non-High-Density Lipoprotein Cholesterol 
NYHA 
New York Heart Association 
OHP 
Off-site Healthcare Professional 
p.o. 
oral(ly) 
PCE 
Pooled cohort equations 
PCR 
Protein-creatinine ratio 
PCSK9 
Proprotein Convertase Subtilisin/Kexin type 9 
PD 
Pharmacodynamic(s) 
PMM 
Pattern-Mixture Model 
PT 
Prothrombin time 
QMS  
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RAS 
Randomized Analysis Set 
RDO 
Retrieved Drop Out 
RISC 
Ribonucleic acid-Induced Silencing Complex 
RNA 
Ribonucleic acid 
RNAi 
Ribonucleic acid interference 
s.c. 
subcutaneous(ly) 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 also referred to as COVID-19 
SCR 
Screened Set 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TBL 
Total bilirubin 
TC 
Total cholesterol 
TEAE 
Treatment-Emergent Adverse Event 
TFQ 
Trial Feedback Questionnaire 
TSH 
Thyroid stimulating hormone 
U/L 
Units/Liter 
ULN 
Upper limit of normal 
US 
United States (of America) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant  
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical trial 
activities. Examples of team members include the Study Lead, Medical Monitor, Trial 
Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, or a 
group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Discontinuation 
from study 
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific request 
is made to stop the use of their samples or data. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study treatment for any 
reason (prior to the planned completion of study drug administration, if any). Participant 
agrees to the other protocol required assessments including follow-up. No specific 
request is made to stop the use of their samples or data. 
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 source 
data/documents used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant. 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants 
Estimand 
As defined in the International Council for Harmonization (ICH) E9(R1) addendum, 
estimand is 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 participants 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. 
Hybrid Trial Design 
A trial model incorporating both onsite (traditional site based) and offsite (decentralized) 
elements within the same study design. 
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 
or the participant allocated to an invalid stratification factor 


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Off-site 
Describes any trial activities that are performed at a location that is not the investigative 
site (where the investigator will conduct the trial), such as a home or another appropriate 
location. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, including those used in a study e.g. Nurse, 
Phlebotomist, Physician, who performs certain protocol procedures for the participant at 
an off-site location such as a participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" terminology is 
used in the protocol whereas term "Subject" is used in data collection 
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 
The process of assigning trial participants to investigational drug or control/comparator 
drug using an element of chance to determine the assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Re-screening 
If a participant fails the initial screening and is considered as a Screen Failure, he/she 
can be invited once for a new Screening visit after medical judgment and as specified by 
the protocol 
Remote 
Describes any trial activities performed at a location that is not the investigative site 
where the investigator will conduct the trial, but is for example a home or another 
appropriate location 
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 electronic source. 
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 
Telemedicine 
Electronic information and telecommunications technologies (both video-based and 
audio-only) to facilitate the delivery of health care and health related education where 
participant and investigator and site personnel are not in the same location. 
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. 


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Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and biological samples (opposition to use data and biological 
samples) AND no longer wishes to receive study treatment, AND does not agree to 
further protocol required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
This request should be distinguished from a request to discontinue the study. Other 
study participant's privacy rights are described in the corresponding informed consent 
form (ICF). 


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Amendment 1 (08-Feb-2023)  
Amendment rationale 
In order to minimize missing data after discontinuation of study treatment, the amendment 
incorporates continued efforts to measure endpoints on all participants until Day 180, even for 
those who may have prematurely discontinued study treatment. 
For regulatory purposes, to provide an estimate of treatment effect under conditions that better 
resemble clinical practice, the amendment includes a “Treatment-policy Estimand” that 
assesses efficacy of inclisiran in LDL-C lowering irrespective of addition of other LLTs, in 
parallel to the original estimand, referred to as “Monotherapy Estimand”, which directly 
evaluates effect of inclisiran as monotherapy. 
This amendment also incorporates additional guidance for the investigator on lifestyle 
instructions to be given to the participants as recommended by the 2019 ACC/AHA Guideline 
on the Primary Prevention of Cardiovascular Disease (Arnett et al 2019). 
In addition, the discontinuation from study treatment criteria are updated to provide additional 
guidance to the investigator on specific reasons for discontinuation of study treatment including 
liver enzyme elevation and CK criteria, severe and persistent (> 14 days despite appropriate 
treatment) reactions at the injection site and any anaphylactic reactions, and intolerable adverse 
events.  
To avoid unnecessary study treatment discontinuations, the actions taken in response to addition 
of other LLTs have been updated so that study treatment will not be automatically discontinued 
when other LLTs are taken after randomization (except for those targeting PCSK9, and RNAi-
based therapies). 
Finally, minor typos and inconsistencies have been corrected in the protocol. 
As of the date of this amendment, no sites were initiated and no participants were recruited. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
The protocol summary was updated to reflect a ±5 day study window for the double-blind 
treatment period based on the Day 1 randomization date and a window of +5 days after the Day 
150 visit for the Safety Follow-up / End of Study (EOS) visit. The summary also specifies that 
the last dose of p.o. ezetimibe/placebo will be taken the day before the Day 150 visit. Finally, 
inclusion criterion #4 states that triglycerides will be measured from participants in a fasting 
state, and exclusion criterion #10 was clarified to reflect Secondary hypercholesterolemia e.g., 
hypothyroidism (thyroid stimulating hormone (TSH) above the upper limit of normal (ULN)) 
rather than below the lower limit of normal at screening. In the Treatment of Interest Section, 
the additional clarification that treatment of interest is without other LLT was removed. 
Section 2 was updated to add a “Treatment-policy Estimand” that assesses efficacy of inclisiran 
irrespective of addition of other LLTs, in parallel to the “Monotherapy Estimand” which is 


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based on the original estimand but uses the hypothetical strategy to handle discontinuation of 
study treatment instead of the treatment-policy strategy as previously specified. 
Section 3 and Figure 3-1 were updated to specify that participants who prematurely discontinue 
study treatment are expected to continue to with all planned study visits and be retained in the 
study until Day 180 End of Study (EOS). This section also describes that a window of ± 5 days 
based on the Day 1 randomization date is allowed for the double-blind treatment period of 150 
days. Clarified that safety follow-up/EOS will be conducted 30+5 days after the Day 150 Visit. 
Section 3.3 clarifies that the last dose of p.o. ezetimibe/placebo will be taken by the participant 
on the day before the Day 150 visit. 
In Section 3.4, the visit window is specified as 30 + 5 days after the Day 150 Visit.  
Figure 3-1 inclisiran/placebo at the Day 90 post-baseline visit. Section 9.1.1 is cited to describe 
the circumstances under which study treatment is discontinued. Section 9.2 is referred to in case 
a subject withdrawals consent and the follow-up actions that are needed by the Investigator. 
Section 5.1 Inclusion criteria 
• Inclusion criterion #4 was updated to clarify that triglycerides will be obtained from 
participant’s lipids panel in a fasting state. 
Section 5.2 Exclusion criteria 
• Exclusion criterion #10 was clarified to reflect Secondary hypercholesterolemia e.g., 
hypothyroidism (thyroid stimulating hormone (TSH) above the upper limit of normal 
(ULN)) rather than below the lower limit of normal at screening. 
• Exclusion criterion #12 specifies Estimated glomerular filtration rate (eGFR) < 30 
mL/min/1.73m2 at screening will be determined by the central laboratory using the 
Modification of Diet in Renal Disease (MDRD) formula 
Section 6.1.4, The safety follow-up / End of Study (EOS) visit window is specified as between 
30 and 35 days after the Day 150 Visit. 
Table 6-3 Prohibited medication, the prohibited medication table clarifies the prohibition 
periods and actions taken for the different medication classes, prior to randomization and 
starting from randomization and throughout the study. Any prohibited medication taken during 
the prohibition period until randomization result in non-randomization of a participant. The 
action taken for other LLTs (except for PCSK9 monoclonal antibodies) starting after 
randomization was modified to have the investigator request the participant to stop the LLTs, 
and to contact Novartis for further guidance. Investigators should also contact Novartis if the 
participant receives systemic cyclosporine and tacrolimus, systemic steroids, vitamin A 
derivatives or retinal derivatives for the treatment of dermatologic conditions or antiviral 
therapies after randomization and until the end of the study. 
Section 6.7.1, added that the treatment compliance for p.o. ezetimibe/placebo should also be 
captured in the appropriate eCRF at each visit from Visit 2 / Day 30 through Visit 4 / Day150 .  
Section 8 and Table 8-1 were updated to specify that participants who prematurely discontinue 
study treatment, are required to complete all planned study visits and be retained until Day 180. 
This section also describes that a window of ± 5 days based on the Day 1 randomization date is 


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allowed for the double-blind treatment period of 150 days. Day 180 is clarified as occurring 
between 30 + 5 days after the Day 150 Visit 
Table 8-1 Assessment schedule was updated as follows: 
• HbA1c will be collected at screening (and not at randomization). 
• Ezetimibe/placebo compliance will be captured in the clinical database from Day 30 until 
the visit following the last dose of p.o. ezetimibe/placebo.  
• End of Treatment Disposition form will be completed prior to Day 150 for participants who 
discontinue study treatment early. 
• Footnote #14 specifies that if the urinalysis dipstick results are abnormal, then the urine 
sample will be sent to the central laboratory where a macroscopic panel will be performed 
with a reflexive microscopic panel.  
Section 8.3 specifies that the unblinded lipid panel results will be provided to the Investigator 
and Sponsor at the Screening Visit only.  
Table 8-3, an assessment of HbA1c only has been added at Screening, to ensure that the 
participant does not meet the HbA1c exclusion criterion. The Hematology panel on Day 1 will 
not include a HbA1c measurement. Urinalysis and renal follow-up section was updated to 
specify that central lab will perform a macroscopic panel, followed by a reflexive microscopic 
panel.  
Section 8.4.2 describes that the baseline ECG is read and interpreted locally by the Investigator 
and any clinically significant abnormalities will be reported on the adverse events CRF.  
Section 8.5.3 Lifestyle instructions, were added so that investigators can instruct their 
participants between randomization and Day 180 on the ways to prevent ASCVD by promoting 
a healthy lifestyle throughout life. 
Section 9.1.1, was updated to clarify that if the participant permanently discontinues p.o. 
ezetimibe/placebo or s.c. inclisiran/placebo, then the participant’s entire study treatment must 
be stopped. Language has been added to state that participants must be retained in the study 
until Day 180 even if they prematurely discontinue study treatment. To provide the investigator 
with specific examples and to be consistent with prior inclisiran studies, specific liver enzyme 
elevation and CK criteria, language regarding severe and persistent (>14 days despite 
appropriate treatment) reactions at the injection site and any type of anaphylactic reactions, and 
intolerable adverse events are added to the list of discontinuation criteria from study treatment. 
Section 9.3, was updated to clarify that the safety follow-up call or the EOS visit should be 
conducted at least 30 days after the Day 150 visit. 
Section 10.1.1, For action taken regarding investigational study drug or comparator, it was 
clarified that the action taken for ‘Drug Interrupted’ is applicable for ezetimibe/placebo only, 
whereas, ‘Dose not Changed’ and ‘Permanently Discontinued’ is applicable to both, study drug 
and comparator drug.  
Section 12.4.2 was updated to reflect the changes in the estimands in Section 2.1. The last 
paragraph of this section was removed in the amendment because the method described does 
not apply to all the missing values under the new estimands. 


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Section 12.4.3 was updated to describe the strategies used by each of the two estimands for 
handling intercurrent events. 
Section 12.4.4 was updated to summarize the methods for imputing missing values not related 
to intercurrent events. 
Section 12.4.5 was updated to include the tipping point analyses to assess the robustness of the 
inferences to various assumptions about the missing data. 
Section 12.4.6 was updated to remove the originally specified supplementary analyses as they 
are no longer necessary or applicable. 
Section 12.5.1 was updated to reflect the changes in the estimands in Section 2.1. Also, the 
paragraph about missing value imputation was updated to be in line with the strategy for the 
primary endpoints. 
Table 16-2 is updated to be consistent with Section 9.1.1 for the liver laboratory triggers and 
action taken. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol number 
CKJX839D12304 
Full Title 
A Double-blind, Randomized, Placebo- and Active-Comparator Controlled Study to 
Evaluate the Efficacy of Inclisiran as Monotherapy in Patients with Primary 
Hypercholesterolemia Not Receiving Lipid-Lowering Therapy (VictORION-Mono) 
Brief title 
Efficacy and safety of inclisiran as monotherapy in patients with primary 
hypercholesterolemia not receiving lipid-lowering therapy. 
Sponsor and 
Clinical Phase 
Novartis / Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose 
The purpose of the study is to evaluate the efficacy and safety of inclisiran sodium 300 
mg, administered as monotherapy to participants with primary hypercholesterolemia 
who are not on any lipid-lowering therapy (LLT). 
Primary 
Objective(s) 
The primary objectives of the study are: 
● To demonstrate the superiority of inclisiran as monotherapy, compared with placebo, 
in reducing low-density lipoprotein cholesterol (LDL-C) as measured by percentage 
change from baseline to Day 150 
● To demonstrate the superiority of inclisiran as monotherapy, compared with 
ezetimibe, in reducing LDL-C as measured by percentage change from baseline to Day 
150 
Secondary 
Objectives 
The secondary objectives of this study are: 
● To assess the efficacy of inclisiran as monotherapy, compared to ezetimibe and 
placebo, on absolute change in LDL-C, percentage change in Proprotein Convertase 
Subtilisin/Kexin type 9 (PCSK9), non-high-density lipoprotein cholesterol (non-HDL-C), 
total cholesterol (TC)/high -density lipoprotein cholesterol (HDL-C) ratio, apolipoprotein 
B (Apo B), Apo B/apolipoprotein A-1 (Apo A-1) ratio and lipoprotein (a) (Lp(a)) from 
baseline to Day 150 
● To assess the safety and tolerability of inclisiran as monotherapy, compared to 
placebo and ezetimibe. 
Study design 
This study is a randomized, double-blind, placebo- and active comparator-controlled, 
multicenter study in adult participants with primary hypercholesterolemia, not receiving 
any lipid-lowering therapy (LLT) and who have a 10-year Atherosclerotic Cardiovascular 
Disease (ASCVD) risk of less than 7.5%. 
The study consists of: 
● A screening period up to 14 days 
● A double-blind treatment period of 150 ± 5 days based on the Day 1 randomization 
date; and 
● A Safety Follow-up / End of Study (EOS) visit conducted 30 +5 days after the Day 150 
visit 
All participants who fulfill the inclusion/exclusion criteria will be randomized at baseline 
(Day 1) in a 2:1:1 double-blind fashion to one of three treatment arms: 
● subcutaneous (s.c.) inclisiran and oral (p.o.) placebo (inclisiran arm) 
● s.c. placebo and p.o. ezetimibe (ezetimibe arm) 
● s.c. placebo and p.o. placebo (placebo arm). 
Participants will receive inclisiran sodium 300 mg or placebo by s.c. injection by a 
healthcare professional at the study site on Day 1 and Day 90. Participants will also be 
dispensed oral ezetimibe or placebo on Day 1, Day 30, and Day 90, and will be asked 
to take 1 capsule once a day from Day 1 through the day before the Day 150 visit. 
The overall study duration is approximately 190 days but can vary depending on 
individual screening and the visit windows allowed for the treatment period and EOS 
visit. 
Rationale 
Statin use up-regulates PCSK9 levels. Therefore, therapies that target PCSK9 may 
perform differently as monotherapy than when added to statin treatment. The study is 
aimed to evaluate the efficacy and safety of inclisiran sodium 300 mg, administered as 
monotherapy to participants without background lipid-lowering agents, to inform an 


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understanding of the new PCSK9 inhibition approach with inclisiran and help establish 
efficacy expectations for inclisiran in patients who cannot take statins. 
Study population 
Approximately 300 randomized adult participants (≥ 18 to ≤ 75 years of age) with 
primary hypercholesterolemia at low risk for their first cardiovascular event (10-year 
ASCVD risk of less than 7.5%), and who are not on any LLT. 
Key Inclusion 
criteria 
● Signed informed consent must be obtained prior to participation in the study 
● Adults ≥ 18 to ≤ 75 years of age 
● Fasting LDL-C value of ≥ 100 mg/dL (equivalent to 2.59 mmol/L) but < 190 mg/dL 
(equivalent to 4.92 mmol/L) 
● Fasting Triglycerides ≤ 400 mg/dL (equivalent to 4.52 mmol/L) 
● With a 10-year ASCVD risk score of less than 7.5%, estimated using the pooled 
cohort equations (PCE) 
● Have not been on any LLT within 90 days 
Key Exclusion 
criteria 
● Use of any LLT within 90 days of screening including statins, ezetimibe, bempedoic 
acid, psyllium preparations, fibrates, bile-acid sequestrants, PCSK9 monoclonal 
antibodies, red yeast rice, niacin > 200 mg/day, omega-3 fatty acids [docosahexaenoic 
acid (DHA) and/or eicosapentaenoic acid (EPA), with a total dose > 1000 mg/day], or 
any drug with unknown ingredients taken for the purpose of lipid-lowering, including 
over-the-counter or herbal therapies  
● Use of systemic cyclosporine or tacrolimus, systemic steroids, vitamin A derivatives or 
retinal derivatives for the treatment of dermatologic conditions (vitamin A in a 
multivitamin preparation is permitted), or antiviral therapies (protease inhibitors or direct 
acting antivirals) within 30 days of screening 
● Participants on medications that are known to induce changes in lipids and 
lipoproteins (including but not limited to anticoagulants, loop diuretics, thiazide diuretics, 
beta blockers, amiodarone, estrogens, selective estrogen receptor modulators, 
androgens, anabolic steroids, and anticonvulsants) unless they are on a stable dose of 
such medications for at least 30 days prior to screening and have no planned dose 
change or treatment discontinuation during the study duration 
● History of ASCVD (including acute coronary syndrome, history of myocardial 
infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, 
transient ischemic attack, and peripheral artery disease including aortic aneurysm) 
● Diabetes mellitus or fasting plasma glucose (FPG) at screening ≥ 7.0 mmol/L 
(equivalent to 126 mg/dL) or glycated hemoglobin (HbA1c) ≥ 6.5% (equivalent to 7.8 
mmol/L or 140 mg/dL) 
● Secondary hypercholesterolemia, e.g., hypothyroidism [thyroid stimulating hormone 
(TSH) above the upper limit of normal (ULN)] or nephrotic syndrome at screening 
Study treatment 
Study drug: 
● KJX839 / Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution 
for injection 
● Matching s.c. placebo in 1.5 mL solution for injection 
Control drug: 
● Ezetimibe 10 mg p.o. 
● Matching p.o. placebo 
Treatment of 
interest 
The randomized 2:1:1 double-blind treatment of: 
● s.c. injections of inclisiran sodium 300 mg and p.o. placebo (inclisiran arm),  
● s.c. injections of placebo and p.o. ezetimibe (ezetimibe arm) or  
● s.c. injections of placebo and p.o. placebo (placebo arm) 
Efficacy 
assessments 
Efficacy assessments (using Central lab) are as follows: 
● LDL-C (primary) 
● PCSK9 
● non-HDL-C 
● TC/HDL-C ratio 
● Apo B 
● Apo B/Apo A-1 ratio 
● Lp(a) 
Key safety 
assessments 
Adverse event monitoring (adverse events (AEs) and serious AEs (SAEs), vital signs, 
laboratory parameters (blood, urine) 




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1 
Introduction 
1.1 
Background 
The prevalence of atherosclerotic cardiovascular disease (ASCVD) is increasing in many 
countries due to an aging population combined with atherogenic lifestyles. Mortality from 
ASCVD has been declining in most developed countries as a result of improvement in risk 
management and clinical intervention. However, ASCVD remains the leading cause of death 
among chronic diseases. Cardiovascular disease (CVD) results in over 17 million deaths 
annually (WHO 2021). ASCVD continues to be the most important health issue in the 
developed world and has also become one of the most pressing health problems in developing 
countries in the past decade. 
High blood cholesterol is a major risk factor for ASCVD. Reduction in Low-Density 
Lipoprotein Cholesterol (LDL-C) levels have been shown to reduce subsequent cardiovascular 
events, for both primary and secondary prevention of ASCVD. Current consensus statements 
recommend consideration of an aggressive treatment goal of LDL-C less than 70 mg/dL  
(1.8 mmol/L) for high risk or very high risk patients. 
Despite the success of statin therapy, significant gaps remain in the treatment of 
hypercholesterolemia. Many patients on statin regimens still experience complications of 
atherosclerosis. Others have persistently high LDL-C levels due to severe forms of 
hypercholesterolemia, poor tolerability of available medications, or persistent non-compliance 
to available medications due to complex reasons such as behavioral, psychological, and 
educational factors. For these populations, new effective lipid-lowering therapies (LLT) that 
impose less medication administration burden and improve compliance may offer significant 
clinical benefits (Assmann et al 2006, Banach et al 2016, Fox et al 2018). 
The hepatic cell surface low-density lipoprotein receptor (LDLR) plays an essential role in 
plasma clearance of circulating LDL-C and in whole body cholesterol homeostasis, while 
proprotein convertase subtilisin/kexin type 9 (PCSK9) is instrumental in recycling and 
regulation of LDLR (Brown and Goldstein 2006, Horton et al 2007). PCSK9 is expressed and 
secreted into the bloodstream predominantly by the liver. It binds to the LDLR both 
intracellularly and extracellularly, promotes the lysosomal degradation of these receptors in 
hepatocytes (Lakoski et al 2009, Mousavi et al 2009), and consequently increases the 
circulating LDL-C levels. The inhibition of PCSK9 offers an effective approach to lower  
LDL-C. 
The inhibition of PCSK9 can be achieved by PCSK9-binding monoclonal antibodies that 
prevent the interaction of PCSK9 with LDLR. PCSK9-binding monoclonal antibodies have 
shown to reduce LDL-C by 55-65% (Sabatine et al 2017, Schwartz et al 2018). These PCSK9 
monoclonal antibodies require an injection frequency of every 2 to 4 weeks, necessitating up to 
26 injections per year (Navarese et al 2015, Zhang et al 2015), which leads to a significant 
medication administration burden on patients. 
The inhibition of PCSK9 can also be achieved by small interfering RNA (siRNA) that can 
selectively and catalytically silence the translation of messenger ribonucleic acids (mRNAs) to 
reduce the intracellular synthesis of PCSK9 protein. Inclisiran (KJX839) is a chemically 
modified double-stranded siRNA, conjugated on the sense strand with triantennary  


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N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, the 
antisense strand is incorporated in the RNA-induced silencing complexes (RISC) and directs 
catalytic breakdown of mRNA for PCSK9. This then leads to the inhibition of the synthesis of 
PCSK9 protein. Reduced intrahepatic PCSK9 increases LDL-C receptor recycling and 
expression on the hepatocyte cell surface, which ultimately improves LDL-C uptake and lowers 
LDL-C levels in the circulation (Fitzgerald et al 2017). This novel mechanism has been proven 
to be effective. In the ORION-9, -10, and -11 Phase III studies, treatment with inclisiran  
sodium 300 mg administered by subcutaneous (s.c.) injection on Day 1, Day 90 and every  
6 months thereafter, resulted in placebo-adjusted percentage reductions in LDL-C from baseline 
to Day 510 of 48% to 52%, with time-adjusted average reductions of 44% to 54% over  
18 months in participants with ASCVD, ASCVD risk equivalent, and/or heterozygous familial 
hypercholesterolemia (HeFH) (Raal et al 2020, Ray et al 2020). There were no clinically 
relevant differences in the safety profile of inclisiran compared with placebo, except for a higher 
incidence of treatment-emergent adverse events (TEAEs) at the injection site with inclisiran in 
these Phase III trials. AEs at the injection site were localized, mild and transient in nature. 
Inclisiran is not associated with an increased risk for hepatic or renal dysfunction, 
hypersensitivity, neurologic events and neurocognitive disorders, or ophthalmological events 
and there is no difference from placebo in new onset or worsening of diabetes. The potential 
for immunogenicity of inclisiran is low. 
The long-term safety of inclisiran has been observed in two safety extension studies ORION-8 
(the extension study of ORION-9, -10 and -11) and ORION-3 (the extension study of the Phase 
II trial ORION-1). The overall safety profile observed in ORION-8 and ORION-3 was similar 
to that reported in inclisiran-treated participants of its feeder studies (ORION-9, -10, and -11; 
ORION-1). The favorable safety profile for inclisiran remains unaltered in light of the additional 
longer-term safety data from ORION-8 and -3. Additional details on the efficacy and safety of 
inclisiran are available in the Investigator’s Brochure (IB). 
1.2 
Purpose 
The purpose of the study is to evaluate the efficacy and safety of inclisiran sodium 300 mg, 
administered as monotherapy to participants with primary hypercholesterolemia who are not on 
any LLT. This selected, not-on-treatment population allows for an assessment of the treatment 
effects and safety of inclisiran in the absence of confounding factors, such as statin intolerance 
or concomitant treatment with other LLT such as statins or ezetimibe. For ethical reasons related 
to conducting a placebo-controlled study in which some participants would receive no active 
anti-hyperlipidemia treatment, this trial will enroll patients with low cardiovascular risk who 
do not require cholesterol lowering therapy per treatment guidelines. 


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2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● To demonstrate the superiority of inclisiran as 
monotherapy, compared with placebo, in reducing 
LDL-C as measured by percentage change from 
baseline to Day 150 
● Percentage change in LDL-C from baseline to  
Day 150 
● To demonstrate the superiority of inclisiran as 
monotherapy, compared with ezetimibe, in reducing 
LDL-C as measured by percentage change from 
baseline to Day 150 
● Percentage change in LDL-C from baseline to  
Day 150 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To assess the efficacy of inclisiran as monotherapy, 
compared to ezetimibe and placebo, on absolute 
change in LDL-C, percentage change in PCSK9, non-
HDL-C, TC/HDL-C ratio, Apo B, Apo B/Apo A-1 ratio 
and Lp (a) from baseline to Day 150 
● Absolute change in LDL-C, percentage change in 
PCSK9, non-HDL-C, TC/HDL-C ratio, Apo B,  
Apo B/Apo A-1 ratio and Lp (a) from baseline to  
Day 150 
● To assess the safety and tolerability of inclisiran as 
monotherapy, compared to placebo and ezetimibe 
● Incidence of TEAEs and SAEs, safety laboratory 
values at each visit 
2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g., premature discontinuation of treatment). 
There will be two estimands of interest in comparing efficacy of inclisiran as monotherapy 
against that of placebo or ezetimibe: a “Monotherapy Estimand” and a “Treatment-policy 
Estimand”. 
For the “Monotherapy Estimand,” the clinical question of primary interest is: what is the 
reduction in LDL-C, quantified by difference of mean percentage changes from baseline to Day 
150, in trial participants with primary hypercholesterolemia and a 10-year ASCVD risk of less 
than 7.5% who are not on any LLT, and receive inclisiran as monotherapy, compared to the 
reduction in those who are on placebo or ezetimibe, if participants had not died or discontinued 
study treatments, and if other lipid-lowering therapy were not available. 
The justification for the Monotherapy Estimand is that it will capture the effect of inclisiran as 
monotherapy in reducing LDL-C, in line with the study purpose of assessing the treatment 
effects of inclisiran in the absence of confounding factors such as concomitant treatment with 
other LLTs. 
The Monotherapy Estimand is described by the following attributes: 
Population: Participants with primary hypercholesterolemia and a 10-year ASCVD risk of less 
than 7.5%, who are not on any LLT. ASCVD risk will be estimated using the Pooled Cohort 
Equations (PCE) (Grundy et al 2019). 
Endpoint: Percentage change from baseline to Day 150 in LDL-C. 


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Treatments of interest: Inclisiran as monotherapy compared to the use of comparator (placebo 
or ezetimibe). 
Handling of intercurrent events: 
• Information following permanent discontinuation of study treatment will be handled with 
a hypothetical scenario of what would happen if the participants had not prematurely 
discontinued any study treatment (hypothetical strategy). 
• Participants who died will be handled in a hypothetical scenario of what would have 
happened had they not died (hypothetical strategy). 
• Use of other LLT will be treated in a hypothetical scenario of what would happen if other 
LLT were not available (hypothetical strategy). 
Summary measure: The summary measure to be used is the difference of mean percentage 
changes. 
In addition, for regulatory purposes, the “Treatment-policy Estimand” was added in parallel as 
a primary estimand. This estimand shares the same population, endpoint, and summary measure 
as the Monotherapy Estimand but considers different treatments of interest and adopts 
alternative strategies for handling intercurrent events: 
Treatments of interest: Inclisiran as monotherapy compared to the use of comparator (placebo 
or ezetimibe) with or without other LLTs added during the study. 
Handling of intercurrent events: 
• Permanent discontinuation of study treatment will be ignored (treatment-policy strategy). 
• Death will be handled as an unfavorable outcome using a composite variable strategy. 
• Use of other LLTs will be ignored (treatment-policy strategy). 
The Treatment-policy Estimand answers the clinical question regarding inclisiran efficacy in 
LDL-C lowering as compared to placebo or ezetimibe irrespective of adherence to study drug 
or addition of other LLTs, with death being an unfavorable outcome.  
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 12.4. 
2.2 
Secondary estimands 
The secondary estimands address the same clinical question as the primary estimands, albeit for 
different endpoints. For each of the secondary efficacy endpoints, the Treatment-policy 
Estimand and the Monotherapy Estimand will be defined in a similar way as for the primary 
endpoint. They share the same population, strategies for handling intercurrent events, summary 
measure, as well as the same treatments of interest as the primary estimands. They differ by the 
definition of the endpoints, these being: 
• Absolute change in LDL-C from baseline to Day 150 
• Percentage change in PCSK9, non-HDL-C, TC/HDL-C ratio, Apo B, Apo B/Apo A-1 
ratio and Lp(a) from baseline to Day 150 
The statistical methods and inference approaches are described in Section 12.5. 


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3 
Study design 
This study is a randomized, double-blind, placebo- and active comparator-controlled, 
multicenter study in adult participants with primary hypercholesterolemia not receiving any 
LLT and who have a 10-year ASCVD risk of less than 7.5%, estimated using the PCEs 
(Grundy et al 2019). This study will evaluate the efficacy and safety of inclisiran sodium  
300 mg, administered as a monotherapy in comparison to ezetimibe and placebo. 
The study design is depicted in Figure 3-1. The study consists of: 
• a screening period of up to 14 days; 
• a double-blind treatment period of 150 ± 5 days based on the Day 1 randomization date; 
and 
• a safety follow-up / End of Study (EOS) visit conducted 30 +5 days after the Day 150 
Visit  
The overall study duration is approximately 190 days but can vary depending on individual 
screening and the visit windows allowed for the treatment period and EOS visit. 
Figure 3-1 
Study Design 
 
3.1 
Off-site procedures 
At the investigator's direction and based on benefit-risk considerations of the participant's 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures performed at an off-site location, as defined in Table 8-1. A hybrid model is planned 
for this study incorporating both onsite and off-site visits. The off-site procedures will be 


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utilized in certain countries and sites as determined by protocol needs and based on national 
and local/site regulations. 
One or more of the following elements may be implemented to support off-site visits where 
allowed by national and local regulations: 
• Telemedicine 
• Off-site healthcare professional (OHP) 
• Direct-to-participant shipment of study supplies  
• Direct-to-participant shipment of study treatment (i.e., oral ezetimibe/placebo, refer to 
Section 6.3) 
3.1.1 
Responsibility of Investigators 
Procedures that are performed off-site remain under the oversight of the investigator, who 
retains accountability for the conduct of all safety and efficacy assessments delegated to an 
OHP, and will ensure the rights, safety and wellbeing of participants. This includes the 
following (including, but not limited to): 
• the identification, management and reporting of AEs and SAEs are performed in 
accordance with the protocol and applicable regulations 
• OHPs have appropriate qualifications, training, and experience to successfully conduct 
off-site procedures 
• source data collected off-site are reviewed and evaluated in a timely manner 
• the investigator or delegate is available to be contacted by the OHP if any issues or 
concerns are noted during an off-site visit 
• where relevant, the investigator or delegate will be present via telemedicine for a portion 
of the off-site visit to support the physical examination 
3.1.2 
Responsibility of OHPs 
OHPs must have the required qualifications, training, and experience to conduct off-site 
assessments. OHPs are responsible to conduct delegated assessments and collect relevant data 
at off-site visits in accordance with the clinical trial protocol, International Council for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and national and local 
regulations and guidelines. 
The OHPs will be provided by a third-party vendor sourced by Novartis. Where a site wishes 
to use OHPs that are not provided by Novartis this must be agreed with Novartis before use. 
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
investigator or delegate according to a pre-defined communication plan. 
3.1.3 
Telemedicine 
The sponsor has qualified and contracted a third-party vendor to provide telemedicine platform 
technology for this study. The selected platform is a validated system complying with relevant 
ICH E6 GCP guidelines (ICH E6 Guideline 2017). Trial participants can interact with site 


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personnel using online communication tools built into the platform, enabling the following 
capabilities: 
• Secure videoconferencing which allows the participant, OHP and site personnel to be 
connected 
• Reminders to be automatically sent to participants (e.g. visit or dosing reminders) 
3.2 
Screening 
At screening, participants will sign the Informed Consent Form (ICF) and their eligibility will 
be assessed through the review of study inclusion/exclusion criteria. The ICF must be signed 
before initiation of any study-specific procedures and assessments (see Section 5.1 and 
Section 7 for details). If at the time of ICF signature the participant is not fasting, he/she will 
have to return for the blood draw in a fasting state. 
During the screening visit, the participant’s individual 10-year ASCVD risk will be estimated 
using the PCEs, an algorithm derived from five prospective community-based studies 
representing a broad spectrum of the US-population as described in the multi-society guideline 
on the management of blood cholesterol (Grundy et al 2019). 
The investigator must ensure that each participant has not been treated with LLT or other 
prohibited medications (see Table 6-3) for at least 90 days prior to the screening visit. If the 
participant is on any of the permitted concomitant medications (see Table 6-2) known to induce 
lipid and lipoprotein changes, the dose of such medications must have been stable for ≥ 30 days 
prior to the screening visit with no plan to change the dose or to discontinue during the study 
duration. 
The screening period can be up to 14 days to allow adequate time for the completion of all 
qualifying screening and eligibility evaluations and potentially repeating some of the screening 
evaluations (e.g., laboratory results), as applicable (see Section 8.1). A participant who enters 
screening and is determined not eligible during the screening period or at the time of 
randomization will be considered a screen failure. 
3.3 
Double-blind treatment 
Baseline visit 
All participants who fulfill the inclusion/exclusion criteria (Section 5.1 and Section 5.2) will be 
randomized at baseline (Day 1) in a 2:1:1 double-blind fashion to one of three treatment arms: 
s.c. inclisiran and p.o. placebo (inclisiran arm); s.c. placebo and p.o. ezetimibe (ezetimibe arm); 
or s.c. placebo and p.o. placebo (placebo arm). Participants will be stratified by their screening 
LDL-C result (LDL-C ≤ 130 mg/dL vs. LDL-C > 130 mg/dL). Following randomization at the 
Baseline visit (Day 1), the participant will receive inclisiran sodium 300 mg or placebo by 
subcutaneous injection by a healthcare professional at the study site. The participant will also 
be dispensed one bottle of oral ezetimibe or placebo, and will be asked to take 1 capsule once a 
day, starting with the day of the Baseline visit (Day 1). 


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At the Baseline visit, all participants will be instructed to comply with lifestyle changes 
according to clinical guidelines (Grundy et al 2019), and these instructions will be reinforced at 
every visit. 
Post-Baseline visits 
Following the Baseline visit, participants will have study visits on Day 30, Day 90, and Day 
150. The participant will receive a second subcutaneous injection of 300 mg inclisiran sodium 
or 
placebo 
on 
Day 
90  
(Figure 3-1), administered by a healthcare professional at the study site. The participant will 
also be dispensed oral ezetimibe or placebo on Day 1, Day 30, Day 90 and will be asked to 
continue to take 1 capsule once a day from Day 1 through the day before the Day 150 visit. 
Please refer to Section 9.1.1 for reasons for early discontinuation of study treatment and the 
study procedures to follow. Section 9.2 provides instructions in case a participant withdraws 
informed consent. 
3.4 
Safety Follow-up/EOS 
The End of Study (EOS) visit (Day 180) will be the safety follow-up conducted 30 +5 days 
after the Day 150 visit. No data beyond EOS will be collected in the electronic Case Report 
Form (eCRF). If a participant discontinues from the study early, the investigator must do their 
best to ensure that the participant returns for an EOS visit. 
4 
Rationale 
4.1 
Rationale for study design 
Statin use up-regulates PCSK9 levels. Therefore, therapies that target PCSK9 may perform 
differently as monotherapy than when added to statin treatment. The study is aimed to evaluate 
the efficacy and safety of inclisiran sodium 300 mg, administered as monotherapy to 
participants without background LLT, to inform an understanding of the new PCSK9 inhibition 
approach with inclisiran and help establish efficacy expectations for inclisiran in patients who 
cannot take statins. 
LLT is not required per American Heart Association (AHA)/American College of Cardiology 
(ACC) primary prevention guidelines in patients with primary hypercholesterolemia who have 
a low 10-year ASCVD risk (< 5%) or a borderline risk (5% to < 7.5%) without risk enhancers 
if the participants have LDL-C measured less than 190 mg/dL (Arnett et al 2019,  
Grundy et al 2019). This trial is designed to be conducted in this population, in order to remove 
confounding by statin use or a history of statin intolerance, and to meet ethical requirements. 
4.1.1 
Rationale for choice of background therapy 
The participants must fulfill the requirement of not being on any lipid-lowering background 
therapy within 90 days prior to the screening and throughout the study. The purpose is to remove 
any potential confounding effect caused by statin intolerance or concomitant LLT such as 
statins or ezetimibe, in the monotherapy setting. 


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4.2 
Rationale for dose/regimen and duration of treatment 
A Phase II study (ORION-1) has shown that 300 mg dose of inclisiran sodium administered as 
one or two doses is the lowest dose to achieve near‑maximal reductions in PCSK9 (70.9% and 
74.5%, respectively) and LDL‑C (50.9% and 59.7%, respectively) levels. Three Phase III 
studies (ORION-9, -10, and -11) in adults with ASCVD, ASCVD risk equivalents and/or HeFH 
demonstrated that 300 mg inclisiran sodium s.c. on Day 1, Day 90 and every 6 months thereafter 
resulted in placebo-adjusted percentage reductions in LDL-C from baseline at Day 510 of 50% 
to 58%, with time-adjusted average reductions of 44% to 54% sustained over 18 months. In 
these studies, this dose also showed good tolerability of inclisiran, with a safety profile similar 
to placebo, except for a higher incidence of AEs at the injection site. Based on nonclinical and 
clinical data, including Phase I, II and III clinical studies as well as pharmacodynamic (PD) 
modeling in adult participants, the same dose will be used in the present study. The inclisiran 
dose and regimen in the study is 300 mg s.c. administered at Baseline and Day 90. This is the 
approved dose by the United States Food and Drug Administration (FDA) and in the European 
Union (EU). 
ORION-1 also demonstrated that two injections on Day 1 and on Day 90 produced a significant 
percentage LDL-C reduction of 52.6% at Day 180. In ORION-9, -10, and -11, two initial 
injections (Day 1 and Day 90) led to a similar percentage reduction in LDL-C at Day 150. The 
magnitude of this reduction was then maintained with subsequent injections every 6 months. 
Based on these data, a 6-month study duration with two injections of blinded study medication 
is deemed as sufficient for observing the effect of inclisiran as a monotherapy, compared to 
placebo and ezetimibe. In addition, this duration will leave placebo-treated participants with the 
shortest unprotected period of no LLT as participants' lipid-lowering need may change 
following the study enrollment. 
4.3 
Rationale for choice of control drugs (comparator/placebo) 
A placebo-controlled arm is a standard design in drug development to assess efficacy and safety 
and ensures that differences in outcome will be a reliable and realistic measure of the treatment 
effect of inclisiran. The use of placebo as a comparator is justified as the trial population has a 
10-year ASCVD risk of less than 7.5% and does not need to be on any LLT per AHA/ACC 
primary prevention guidelines (Arnett et al 2019). 
The monotherapy use of inclisiran is anticipated mostly in participants who do not tolerate 
statins well or are unwilling to take a statin due to their concerns on the side effects of statins. 
The current non-statin treatment options include ezetimibe, fibrates and nicotinic acid, used 
alone or in combination. Ezetimibe, an intestinal cholesterol absorption inhibitor, is the most 
commonly used non-statin therapy that selectively inhibits the intestinal absorption of 
cholesterol and related phytosterols. Therefore, it is reasonable to use ezetimibe as an active 
comparator, in addition to a placebo arm. 
4.4 
Purpose and timing of interim analyses/design adaptations 
There are no planned interim analyses or design adaptations. 


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4.5 
Risks and benefits 
In general, the risk of participants in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, and close clinical monitoring of safety parameters. The 
risk is further reduced by a minimal study duration of approximately 6 months. Participants are 
not anticipated to be exposed to greater risks when participating in off-site assessments. OHPs 
will perform assessments for sites participating in the hybrid trial model according to the 
protocol and study manuals for onsite visits wherever possible, thus data integrity is also 
expected to be comparable to onsite assessments. Safety management in an off-site setting will 
adhere to the same quality standards as for the traditional onsite model and remains under the 
responsibility of the investigator (refer to Section 3.1.1). 
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 outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
In non-clinical toxicity studies, inclisiran was not carcinogenic or genotoxic. There was no 
effect on paternal performance, spermatogenesis, estrous cycle, and uterine or ovarian 
parameters. Inclisiran did not show evidence of embryolethality, fetotoxicity, or teratogenicity. 
In addition, there were no effects of inclisiran on the development of the F1 generation, 
including survival, growth, physical and reflexological development, behavior, and 
reproductive performance. 
The overall clinical experience with inclisiran includes the following completed studies: 
• Three completed Phase I studies; ALN-PCSSC-001 in participants with elevated LDL-C, 
ORION-6 in participants with mild to moderate hepatic impairment, and ORION-7 in 
participants with renal impairment (mild, moderate, severe) 
• Two completed Phase II studies; ORION-1 in participants with ASCVD or ASCVD risk 
equivalent, and ORION-2 in participants with homozygous familial hypercholesterolemia 
• Three completed Phase III studies; ORION-9, -10, and -11 in participants with HeFH, 
ASCVD or ASCVD risk equivalents 
The safety profile of inclisiran in clinical studies is well characterized and based on data 
obtained from 3 large pivotal trials (ORION-9, -10, -11) that included 1,833 participants treated 
with inclisiran for up to 18 months (Wright et al 2021) and was generally comparable to placebo. 
The only inclisiran-related adverse drug reaction (ADR) identified in clinical studies was a 
higher incidence of TEAEs at the injection site, including injection site erythema, injection site 
hypersensitivity, injection site pruritus, injection site rash, and injection site reaction. All 
TEAEs at the injection site were localized, mild or occasionally moderate, transient and 
resolved without sequelae. The impact of this side effect is further mitigated by the infrequent 
dosing regimen of inclisiran. 
In Phase III studies (ORION-9, -10, -11) in participants with HeFH, ASCVD or ASCVD risk 
equivalents, inclisiran administered on Day 1, Day 90 and every 6 months thereafter lowered 
LDL-C by approximately 50% or more versus placebo in participants on maximally tolerated 
statin therapy with or without other LLT (Raal et al 2020, Ray et al 2020). 


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It is widely recognized that LDL-C plays a major role in the initiation and progression of 
ASCVD, and accumulated exposure of elevated LDL-C is causally related to the development 
of ASCVD. As the degree and duration of exposure to elevated LDL-C levels increases the 
atherosclerotic burden, early treatment of hypercholesterolemia in primary prevention is 
essential to the prevention of ASCVD events. The participants in this trial have a 75% chance 
of being randomized to a LLT (inclisiran or ezetimibe). In addition to the potential reduction in 
LDL-C, the benefit a participant may have by participating in this study is the opportunity to 
learn more about primary hypercholesterolemia and how to reduce future progression to clinical 
ASCVD and prevention of ASCVD events. 
4.6 
Rationale for planned off-site procedures 
Off-site procedures are planned in this study to minimize burden on participants, and offer them 
increased flexibility to participate in the study from an off-site location (as described in 
Section 3.1 and defined in Table 8-1). This has the potential to broaden access to clinical trials 
for both participants and investigators. The hybrid approach will allow participants to maintain 
contact with investigator, both in person during clinic visits at site and through the telemedicine 
platform during off-site participation. 
4.7 
Rationale for Public Health Emergency mitigation procedures 
In addition to the planned off-site procedures, in the event of a Public Health emergency as 
declared by Local or Regional authorities i.e. pandemic, epidemic or natural disaster, additional 
mitigation procedures to ensure participant safety and trial integrity may be implemented. If 
allowable by a local Health Authority and depending on operational capabilities, phone calls, 
virtual contacts (e.g. tele consult) or additional visits by OHPs to the participant's home, can 
replace onsite study visits (in addition to the already planned off-site visits), for the duration of 
the disruption until it is safe for the participant to visit the site again. 
Notification of the Public Health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate. 
5 
Study Population 
The study population consists of approximately 300 randomized adult participants ( ≥ 18 to  
≤ 75 years of age) with primary hypercholesterolemia (fasting LDL-C ≥ 100 mg/dL but  
< 190 mg/dL) at low risk for their first cardiovascular event (10-year ASCVD risk score of  
< 7.5%), and who are not receiving any LLT. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria at 
screening: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Adults ≥ 18 to ≤ 75 years of age 
3. Fasting LDL-C value of ≥ 100 mg/dL (equivalent to 2.59 mmol/L) but < 190 mg/dL 
(equivalent to 4.92 mmol/L) 


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4. Fasting triglycerides ≤ 400 mg/dL (equivalent to 4.52 mmol/L) 
5. With a 10-year ASCVD risk score of less than 7.5%, estimated using the pooled cohort 
equations (PCE) 
6. Have not been on any lipid-lowering therapy within 90 days 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Use of any lipid-lowering therapy within 90 days of screening including statins, ezetimibe, 
bempedoic acid, psyllium preparations, fibrates, bile-acid sequestrants, PCSK9 
monoclonal antibodies, red yeast rice, niacin > 200 mg/day, omega-3 fatty acids (DHA 
and/or EPA, with a total dose > 1000 mg/day), or any drug with unknown ingredients 
taken for the purpose of lipid-lowering, including over-the-counter or herbal therapies 
2. Use of systemic cyclosporine or tacrolimus, systemic steroids, vitamin A derivatives or 
retinal derivatives for the treatment of dermatologic conditions (vitamin A in a 
multivitamin preparation is permitted), or antiviral therapies (protease inhibitors or direct 
acting antivirals) within 30 days of screening 
3. Participants on medications that are known to induce changes in lipids and lipoproteins 
(including but not limited to anticoagulants, loop diuretics, thiazide diuretics, beta 
blockers, amiodarone, estrogens, selective estrogen receptor modulators, androgens, 
anabolic steroids, and anticonvulsants) unless they are on a stable dose of such 
medications for at least 30 days prior to screening and have no planned dose change or 
treatment discontinuation during the study duration 
4. History of ASCVD (including acute coronary syndrome, history of myocardial infarction, 
stable or unstable angina, coronary or other arterial revascularization, stroke, transient 
ischemic attack, and peripheral artery disease including aortic aneurysm) 
5. Diabetes mellitus or fasting plasma glucose at screening ≥ 7.0 mmol/L (equivalent to  
126 mg/dL) or HbA1c ≥ 6.5% (equivalent to 7.8 mmol/L or 140 mg/dL) 
6. New York Heart Association (NYHA) class III or IV heart failure or last known left 
ventricular ejection fraction < 30% at screening. 
7. Uncontrolled severe hypertension: systolic blood pressure (BP) > 160 mmHg or diastolic 
BP > 100 mmHg at screening despite antihypertensive therapy, confirmed with a repeat 
measurement 
8. Uncontrolled serious cardiac arrhythmia (recurrent and highly symptomatic ventricular 
tachycardia, atrial fibrillation, or supraventricular tachycardia) within 90 days prior to 
randomization that is not controlled by medications 
9. 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) > 3 x the upper limit of normal (ULN), or total bilirubin 
(TBL) > 2 x ULN at screening 
10. Secondary hypercholesterolemia, e.g., hypothyroidism (thyroid stimulating hormone 
(TSH) above the upper limit of normal (ULN)) or nephrotic syndrome at screening 
11. Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal 
carcinoma in situ, or stage 1 prostate carcinoma) within 5 years prior to randomization 


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12. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening as 
determined by the central laboratory using the Modification of Diet in Renal Disease 
(MDRD) formula 
13. Pregnant or nursing (lactating) women 
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant unless they are using effective methods of contraception during dosing 
of study treatment. Effective 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 bilateral 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 the 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 if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history 
of vasomotor symptoms). Women are considered not of child bearing potential if they are 
post-menopausal 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 are more stringent than the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the informed consent 
form (ICF). 
15. Use of any RNAi-based therapeutics, including but not limited to siRNA or Antisense 
Oligonucleotide (ASO) Therapies within 5 half-lives or 30 days whichever is longer, prior 
to screening 
16. Participation in another investigational device or drug study currently, or within 5 half-
lives (if drug) or 30 days whichever is longer, prior to screening 
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18. Severe concomitant disease that carries the risk of reducing life expectancy to less than 2 
years 
19. Any condition that according to the investigator could interfere with the conduct of the 
study, such as but not limited to 
• Unlikely to understand or comply with the protocol requirements, instructions, and 
study-related restrictions 
• Have any medical or surgical condition, which in the opinion of the investigator 
would put the participant at increased risk from participating in the study 
• Persons directly involved in the conduct of the study 
6 
Treatment 
6.1 
Study treatment 
Participants will be randomized 2:1:1 to double-blind s.c. injections of inclisiran sodium  
300 mg and p.o. placebo (inclisiran arm); s.c. injections of placebo and p.o. ezetimibe 
(ezetimibe arm); or s.c. injections of placebo and p.o. placebo (placebo arm). 
6.1.1 
Investigational and control drugs 
The sponsor will provide the following investigational and control drugs, refer to Table 6-1. 
Table 6-1 
Investigational and control drug 
Investigational/ Control 
Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor 
(global or local) 
Inclisiran sodium 300 mg 
(equivalent to 284 mg 
inclisiran*) in 1.5 mL 
Solution for 
injection 
s.c. 
Solution for injection 
in prefilled syringe** 
Global 
Matching s.c. placebo in 
1.5 mL 
Solution for 
injection 
s.c. 
Solution for injection 
in prefilled syringe** 
Global 
Ezetimibe 10 mg 
Capsule 
p.o. 
Bottle 
Global 
Matching p.o. placebo 
Capsule 
p.o. 
Bottle 
Global 
*Inclisiran is also referred to as KJX839 
**The prefilled syringe (PFS) is a device component of the combination product, and it is regulated as part of 
the combination product in the context of this clinical trial. The PFS is not investigational, and no separate 
approval is required. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug is included in this trial. 
6.1.3 
Treatment arms/group 
Participants will be randomized at the baseline visit (Day 1) to one of the following three 
double-blind treatment groups in a 2:1:1 ratio: 
A) Inclisiran sodium 300 mg s.c. and placebo p.o. (inclisiran arm) 
B) Placebo s.c. and ezetimibe 10 mg p.o. (ezetimibe arm) 


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C) Placebo s.c. and placebo p.o. (placebo arm) 
Each participant will receive one injection of blinded inclisiran or placebo on Day 1, and a 
second injection of blinded inclisiran or placebo on Day 90, unless there is a need for 
discontinuing inclisiran/placebo in the course of the study (refer to Section 3.3 and 
Section 9.1.1). Each participant will take blinded oral ezetimibe or placebo once daily on Day 
1 until the day before the Day 150 visit, unless there is a need for discontinuing oral 
ezetimibe/placebo in the course of the study. 
Subcutaneous injections of inclisiran sodium 300 mg and placebo will not be dispensed to the 
participants but rather administered by qualified, healthcare personnel at the study site on Day 
1 and Day 90 of the study. Oral ezetimibe and placebo will be dispensed to the participants on 
Day 1, Day 30 and Day 90; and taken by the participant daily from Day 1 until the day before 
the Day 150 visit. Randomization will be stratified by screening LDL-C level (≤ 130 mg/dL 
versus > 130 mg/dL). 
6.1.4 
Treatment duration 
The planned study treatment duration is 150 ±5 days . The EOS visit will be conducted 30 +5 
days after the Day 150 visit. 
Participants may be discontinued from the study treatment earlier due to safety reasons, at the 
discretion of the investigator or the participant. They will continue to be followed up in the 
study until EOS as per Assessment Schedule (Table 8-1). 
Depending on the availability of inclisiran in the investigator's country, the decision to switch 
a participant to a commercially available inclisiran product or to one of the locally available 
standard of care treatments after EOS will be left to the investigator's clinical judgment. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a 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. 
The investigator should instruct the participant to notify the study site about any new 
medications he/she takes after the participant is enrolled into the study. All medications, 
procedures, and significant non-drug therapies used by/performed on the participant within  
30 days prior to the first visit (Screening visit) must be documented in the appropriate page of 
the eCRF. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “prohibited” as 
listed in Table 6-3. Specifically, participants should receive full supportive care during the study, 


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including treatment with antibiotics, antiemetics, antidiarrheals, analgesics, and other care as 
deemed appropriate, and in accordance with their institutional guidelines. 
Several medications and medication classes have been reported to affect the lipid profile. In 
order to accurately assess the effect of inclisiran as a monotherapy, it is desired to avoid any 
changes in lipids and lipoproteins induced by other medications. The medications listed in 
Table 6-2 are permitted if the doses of such medications are stable at least for 30 days prior to 
screening. The use of these medications by participants must remain unchanged from screening 
and throughout the trial. If the investigator suspects any drug to be lipid-change inducing but 
not listed in Table 6-2, the investigator should contact the Novartis medical monitor before 
randomizing a participant. 
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2, also referred to as COVID-19) 
vaccines are permitted among participants in this trial. There is no evidence to suggest that 
participants receiving either inclisiran/placebo or ezetimibe are at increased risk for AEs 
following a COVID-19 vaccination. However, since both inclisiran/placebo and COVID-19 
vaccines are administered s.c., it is recommended that the COVID-19 vaccine is administered 
+/- 7 days from s.c. inclisiran/placebo administration. Further, it is recommended that a different 
anatomical location is used for COVID-19 vaccine and s.c. inclisiran/placebo to help 
differentiate potential local adverse reactions. COVID-19 vaccination administrations that 
occur either within 30 days prior to the first visit (Screening visit) and during the course of this 
study should be documented on the appropriate eCRF. 
Influenza vaccination, pneumococcal vaccination, or any other vaccines are also permitted 
among participants in this trial. Similar to the recommendations on COVID-19 vaccines, a  
7-day window between these vaccines and s.c. inclisiran/placebo administration and a different 
anatomical location are suggested. 
Table 6-2 
Medication allowed under certain conditions 
Class of medication 
Condition 
Anticoagulants 
Stable dose for at least 30 days prior to screening and throughout the study 
Loop diuretics and thiazide 
diuretics 
Stable dose for at least 30 days prior to screening and throughout the study 
Beta blockers 
Stable dose for at least 30 days prior to screening and throughout the study 
Amiodarone 
Stable dose for at least 30 days prior to screening and throughout the study 
Estrogens* 
Stable dose for at least 30 days prior to screening and throughout the study 
Selective estrogen receptor 
modulators 
Stable dose for at least 30 days prior to screening and throughout the study 
Androgens 
Stable dose for at least 30 days prior to screening and throughout the study 
Anabolic steroids 
Stable dose for at least 30 days prior to screening and throughout the study 
Anticonvulsants 
Stable dose for at least 30 days prior to screening and throughout the study 
*Please note that as per Exclusion Criterion #14, female participants of child-bearing potential who are on oral 
contraception only (i.e. estrogens and progesterone) should be on stable dose for a minimum of 3 months prior 
to Day 1 and throughout the study. 
6.2.2 
Prohibited medication 
Use of the treatments in Table 6-3 is not allowed. This table is not considered all-inclusive. If 
in doubt, the investigator should contact the Novartis medical monitor before randomizing a 


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participant or allowing a new medication to be started. If the participant is already enrolled, 
contact Novartis to determine if the participant should continue his/her participation in the study. 
Table 6-3 
Prohibited medication 
Class of medication 
Prohibition 
period 
Action taken 
LLT [statins, ezetimibe (other than control drug), bempedoic 
acid, psyllium preparations, fibrates, bile-acid sequestrants, red 
yeast rice, niacin > 200 mg/day, omega-3 fatty acids (DHA 
and/or EPA with a total dose > 1000 mg/day)], or any drug with 
unknown ingredients taken for the purpose of lipid-lowering, 
including over-the-counter or herbal therapies 
 
At least 90 days 
prior to screening 
and until 
randomization 
 
Randomization 
and throughout the 
study  
Do not randomize 
the participant 
 
Ask participants to 
stop taking LLTs. 
Contact Novartis 
for further 
guidance. 
Systemic cyclosporine and tacrolimus 
Systemic steroids 
Vitamin A derivatives or retinal derivatives for the treatment of 
dermatologic conditions (vitamin A in a multivitamin preparation 
is permitted) 
Antiviral therapies (protease inhibitors or direct acting antivirals) 
At least 30 days 
prior to screening 
and until 
randomization 
Do not randomize 
the participant 
 
Randomization 
and throughout the 
study 
Contact Novartis for 
further guidance. 
Investigational drugs 
Any RNAi-based therapeutics, including but not limited to siRNA 
or ASO Therapies 
 
At least 30 days or 
5 half-lives, 
whichever is 
longer, prior to 
screening and until 
randomization 
Do not randomize the 
participant 
 
Randomization 
and throughout the 
study 
Discontinue study 
treatment 
Monoclonal antibodies directed towards PCSK9 such as 
evolocumab and alirocumab 
At least 90 days 
prior to screening 
and until 
randomization 
Do not randomize the 
participant 
Randomization 
and throughout the 
study 
Discontinue study 
treatment 
6.3 
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. 
Site staff will identify the study medication kits to administer/dispense to the participant by 
contacting the Interactive Response Technology (IRT) and obtaining the medication number(s). 
The study medication has a 2-part label (base plus tear-off label), immediately before 
administration/dispensing the medication kit to the participant, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document. 


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For sites participating in the hybrid trial model with off-site visits by OHPs, where delivery of 
oral ezetimibe/placebo directly to a participant's secure off-site location (e.g. home) is permitted 
by national and local governing regulations, then dispatch of oral ezetimibe/placebo directly to 
the participant may be performed under the accountability of the Investigator. Each 
shipment/provisioning will be for a maximum of 2 months' supply. In this case, regular phone 
calls or virtual contacts will occur between the site and the participant for instructional purposes, 
safety monitoring, investigation of any adverse events, ensuring participants continue to benefit 
from treatment, and discussion of the participant's health status until the participants can resume 
visits at the study site. 
In addition, as per Section 4.7, during a Public Health emergency as declared by Local or 
Regional authorities i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site 
study visits, delivery of study medication(s) directly to a participant's home may be permitted 
(if allowed by Local or Regional Health Authorities and Ethics Committees as appropriate) in 
the event the investigator has decided that an on-site visit by the participant is no longer 
appropriate or possible, and that it is in the interest of the participant's health to administer the 
study treatment(s) even without performing an on-site visit. The dispatch of study medication(s) 
from the site to the participant’s home remains under the accountability of the investigator. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
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 Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
field monitors during site or remote monitoring visits, and at the completion of the trial. 
If study treatment is administered at home (i.e., p.o. ezetimibe/placebo), participants will be 
asked to return all unused study treatment and packaging at the end of the study or at the time 
of discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the investigator folder at each site. 


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6.3.1.2 
Handling of other treatment 
If a participant enters the study on medication that is known to be lipid change inducing (see 
Table 6-2), those medications should be specifically monitored. Changes (dose change or 
discontinuation) are not allowed during the study participation. 
6.3.2 
Instruction for prescribing and taking study treatment 
Blinded s.c. injections of inclisiran/placebo, will not be dispensed to the participants, but will 
be administered by qualified healthcare personnel at the study site. 
The preferred site of injection is the abdomen. Alternative injection sites include the upper arm 
or thigh. Injections should not be made into areas of active skin disease or injury such as 
sunburns, skin rashes, inflammation, tattoos, or skin infections. 
Participants will be administered an injection of blinded s.c. inclisiran/placebo on Day 1 and 
Day 90, as specified in the Assessment Schedule (Table 8-1) after all other study assessments 
have been completed for the visit. 
Blinded bottles containing 35 capsules of p.o. ezetimibe/placebo will be dispensed to the 
participants on Day 1 (1 bottle), Day 30 (2 bottles), and Day 90 (2 bottles) as assigned by the 
IRT. Participants should be instructed to take the p.o. ezetimibe/placebo (1 capsule) at 
approximately the same time each day as follows: 
• Each dose may be taken with a glass of water with or without food. 
• Participants should be instructed to swallow whole capsules and not to chew or open them. 
• If vomiting occurs during the course of treatment, participants should not take the p.o. 
ezetimibe/placebo again before the next scheduled dose. 
• Participants should be instructed not to make up missed doses. A missed dose is defined as 
when the full dose is not taken within 8 hours of the approximate time of the usual daily 
dosing. That day's dose should be skipped and the participant should continue treatment 
with the next scheduled dose. 
• On Day 1, Day 30, and Day 90, the dose should be taken after all assessments have been 
completed for the visit. The last dose of p.o. ezetimibe/placebo should be taken the day 
before the Day 150 visit. 
Table 6-4 
Dose and treatment schedule  
Investigational / Control Drug (Name and 
Strength) 
Dose 
Frequency and/or Regimen 
Inclisiran sodium 300 mg  
(equivalent to 284 mg inclisiran*) 
300 mg 
Day 1 and Day 90 
matching s.c. placebo 
0 mg 
Day 1 and Day 90 
Ezetimibe 10 mg 
10 mg 
once daily, Day 1 until day before Day 150 visit 
matching p.o. placebo 
0 mg 
once daily, Day 1 until day before Day 150 visit 
*also known as KJX839 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. All injections 
of inclisiran/placebo given to the participant as well as study drug interruptions/discontinuations 
(i.e., no injection at a designated dosing visit) during the study must be recorded on an 
appropriate eCRF and within IRT. All interruptions/discontinuations of p.o. ezetimibe/placebo 


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(i.e., doses not taken by the participant) during the study must be recorded on an appropriate 
eCRF; whereas bottles not dispensed to a participant must be recorded within IRT. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
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. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative 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. 
6.4.2 
Treatment assignment, randomization 
At Visit 1 (Day 1), all eligible participants will be randomized via 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 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
Randomization will be stratified by screening LDL-C results (≤ 130 mg/dL vs. > 130 mg/dL). 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.5 
Treatment blinding 
Participants, investigator staff, persons performing the assessments, and the Novartis trial team 
will remain blind to the identity of the treatment from the time of randomization until database 
lock. 
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. As a result, the participant should be 
discontinued from the study treatment. 
The following methods will be used to maintain the blind: 


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(1) Randomization data will be kept strictly confidential until the time of final database lock. 
(2) The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor. A 
double-dummy design is used because the identity of the study treatment (inclisiran versus 
ezetimibe and matching placebos) cannot be disguised, as the drug products are visibly different. 
(3) Data with unblinding potential, such as lipid results and PCSK9 results collected after the 
randomization visit, will be kept blind until the time of final database lock. 
6.6 
Dose escalation and dose modification 
6.6.1 
Definitions of dose limiting toxicities (DLTs) 
DLTs are not applicable for the study. 
6.6.2 
Dose modifications 
There are no dose adjustments or modifications of study treatment [i.e., study drug (s.c. 
inclisiran/placebo) or control drug (p.o. ezetimibe/placebo)]. For study treatment interruptions, 
discontinuations, and other follow-up requirements, please refer to Section 10.1.1, 
Section 10.2.1, Table 16-2, and Table 16-3. 
6.6.3 
Follow-up for toxicities 
All participants must be followed up for adverse events and serious adverse events for 30 days 
following the last doses of s.c. inclisiran/placebo or p.o. ezetimibe/placebo, whichever comes 
last. 
6.6.3.1 
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 drug-induced liver injury (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 TBL > 1.5 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 
[TBL > 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. 


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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, TBL, direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/International Normalized Ratio (INR), alkaline 
phosphatase (ALP), albumin, and creatine kinase (CK). If available, testing of Glutamate 
Dehydrogenase (GLDH) is additionally recommended. 
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). 
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. 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. 
Table 6-5 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 6-5 
Guidance on clinical and diagnostic assessments to rule out 
alternative causes of observed LFT abnormalities 
Disease 
Assessment 
Hepatitis A (HAV), B (HBV), C 
(HCV), E (HEV) 
● Immunoglobulin (Ig) M anti-HAV; hepatitis B virus surface antigen 
(HBsAg), IgM & IgG anti-hepatitis B core antigen (HBc), HBV 
deoxyribonucleic acid (DNA); anti-HCV, HCV ribonucleic acid (RNA), IgM 
& IgG anti-HEV, HEV RNA 
Cytomegalovirus (CMV), herpes 
simplex virus (HSV), Epstein-Barr 
virus (EBV) infection 
● IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
● Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA) 
titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
● Ethanol history, GGT, mean corpuscular volume (MCV), carbohydrate-
deficient (CD)-transferrin 
Nonalcoholic steatohepatitis 
● Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
● Medical history: acute or chronic congestive heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
● Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 years 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 – triiodothyronine (T3), thyroxine (T4), TSH; 


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cardiovascular disease (CV) / ischemic hepatitis – electrocardiogram (ECG), prior hypotensive 
episodes; Type 1 diabetes / 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. 
Please also refer to Section 16.2 for liver event and laboratory trigger definitions & follow-up 
requirements. 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
The investigator must promote compliance of the p.o. study treatment (ezetimibe/placebo) by 
instructing the participant to take it exactly as prescribed and by stating that compliance is 
necessary for the participant’s safety and the validity of the study. The participant must also be 
instructed to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed. Compliance will be assessed by the investigator and/or study personnel 
at each visit using pill counts and information provided by the participant. This information 
should be captured in the source document and the appropriate eCRF at each visit. All study 
treatment dispensed and returned must be recorded in the Drug Accountability Log. 
Blinded investigational s.c. injections (inclisiran/placebo) will be administered at the study site. 
This information must be captured in the source document, the appropriate eCRF and in the 
Drug Accountability Log. 
6.7.2 
Recommended treatment of adverse events 
AEs should be treated according to local practice and guidelines, and is at the discretion of the 
investigator and treating physician. 
For participants with injection site reaction, antihistamines, local or systemic steroids can be 
used at the investigator’s discretion depending on the severity of the reaction. 
Medication used to treat AEs must be recorded on the appropriate eCRF. 
6.7.3 
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. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency condition. 


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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/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• name 
• 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 treatment 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) or until participant completed the EOS visit as per Assessment 
Schedule (Table 8-1). 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation) Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the (ICH E6 Guideline 2017) guidelines and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational treatment 
(inclisiran) can be found in the IB and information about common side effects known about the 
other study treatment (ezetimibe) can be found in the local package insert. This information will 
be included in the participant informed consent and should be discussed with the participant 


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during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate, 
for example, via an investigator notification (IN) or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant. 
The following informed consents are included in this study: 
• Main study consent 
• Optional Consent for Additional Research to allow future research on data/samples 
collected during this study  
• As applicable, Informed Consent for Off-site Visits/Procedures to allow for off-site 
visits/procedures as described in Section 3.1 
• 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. 
Participants will be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g., the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists when all study assessments are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation. 
The “X” in the table denotes the assessments to be recorded in the clinical database or received 
electronically from a vendor. The "S" in the table denotes the assessments that are only in the 
participant's source documentation and do not need to be recorded in the clinical database. 
Participants should be seen for all visits/assessments as outlined in the Assessment Schedule 
(Table 8-1) During the double-blind treatment period, a window of +/- 5 days based on the Day 
1 randomization date is acceptable for Visit 2 (Day 30), Visit 3 (Day 90), and Visit 4 (Day 150). 
Visit 5 (Day 180 or EOS) will be 30 days after Day 150 visit, with an acceptable window of up 
to + 5 days. Missed or rescheduled visits should not lead to automatic discontinuation. 


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Participants who prematurely discontinue from study treatment are to continue with planned 
study visits and be retained until Day 180 as indicated in the Assessment Schedule. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications not previously reported must 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 to obtain fasting lipids and/or glucose blood 
samples. If the participant is not fasting at the time of Informed Consent signature, he/she 
will have to return for a blood draw in a fasting state. 
• Must refrain from unaccustomed strenuous physical activity for 48 hours prior to any 
study visit. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities (i.e., pandemic, epidemic or natural disaster) that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented by the investigator 
as the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g., tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 


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Table 8-1 
Assessment Schedule 
Period 
Screening 
Baseline 
Double-Blind Treatment Period4 
Safety Follow-up 
Visit Name 
Screening1 
V1  
V21 
V3 
V4 2 
V5 (EOS)3,4 
Days 
-14 to -1 
1 
30  
90 
150 
180 +5 
Informed consent 
X 
  
  
  
  
  
Inclusion / 
Exclusion criteria 
X 
X 
  
  
  
  
Demography 
X 
  
  
  
  
  
Smoking and 
alcohol history 
X 
  
  
  
  
  
Medical 
history/current 
medical 
conditions 
X 
  
  
  
  
  
Prior or 
concomitant 
medication5 
X 
X 
X 
X 
X 
X 
Surgical/medical 
procedures5 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
S 
S 
  
S 
 
S 
Body 
Height/Weight 
X 
  
  
  
  
  
Vital Signs6 
X 
X 
X 
X 
X 
X 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
Lifestyle 
instructions 
  
S 
S 
S 
S 
S 
Electrocardiogram 
(ECG) 
  
X 
  
  
  
  
Follicle stimulating 
hormone (FSH) 
X7 
  
  
  
  
  


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Period 
Screening 
Baseline 
Double-Blind Treatment Period4 
Safety Follow-up 
Visit Name 
Screening1 
V1  
V21 
V3 
V4 2 
V5 (EOS)3,4 
Days 
-14 to -1 
1 
30  
90 
150 
180 +5 
Pregnancy Test 
(serum)8 
X 
  
  
  
  
  
Pregnancy Test 
(urine)9 
  
X 
X 
X 
X 
X 
Thyroid 
stimulating 
hormone10 
X 
  
 
  
  
  
  
  
Fasting Lipid 
Profile11 
X 
X 
X 
X 
X 
  
Fasting Lp(a)12 
  
X 
  
  
X 
  
PCSK913 
  
X 
X 
X 
X 
  
Clinical 
Chemistry10 
X 
  
  
  
  
  
Limited 
Chemistry10 
  
X 
X 
  
X 
X 
Hematology10 
 
X 
  
  
  
X 
HbA1c10  
X 
 
 
 
 
X 
Urinalysis14 
X 
  
  
  
  
X 
Coagulation 
Panel10 
  
X 
  
  
  
  
Enter participant 
visit in IRT 
X 
X 
X 
X 
X 
X 
Randomization 
  
X 
  
  
  
  
Study drug 
administration - 
s.c. 
inclisiran/placebo 
  
X15 
  
X15 
  
  
Dispense 
ezetimibe/placebo 
  
S 
S 
S 
  
  


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Period 
Screening 
Baseline 
Double-Blind Treatment Period4 
Safety Follow-up 
Visit Name 
Screening1 
V1  
V21 
V3 
V4 2 
V5 (EOS)3,4 
Days 
-14 to -1 
1 
30  
90 
150 
180 +5 
Control drug 
administration - 
p.o. 
ezetimibe/placebo 
 
 
   
X16 
X16 
X16 
X16 
  
Ezetimibe/placebo 
compliance 
  
  
X16 
X16 
X16 
  
Disposition form 
X 
  
  
  
X17 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit may be performed off-site in certain countries and sites as determined by protocol needs and based on national and local/site regulations. 
2 Visit 4 is also the EOT visit if the participant completes the study treatment as per protocol. 
3 Visit may be performed off-site in certain countries and sites as determined by protocol needs and based on national and local/site regulations 
or over the telephone if an on-site visit is not possible. During a telephone call, only AEs/SAEs and concomitant medications will be followed. 
4 When study treatment is discontinued early, participants should continue with all of their planned study visits and be retained until Day 180. A 
window of +/- 5 days based on the Day 1 visit date is acceptable for Visit 2 (Day 30), Visit 3 (Day 90), and Visit 4 (Day 150). 
5 All medications, procedures, and significant non-drug therapies used by/performed on the participant within 30 days prior to the first visit 
(Screening visit) and throughout the study must be documented in the appropriate page of the eCRF. 
6 Blood pressure and pulse will be taken 3 times in sitting position. 
7 Required for any female participant who is considered as surgically sterile or post-menopausal in the absence of medical documentation 
confirming this reproductive/menopausal status at screening (see Section 8.4.3). 
8 Only in women of childbearing potential (see Section 5.2 - Exclusion Criterion #14 and Section 8.4.3). Serum samples will be sent to the 
central lab for analysis.  
9 Only in women of childbearing potential (see Section 5.2- Exclusion Criterion #14 and Section 8.4.3). Performed locally, using central 
laboratory kit supplies. If urine test is positive, a serum sample will be sent to the central lab for analysis. 
10 Performed by the central lab. See Table 8-3. 
11 Performed by the central lab. Includes LDL-C, Apo A-1, Apo B, Apo B/Apo A-1 ratio, non-HDL-C, TC, HDL-C, TC/HDL-C ratio, triglycerides. 
12 Performed by the central lab. 
13 Performed by the central lab. An additional aliquot will be made from the PCSK9 sample in order to allow analysis of proteins related to 
dyslipidemia or study drug mechanism. 
14 Performed locally, using central laboratory kit supplies. If Macroscopic Panel (Dipstick) results are positive (abnormal) for Leukocyte 
Esterase, Nitrite, Blood, and/or Protein, then a urine sample will be sent to central lab to perform a Macroscopic Panel and a Microscopic 
Reflexive Panel if positive for Leukocyte Esterase, Nitrite, Blood, Protein. Refer to Table 8-3. 
15 Subcutaneous inclisiran/placebo will be administered by qualified healthcare personnel after all other study assessments have been 
completed for this visit. 


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Period 
Screening 
Baseline 
Double-Blind Treatment Period4 
Safety Follow-up 
Visit Name 
Screening1 
V1  
V21 
V3 
V4 2 
V5 (EOS)3,4 
Days 
-14 to -1 
1 
30  
90 
150 
180 +5 
16 Participant to take one capsule ezetimibe/placebo a day starting from Day 1 until the day before the Day 150 visit (see Section 6.3.2). 
Compliance will be checked until the visit following the last dose of ezetimibe/placebo. 
17 End of Treatment disposition form should be completed prior to Day 150 if the participant discontinues study treatment prior to Day 150.  


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8.1 
Screening 
Screening 
Screening activities must be initiated only after the ICF has been signed. 
If a safety laboratory assessment during the screening period is outside of the range specified 
in the exclusion criteria, the assessment may be repeated one time prior to randomization. If the 
repeat value remains outside of the specified ranges, the participant will be considered a screen 
fail and must be excluded from the study. 
It is generally not permissible to re-screen a participant if he/she fails the initial screening. Re-
screening is allowed once, if a participant has an initiation, a dose change or a discontinuation 
of medications that are known to induce lipid and lipoprotein changes (see Section 5.2 - 
Exclusion Criterion #3) within 30 days prior to screening or post screening but before 
randomization. Participants may be re-screened after being on a stable dose for 30 days or after 
treatment discontinuation of such medications for 30 days. 
Re-screened participants must provide new written informed consent. A new participant 
number will be assigned to the re-screened participants and the site must record the re-screening 
information in the corresponding eCRF and in IRT. All screening procedures will need to be 
re-performed. 
8.1.1 
Information to be collected on screening failures 
Participants who sign the ICF and are subsequently found to be ineligible at time of 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate eCRF page. The demographic information, informed consent, and 
inclusion/exclusion eCRF pages must be completed for screen failure participants. No other 
data are required to be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a SAE during the screening period (see Section 10.1.3 for 
reporting details). If the participant fails to be randomized, the IRT must be notified within  
2 days of the screen fail. 
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 in the appropriate eCRF page. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the eCRF. 
Participant demographic and baseline characteristics collected on all participants include: age, 
sex, race, ethnicity, vital signs, height, weight, smoking/alcohol history, medical history/current 
medical conditions present before signing the ICF(where possible, diagnoses and not symptoms 
should be recorded), and relevant laboratory tests. 


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Participant race/ethnicity data are collected and analyzed to identify any differences in safety 
and/or efficacy due to these factors, as well as to assess the diversity of the study population as 
required by Health Authorities. 
All prescription and over-the-counter medications, procedures, and significant non-drug 
therapies, used by/performed on the participant within 30 days prior to the first visit (Screening 
visit) and throughout the study must be documented in the appropriate page of the eCRF (see 
Section 6.2.1). 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy 
All efficacy assessments are biomarkers which will be analyzed at a central laboratory. 
Specimens for efficacy assessments will be collected at time points specified in the Assessment 
Schedule (Table 8-1). Participants must be in a fasted state for all of these laboratory 
assessments. Details regarding the collection, processing, shipping and storage of the samples 
for central laboratory will be provided in a Laboratory Manual. 
Starting from the time of the randomization visit (Day 1), the results from all lipid parameter 
measurements must be blinded to participants, investigator staff, persons performing the 
assessments, the monitors, and the Novartis Clinical Trial Team (CTT) until database lock. 
8.3.1 
LDL-C 
The primary efficacy assessment will be LDL-C, as tested and reported by the central laboratory 
as part of the Lipid Panel at the frequency shown in Table 8-1. Participants must be fasting for 
all LDL-C assessments. 
8.3.2 
Additional efficacy assessments 
Additional efficacy assessments will include non-HDL-C, HDL-C, TC, TC/HDL-C ratio, Apo 
A-1, Apo B, Apo B/Apo A-1 ratio, Lipoprotein A (Lp(a), and PCSK9. Lipid parameters, Lp(a) 
and PCSK9 will be tested and reported by the central laboratory at the frequency shown in 
Table 8-1. Participants must be fasting for all lipid and lipoprotein testing. 
8.3.3 
Appropriateness of efficacy assessments 
Inclisiran is a siRNA which acts to inhibit the synthesis of PCSK9 protein, which consequently 
reduces LDL-C in circulation. LDL-C is a well-defined and validated laboratory parameter and 
is routinely assessed in clinical trials. LDL-C reduction is an accepted surrogate for CV risk 
reduction, e.g., for statins and PCSK9- blocking monoclonal antibodies. While multiple factors 
contributing to the development of ASCVD have been described, strong and consistent 
evidence from genetics, epidemiology, Mendelian randomization studies, and randomized trials 
have established that LDL-C is not only a laboratory parameter of increased risk, but also a 
causal and modifiable factor in ASCVD (Mach et al 2020). Laboratory tests related to the 
primary and secondary endpoints are in line with the expected efficacy of inclisiran. 


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8.4 
Safety 
Safety assessments are specified below, with the Assessment Schedule (Table 8-1) detailing 
when each assessment is performed. 
For details on AE collection and reporting, refer to AE section (Section 10.1). 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every 4 weeks or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
Table 8-2 
Safety assessments 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, 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 AE. 
Vital signs 
Vital signs include blood pressure (BP) 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 and pulse will be measured three times using an 
automated validated device 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. 
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. 
8.4.1 
Laboratory evaluations 
Specimens will be obtained at the time points detailed in the Assessment Schedule (Table 8-1). 
Details on what is included in chemistry (full and limited panels), hematology, coagulation, 
thyroid stimulating hormone, and urinalysis laboratory evaluations as well as pregnancy testing 
and FSH are provided in Table 8-3. 
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF. Any clinically significant abnormal 
laboratory value should be evaluated and followed-up by the investigator until normal or a cause 
for the abnormality is determined. Clinically significant abnormalities must be recorded as 
either medical history/current medical conditions or AEs as appropriate. 
In addition to Table 8-3, see Section 6.6.3.1 for follow-up on potential DILI cases, 
Section 10.2.1 for liver safety monitoring, and Section 16.2 for specific liver event and 


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laboratory test trigger definitions and follow-up requirements and Section 10.2.2 for renal 
safety monitoring. 
Central laboratory will be used for analysis of all specimens collected, with the exception of 
urine pregnancy tests and manual dipstick urinalysis, 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. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities, i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
if participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab (local) collection site may be used. 
Table 8-3 
Safety Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular 
Hemoglobin Concentration (MCHC), MCV, Platelets, Erythrocytes, Leukocytes, 
Differential (% of Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
HbA1c 
HbA1c 
Chemistry (full 
panel) 
AST, ALT, ALP, GGT, TBL, Direct Bilirubin, Indirect Bilirubin, Albumin, Creatinine, 
eGFR, Blood Urea Nitrogen (BUN), Uric Acid, Fasting Plasma Glucose (FPG), CK, 
Calcium, Magnesium, Phosphate, Chloride, Sodium, Potassium 
Chemistry 
(limited panel) 
AST, ALT, ALP, GGT, TBL, Creatinine, eGFR, FPG, CK 
Urinalysis 
Macroscopic Panel (Dipstick): Color, Bilirubin, Occult Blood, Macroscopic Blood, 
Glucose, Ketones, Leukocyte esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen. 
If dipstick results are positive (abnormal) for Leukocyte Esterase, Nitrite, Blood, and/or 
Protein, then a urine sample will be sent to the central lab to perform a Macroscopic 
Panel and a Microscopic Reflexive Panel if there are positive results for Leukocyte 
Esterase, Nitrite, Blood, and/or Protein. 
Microscopic Panel: Erythrocytes, Leukocytes, Casts, Crystals, Bacteria, Epithelial cells. 
Coagulation 
PT, INR, Activated partial thromboplastin time (APTT) 
Thyroid Function 
Thyroid Stimulating Hormone 
Pregnancy Test 
Serum and Urine Pregnancy (see Section 8.4.3) 
A confirmatory serum pregnancy test is required in case of a positive urine pregnancy 
test. 
Follicle 
Stimulating 
Hormone 
FSH (see Section 8.4.3) 
Required for any female participant considered surgically sterile or post-menopausal in 
the absence of medical documentation confirming this reproductive/menopausal status 
at screening. 
Liver Event 
Testing and Liver 
Follow-up Testing 
Albumin, ALP, ALT, AST, CK, GGT, GLDH, INR, PT, and Total Bilirubin (TBL). Test for 
hemolysis (haptoglobin, reticulocytes, unconjugated [indirect] bilirubin). 
These tests are in addition to routine testing, to be performed only in follow-up to safety 
events when indicated in Section 6.6.3.1, Section 10.2.1 and Section 16.2. 
Renal Follow-up 
Urine protein for Protein:Creatinine ratio (PCR), Serum Creatinine. 
Repeat standard urinalysis. 
Macroscopic Panel (Dipstick) Color, Bilirubin, Occult Blood, Macroscopic Blood, 
Glucose, Ketones, Leukocyte esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen. 
If dipstick results are positive (abnormal), for Leukecyte Esterase, Nitrite, Blood and/or 
Protein, then a urine sample will be sent to the central lab to perform a Macroscopic  
Macroscopic Panel and a Microscopic Reflexive Panel if there are positive results for 


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Test Category 
Test Name 
Leukocyte Esterase, Nitrite, Blood, and/or Protein. 
Microscopic Panel: Erythrocytes, Leukocytes, Casts, Crystals, Bacteria, Epithelial cells. 
These tests are in addition to routine testing, to be performed only in follow-up to safety 
events when indicated in Section 10.2.2. 
8.4.2 
Electrocardiogram (ECG) 
Single 12 lead ECGs will be conducted using local ECG machines. ECGs must be recorded 
after 10 minutes rest in the supine position to ensure a stable baseline. The preferred sequence 
of cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. 
ECGs will be locally collected and evaluated. Interpretation of the baseline tracing must be 
made by a qualified physician and documented on the ECG CRF. Each ECG tracing should be 
labeled with the study number, participant initials (where regulations permit), participant 
number, date, and kept in the source documents at the study site. 
 The QT interval corrected by Fridericia's formula (QTcF) should be used for clinical decisions. 
The investigator must calculate QTcF if it is not auto-calculated by the ECG machine. Clinically 
significant abnormalities at baseline should be reported on the adverse events eCRF. 
Clinically significant findings must be discussed with Novartis prior to enrolling the participant 
in the study. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
New or worsened clinically significant findings occurring after informed consent must be 
recorded as adverse events. The original ECGs on non-heat-sensitive paper and a certified copy 
on non-heat sensitive paper, appropriately signed, must be collected and archived at the study 
site. 
8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
performed at the screening visit, and urine pregnancy tests at all other study visits. If a urine 
pregnancy test is positive, then a serum pregnancy test will be performed. 
Additional pregnancy testing might be performed if requested by local requirements. 
If participants cannot visit the site to have serum pregnancy tests during a Public Health 
emergency as declared by Local or Regional authorities, i.e., pandemic, epidemic or natural 
disaster, that limits or prevents on-site study visits, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. It is important that participants are instructed to perform the urine pregnancy test first and 
only if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the participant so that the Site is informed 
and can verify the pregnancy test results (e.g., following country specific measures). 




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9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug or control drug 
administration, if any) and can be initiated by either the participant or the investigator. If the 
participant permanently discontinues p.o. ezetimibe/placebo or s.c. inclisiran/placebo, then the 
participant’s entire study treatment must be stopped. The treatment disposition CRF will be 
completed to reflect that the participant has permanently discontinued study treatment (both p.o. 
study drug and s.c. study drug).  
The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would negatively impact the participant's well-being.  
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited medication 
Section 6.2.2  
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Severe and persistent (> 14 days despite appropriate treatment) reactions at the injection 
site and any type of anaphylactic reactions 
• Intolerable adverse events 
• Unexplained increases in transaminases (ALT or AST) or total bilirubin confirmed by repeat 
test as follows: 
• ALT or AST > 8 x ULN 
• ALT or AST > 5 x ULN for more than 2 weeks 
• ALT or AST > 3 x ULN with simultaneous or subsequent elevation of total 
bilirubin > 2 x ULN  
• ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
The investigator should evaluate to see if other causes for the laboratory abnormalities are 
immediately apparent, such as obstructive gall bladder or bile duct disease, viral or 
alcoholic hepatitis, malignancy involving the liver, congestive hepatopathy, other 
hepatotoxins or heritable disorders. Please also refer to Section 16.2 Appendix 2. 
• Unexplained CK > 10 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 with no other alternative explanation  
• Following emergency unblinding 


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• Any other laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant's overall status, prevents the participant from continuing 
participation in the study 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment should continue with planned study visits 
and be retained until Day 180 as indicated in the Assessment Schedule. Refer to Table 8-1 
Assessment 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 discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• AEs / SAEs 
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 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participant's 
data privacy rights), 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. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use data/biological samples occurs in countries where the 
legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data , and 


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• No longer wishes to receive study treatment, and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g., in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definition of these terms. 
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 their consent 
exercise data privacy rights and record this information. The Investigator shall clearly document 
if the participant has withdrawn his/her consent for the use of data in addition to a study 
discontinuation. 
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. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table (refer 
to Section 8). 
Further details on withdrawal of consent or the exercise of participant's data privacy rights are 
included in the corresponding informed consent form. 
9.3 
Study completion and post-study treatment 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure or follow-up shown in Table 8-1 Visit Evaluation Schedule for the last 
participant in the study globally. 
Study completion is defined as when the last participant finishes their last study 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 (e.g., each participant will be required to complete the study in its entirety and, 
thereafter, no further study treatment will be made available to them). 
All randomized and/or treated participants should have a safety follow-up call or the EOS visit 
conducted at least 30 days after the Day 150 visit. The information collected is entered on the 
EOS eCRFs and/or kept as source documentation, as applicable. 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. 
Depending on the availability of inclisiran in the investigator's country, the decision to switch 
a participant to a commercially available inclisiran product or to one of the locally available 
standard of care treatments after EOS will be left to the investigator's clinical judgment. 


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9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination may include (but are not limited to) the following: 
• 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 participant who discontinued from study treatment: at that time additional instructions will 
be provided for contacting the participant including information as to when the participant 
should stop taking drug, when the participant should come in for a final visit(s) that the Safety 
Follow-up period must be completed if applicable and which visits to be performed. 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. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence [e.g. any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease] in a clinical 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. Adverse events specified above 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. 
The 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 


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• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the investigational study drug (inclisiran/placebo) or comparator 
(ezetimibe/placebo). 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 ongoing) and the outcome 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 investigational study drug (inclisiran/placebo) or comparator 
(ezetimibe/placebo). All AEs must be treated appropriately. Treatment may include one or 
more of the following: 
• Dose not changed 
• Drug interrupted (applicable for p.o. ezetimibe/placebo only) 
• Permanently discontinued 
• Its outcome, which can be: 
• Not recovered / not resolved 
• Recovered / resolved 
• Recovering / resolving 
• Recovered / resolved with sequelae 
• Fatal 
• 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. 
AE monitoring should be continued for at least 30 days following the last dose of study 
treatment. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be not 
recovered/not resolved (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 ADRs for the investigational study drug (inclisiran) can be found in the IB. 
Information about ADRs for the comparator (ezetimibe) can be found in the Package Insert. 
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 


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• 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. 
As per Section 4.7, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur for safety monitoring and discussion of the participant´s 
health status until it is safe for the participant to visit the site again. 
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 Guideline 2004). 
• 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 (primary hypercholesterolemia) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study 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 
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 


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do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH E2D Guideline 2004). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
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 a SAE irrespective 
if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the last study visit must be reported to Novartis safety 
immediately, without undue delay, under no circumstances later than within 24 hours of 
obtaining knowledge of the events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the Serious Adverse Event Report Form (electronic SAE 
(eSAE) form with paper backup); all applicable sections of the form must be completed in order 
to provide a clinically thorough report. 
The following categories of SAEs must be reported: 
1. 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. SAEs collected between time participant signs ICF until the participant has completed the 
End of Study Visit 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the 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 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, EU Clinical Trial Regulation 536/2014 (if applicable) or as per national 
regulatory requirements in participating countries. 


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Any SAEs experienced after the last study visit should only be reported to Novartis Safety if 
the investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations. 
10.1.4 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the 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 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. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
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 
eCRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 


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For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure 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 16-1 in Section 16.2 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2 and 
Table 16-3 (Section 16.2). Repeat liver chemistry tests (i.e., ALT, AST, TBL, albumin, CK, 
GLDH, 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 (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, either of the following two categories of 
abnormal renal laboratory alert values should be assessed during the study period: 
• Serum creatinine increase ≥ 25% compared to baseline and value above ULN 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 


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• New onset dipstick hematuria ≥ 3+ (after excluding menstruation, urinary tract 
infection, extreme exercise, or trauma) 
Abnormal renal event findings must be confirmed with repeat test done at central lab after  
≥ 24 hours but ≤ 5 days after first assessment. 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff. 
10.3 
Committees 
There are no committees for this trial. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to  
21 Code of Federal Regulations (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 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 contract research organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ACT) classification system. Medical history/current medical conditions 
and AEs 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 


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dosage changes will be tracked using an 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/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., 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 GCP, 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 and identify risks 
and trends for site operational parameters, and provide reports to Novartis clinical teams to 
assist with trial oversight. 
The investigator must maintain source documents for each 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 eCRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original ICF 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 eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
12.1 
Analysis sets 
The following analysis sets will be used for statistical analyses: 


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The screened set (SCR) consists of all participants who signed the informed consent. The SCR 
includes only unique screened participants, i.e., in the case of re-screened participants only the 
chronologically last screening data is counted. 
The Randomized Analysis Set (RAS) consists of all participants who received a randomization 
number, regardless of receiving trial medication. 
The Full Analysis Set (FAS) comprises all randomized participants with the exception of those 
participants who have not been qualified for randomization and have not received study drug, 
but have been inadvertently randomized into the study. Following the intent-to-treat (ITT) 
principle, participants will be analyzed according to the treatment they have been assigned to at 
randomization. Efficacy variables will be analyzed based on the FAS. 
The Safety Analysis Set (SAF) includes all participants who received at least one dose of study 
drug. Participants will be analyzed according to the study treatment actually received. The SAF 
will be used for the analyses of safety variables. 
Note: The last part of the definition of the FAS is what is often referred to as misrandomized 
participants; i.e. participants for whom IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the participant’s final randomization eligibility and 
double-blind medication was not administered to the participant. These participants would 
subsequently not continue to take part in the study or be followed-up. Misrandomized 
participants will not be included in the FAS, but they will be included in the RAS. Further 
exclusions from the FAS may only be justified in exceptional circumstances (e.g., serious GCP 
violations). 
12.2 
Participant demographics and other baseline characteristics 
The number of participants screened, randomized and included in the FAS will be presented by 
treatment group and overall, for the SCR. In addition, the reasons for discontinuation prior to 
randomization will be provided for the SCR as well. The number and percentage of participants 
in the RAS who completed the study, who discontinued the study and the reason for 
discontinuation from study will be presented for each treatment group and all participants. The 
frequency (%) of participants with protocol deviations as well as the criteria leading to data 
exclusion from analysis will be presented in separate tables for the RAS. Finally, the number 
of enrolled and randomized participants by region will be presented descriptively for the RAS. 
Baseline value is defined as the last non-missing assessment prior to the first dose of study drug 
unless specified otherwise. 
Demographic and other baseline data will be summarized descriptively by treatment group for 
the FAS. Categorical data will be presented as frequencies and percentages. Continuous 
variables will be summarized using n, mean, standard deviation, median, Q1 (25th percentile), 
Q3 (75th percentile), minimum, and maximum. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, separately by treatment group. 
Other study specific medical history will also be summarized appropriately. 


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12.3 
Treatments 
The SAF will be used for the analyses in this section. Categorical data will be summarized as 
frequencies and percentages. For continuous data, number of non-missing observations, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Study drug 
The duration of the double-blind treatment will be computed as the time from the first 
administration of study drug to the first of the following events to occur: 
• the last administration plus 180 days for inclisiran or plus 1 day for ezetimibe and placebo, 
• the participant’s death, or 
• the participant’s study completion visit or last contact. 
This algorithm reflects the planned treatment schedule and the exposure attributable period of 
the study drug. The duration of the double-blind treatment period will be summarized for the 
SAF by treatment group descriptively. The overall participant years of treatment will be 
computed as the sum of participant years of double-blind treatment for all participants. 
The number of study doses administered will also be summarized by treatment group. 
Prior and concomitant therapies 
Prior or concomitant medications will be summarized for the SAF in separate tabulations based 
on the coding dictionary used. Medications will be presented in alphabetical order, by preferred 
terms and grouped by anatomical main group, according to the ATC classification system. 
Tables will show the overall number and percent of participants receiving at least one drug of 
a particular preferred term and at least one drug in a particular anatomical main group. 
Prior medications and significant non-drug therapies are defined as any medications and 
significant non-drug therapies taken prior to the randomization visit. Concomitant medications 
and significant non-drug therapies are defined as those used during the double-blind period. 
Concomitant medications that were prohibited as per protocol and given during the conduct of 
the study as well as significant non-drug therapies will be summarized. 
12.4 
Analysis supporting primary objectives 
The primary aim of the study is to demonstrate the superiority of inclisiran to either placebo or 
ezetimibe in reducing LDL-C. 
The FAS will be used for the primary efficacy analysis. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is the percentage change from baseline to Day 150 in  
LDL-C. 


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12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary objectives are to demonstrate the superiority of inclisiran as monotherapy 
compared to the use of placebo or ezetimibe separately, in reducing LDL-C as measured by 
percentage change from baseline to Day 150. To this end, the Monotherapy Estimand assesses 
the treatment effect of inclisiran alone in the absence of confounding factors such as additional 
LLT. 
As described in Section 2.1, in addition to the primary Monotherapy Estimand, the Treatment-
policy Estimand was added for regulatory purposes. Both estimands will be considered in 
parallel as primary analysis. 
The primary statistical hypotheses to be tested are: 
• HIP0: μi - μp ≥ 0 vs. HIPa: μi - μp < 0 
• HIE0: μi - μe ≥ 0 vs. HIEa: μi - μe < 0 
where μi, μp and μe are the mean percentage changes in LDL-C from baseline to Day 150 in the 
inclisiran group, placebo group, and ezetimibe group respectively. The study can be claimed a 
success if at least one of the above two individual hypotheses is rejected. 
The primary efficacy endpoint will be analyzed using an Analysis of Covariance (ANCOVA) 
model with treatment, stratification factor, and baseline value as fixed effects. Due to probable 
heterogeneity of variances between treatment groups, an ANCOVA model that assumes 
unequal variances between treatment groups will be used. The two primary endpoint hypotheses 
will be tested using an equally weighted Dunnett test (Dunnett 1955). 
The multiple comparison procedure (MCP) will be used in statistical hypothesis testing for 
primary and secondary endpoints to control the overall type I error rate at 0.025 (one-sided test). 
For each of the secondary efficacy endpoints, the Treatment-policy Estimand and the 
Monotherapy Estimand will be defined in a similar way as for the primary endpoint, and the 
MCP will be applied to Monotherapy Estimands and Treatment-policy Estimands separately, 
to control the overall type I error rate within each set of estimands. Since the Treatment-policy 
Estimands are intended for regulatory purposes, while the Monotherapy Estimands are intended 
for all other purposes, no multiplicity adjustment will be made across those two sets of 
estimands. The testing procedure to be followed is graphically presented in Figure 12-1, and 
outlined in the following steps: 
• First, a weighted Dunnett test with equal weights assigned to each of the two individual 
primary hypotheses (HIP0 and HIE0) is performed. This test will exploit the correlation of 
the primary endpoint between the two comparisons, with the test statistics derived from 
the ANCOVA model described as above. 
• If one primary hypothesis is rejected, a fraction of its significance level will be passed to 
the other primary hypothesis while the remaining alpha will be propagated to the family of 
secondary hypotheses under the same treatment comparison, according to the pre-
specified weights as indicated in the graph. The choice of weights for passing alpha to the 
other primary hypothesis (0.4 and 0.6 respectively) reflects the importance of 
demonstrating efficacy in the comparison between inclisiran and placebo. 
• Within a family of secondary hypotheses (HIPk or HIEk), the hierarchical testing procedure 
will be used. Refer to Section 12.5.1 for details. 


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• If one secondary hypothesis in the comparison between inclisiran and placebo HIPk is 
rejected, a fraction of its significance level will be passed to the next hierarchy of 
secondary hypotheses under the same treatment comparison, while the remaining alpha 
will be propagated to the primary hypothesis comparing inclisiran and ezetimibe. If there 
is no next hierarchy of secondary hypotheses, then the whole alpha will be propagated to 
the primary hypothesis comparing inclisiran and ezetimibe. Vice versa for the alpha 
passing from HIEk. 
The nodes HIP and HIPk represent the null hypotheses related to the primary and secondary 
endpoints compared between inclisiran and placebo, while the nodes HIE and HIEk represent the 
null hypotheses related to the primary and secondary endpoints compared between inclisiran 
and ezetimibe. The correlations between endpoints and between the two comparisons for each 
endpoint will also be considered. 
The least squares means for the difference between inclisiran and two comparators and 
corresponding unadjusted two-sided confidence intervals (CI) will be provided separately. The 
raw p-value for testing the individual hypothesis will also be provided. The superiority of 
inclisiran to a comparator can be claimed when the corresponding individual null hypothesis is 
rejected or the raw p-value is statistically significant at corresponding alpha level of current 
stage. 
12.4.3 
Handling of intercurrent events of primary estimands 
The Monotherapy Estimand will account for different intercurrent events as explained in the 
following: 
• Discontinuation of study treatment: Discontinuation of study treatments will be treated 
in a hypothetical scenario of what would happen if the participants had not discontinued 
study treatments (hypothetical strategy). 
• Death: Participants who die will be treated in a hypothetical scenario of what would 
happen if participants had not died (hypothetical strategy).  
• Use of lipid-lowering therapy: Use of LLT will be treated in a hypothetical scenario of 
what would happen if other LLT were not available (hypothetical strategy).  
The efficacy endpoints after the intercurrent events will be multiply imputed under the missing-
at-random assumption.  
The Treatment-policy Estimand will account for intercurrent events as follows: 
• Discontinuation of study treatment: Retrieved dropout (RDO) data collected after 
discontinuation from study treatments will be used for the analysis (treatment-policy 
strategy). Missing data after discontinuation from study treatments will be multiply 
imputed based on RDO data, and when there are no sufficient RDO data, a placebo-based 
Pattern-Mixture Model (PMM) will be used for multiple imputation.  
• Death: A composite variable strategy will be utilized to handle the intercurrent event of 
death, and efficacy parameter measurements after death will be imputed using the 
subject’s baseline values. 


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• Use of lipid-lowering therapy: The data collected after use of other LLTs will be used 
for analyses (treatment-policy strategy). Missing data will be multiply imputed using a 
placebo-based PMM. 
The primary analysis will be conducted on each multiply imputed dataset, and the treatment 
effects estimated from each of those imputed datasets will be combined using Rubin’s method 
(Rubin 1987). 
The details will be in the statistical analysis plan (SAP). 
12.4.4 
Handling of missing values not related to intercurrent event 
In the Monotherapy Estimand, missing values not related to intercurrent events will be multiply 
imputed under the missing-at-random assumption. In the Treatment-policy Estimand, missing 
values not related to intercurrent events will be multiply imputed using a placebo-based PMM. 
The primary analysis will be conducted on each multiply imputed dataset, and the treatment 
effects estimated from each of those imputed datasets will be combined using Rubin’s method 
(Rubin 1987). Details will be given in the SAP. 
12.4.5 
Sensitivity analyses 
Sensitivity analyses such as tipping point analyses will be conducted to assess the robustness of 
the inferences to various assumptions about the missing data, and details will be provided in the 
SAP. 
12.4.6 
Supplementary analysis 
If necessary, supplementary analyses will be conducted and described in the SAP. 
Subgroup analyses 
Subgroup analyses to assess the homogeneity of the treatment effect across demographic and 
baseline characteristics may be performed. All subgroup analyses will be defined in the SAP 
prior to database lock. 
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
There are seven secondary efficacy endpoints defined, and fourteen secondary hypotheses to be 
tested for these seven secondary endpoints in the comparison between inclisiran and each 
comparator (placebo or ezetimibe) respectively: 
1. Percentage change in PCSK9 from baseline to Day 150 
2. Absolute change in LDL-C from baseline to Day 150 
3. Percentage change in non-HDL-C from baseline to Day 150 
4. Percentage change in TC/HDL-C ratio from baseline to Day 150 
5. Percentage change in Apo B from baseline to Day 150 
6. Percentage change in Apo B/Apo A-1 ratio from baseline to Day 150 
7. Percentage change in Lp (a) from baseline to Day 150 


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For each of the secondary efficacy endpoints, the Treatment-policy Estimand and the 
Monotherapy Estimand will be defined in a similar way as for the primary endpoint. All 
secondary efficacy endpoints will be analyzed on FAS using the same ANCOVA model as for 
the primary efficacy endpoint as described in Section 12.4.2. Lipoprotein (a) will be log-
transformed before modeling. The model will include treatment, stratification factor, and 
baseline value as fixed effects, and assume unequal variances between treatment groups. The 
least squares means for the difference between inclisiran and two comparators and 
corresponding unadjusted two-sided CIs will be provided separately. 
As stated in Section 12.4.2, the two families of secondary hypotheses HIPk and HIEk (k = 1, 2, ..., 
7, following the order of the seven secondary endpoints as above) are included in the multiple 
testing procedure as presented in Figure 12-1. The hierarchical testing procedure will be used 
to test the seven secondary hypotheses within each family of the secondary endpoints (HIPk or 
HIEk). If one secondary hypothesis in the comparison between inclisiran and placebo HIPk is 
rejected, a fraction of its significance level will be passed to the next hierarchy of secondary 
hypotheses under the same treatment comparison, while the remaining alpha will be propagated 
to the primary hypothesis comparing inclisiran and ezetimibe, according to the pre-specified 
weights as indicated in the graph. If there is no next hierarchy of secondary hypotheses, then 
the whole alpha will be propagated to the primary hypothesis comparing inclisiran and 
ezetimibe. Vice versa for the alpha passing from HIEk. 


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Figure 12-1 
Testing procedure for primary and secondary endpoints 
 
The intercurrent events and missing values will be handled following the same approach as 
described for the primary endpoints. Details of the analyses for secondary efficacy endpoints 
and sensitivity analyses if necessary will be specified in the SAP. 
12.5.2 
Safety endpoints 
For all safety analyses, the SAF will be used. All tables and listings will be presented by 
treatment group. 
Safety data will be summarized by treatment groups. Baseline data will be summarized where 
appropriate (for change from baseline summaries). 




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12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size calculation was based on a two sample t-test for the hypothesis that inclisiran 
is superior to either placebo or ezetimibe in terms of mean percentage change from baseline to 
Day 150 in LDL-C, at a one-sided significance level of 0.0125 (assuming a more conservative 
Bonferroni alpha split between the two primary hypotheses). 
The sample size of 280 completers in total (with randomization ratio of 2:1:1 to inclisiran, 
placebo, and ezetimibe arms) will provide at least 99% power to detect a 40% difference 
between inclisiran and placebo or a 20% difference between inclisiran and ezetimibe at 
significance level of 0.0125 (one-sided test) assuming 30% for the standard deviation. Adjusted 
for 6% potential dropouts, approximately 300 participants in total will be randomized with a 
2:1:1 ratio, i.e., 150 participants in the inclisiran arm, and 75 participants in both the placebo 
and ezetimibe arm. 
12.8.2 
Secondary endpoint(s) 
Statistical power will not be assessed for secondary endpoints. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21 or European Clinical 
Trial Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the 
Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
The 
protocol, 
protocol 
amendments, 
ICF, 
IB, 
and 
other 
relevant 
documents  
(e.g. advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
The Investigator will be responsible for the following: 
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 


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Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and 
regulatory authorities as required. 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
Providing oversight of the conduct of the study at the site and adherence to requirements of  
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 
or EMA's Clinical Trials Information System (CTIS) public website. In addition, after study 
completion (defined as last patient last visit) and finalization of the study report the results of 
this trial will be submitted for publication and posted in a publicly accessible database of clinical 
trial results, such as the Novartis clinical trial results website and all required Health Authority 
websites (e.g. Clinicaltrials.gov, EudraCT or CTIS public website etc.) . 
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. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 
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. 


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13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
• Individual study results - after CSR publication 
• Trial Feedback Questionnaires (TFQ) - start and end of trial 
13.6 
Data Protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
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. 


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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 
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 
Arnett DK, Blumenthal RS, Albert MA, et al (2019) 2019 ACC/AHA Guideline on the 
Primary Prevention of Cardiovascular Disease: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 
Circulation; 140(11):e596-e646. 
Assmann G, Benecke H, Neiss A, et al (2006) Gap between guidelines and practice: 
attainment of treatment targets in patients with primary hypercholesterolemia starting statin 
therapy. Results of the 4E-Registry (Efficacy Calculation and Measurement of Cardiovascular 
and Cerebrovascular Events Including Physicians' Experience and Evaluation). Eur J 
Cardiovasc Prev Rehabil; 13(5):776-83. 
Banach M, Stulc T, Dent R, et al (2016) Statin non-adherence and residual cardiovascular 
risk: There is need for substantial improvement. Int J Cardiol; 225:184-96. 
Brown MS, Goldstein JL (2006) Biomedicine. Lowering LDL--not only how low, but how 
long? Science; 311(5768):1721-3. 
Dunnett, CW (1955) A multiple comparison procedure for comparing several treatments with 
a control. Journal of the American Statistical Association, 50(272):1096-121. 
Fitzgerald K, White S, Borodovsky A, et al (2017) A Highly Durable RNAi Therapeutic 
Inhibitor of PCSK9. N Engl J Med; 376(1):41-51. 
Fox KM, Tai MH, Kostev K, et al (2018) Treatment patterns and low-density lipoprotein 
cholesterol (LDL-C) goal attainment among patients receiving high- or moderate-intensity 
statins. Clin Res Cardiol; 107:380-8. 
Grundy SM, Stone NJ, Bailey AL, et al (2019) 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline 
on the Management of Blood Cholesterol: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am 
Coll Cardiol; 73(24):e285-e350. 
Horton JD, Cohen JC, Hobbs HH (2007) Molecular biology of PCSK9: its role in LDL 
metabolism. Trends Biochem Sci; 32(2):71-7. 
ICH E2D Guideline (2004) ICH E2D Post-approval safety data management (Internet) 
Available from: <ema.europa.eu/en/ich-e2d-post-approval-safety-data-management> 
(Accessed 04-May-2022). 
ICH E6 Guideline (2017) ICH E6 (R2) Good clinical practice (Internet) Available from: 
<ema.europa.eu/en/ich-e6-r2-good-clinical-practice> (Accessed on: 04-May-2022). 
Lakoski SG, Lagace TA, Cohen JC, et al (2009) Genetic and metabolic determinants of 
plasma PCSK9 levels. J Clin Endocrinol Metab; 94(7):2537-43. 
Mach F, Baigent C, Catapano AL, et al (2020) 2019 ESC/EAS Guidelines for the 
management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J; 
41(1):111-88. 


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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. 
Navarese EP, Kolodziejczak M, Schulze V, et al (2015) Effects of Proprotein Convertase 
Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic 
Review and Meta-analysis. Ann Intern Med; 163(1):40-51. 
Raal FJ, Kallend D, Ray KK, et al (2020) Inclisiran for the Treatment of Heterozygous 
Familial Hypercholesterolemia. N Engl J Med; 382(16):1520-30. 
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(16):1507-19. 
Rubin, DB (1987) Underlying Bayesian Therapy. In: Multiple Imputation for Nonresponse in 
Surveys. John Wiley & Sons Inc, p. 75-112. 
Sabatine MS, Giugliano RP, Keech AC, et al (2017) Evolocumab and Clinical Outcomes in 
Patients with Cardiovascular Disease. N Engl J Med; 376(18):1713-22. 
Schwartz GG, Steg PG, Szarek M, et al (2018) Alirocumab and Cardiovascular Outcomes 
after Acute Coronary Syndrome. N Engl J Med; 379(22):2097107. 
WHO (2021) Cardiovascular diseases (CVDs) (Internet) Available from: <who.int/news-
room/fact-sheets/detail/cardiovascular-diseases-(cvds)> (Accessed 22-Apr-2022). 
Wright RS, Ray KK, Raal FJ, et al (2021) Pooled Patient-Level Analysis of Inclisiran Trials 
in Patients With Familial Hypercholesterolemia or Atherosclerosis. J Am Coll Cardiol; 
77(9):1182-93. 
Zhang XL, Zhu QQ, Zhu L, et al (2015) Safety and efficacy of anti-PCSK9 antibodies: a 
meta-analysis of 25 randomized, controlled trials. BMC Med; 13:123. 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF. 
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined. 
See Section 16.2 for specific liver event and laboratory test trigger definitions and follow-up 
requirements. 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-1 
Liver laboratory trigger definitions 
Liver laboratory triggers 
Definition/ threshold 
If ALT, AST and TBL normal at baseline: 
● ALT or AST > 3.0 × ULN 
● TBL > 1.5 × ULN 
● ALP > 2.0 × ULN (in the absence of known bone pathology) 
If ALT, AST, or TBL abnormal at baseline: 
● ALT or AST > 2 x baseline or > 300 U/L, whichever occurs first 
● TBL > 2 x baseline and > 2.0 x ULN 
Table 16-2 
Follow-up requirements for liver laboratory triggers - ALT, AST, TBL  
ALT or AST 
TBL 
Liver Symptoms 
Action 
ALT or AST increase without TBL increase: 
If normal at baseline: 
ALT or AST > 3.0 x ULN 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
• 
No change to study 
treatment 
• 
Measure ALT, AST, ALP, 
GGT, TBL, PT/INR, 
albumin, CK, and GLDH 
in 48-72 hours. 
• 
Follow-up for symptoms. 
If elevated at baseline: 
ALT or AST > 2 x baseline 
If normal at baseline: 
ALT or AST > 5.0 x ULN 
for more than two weeks 
Normal 
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL 
None 
• 
Interrupt study 
treatment 
• 
Measure ALT, AST, ALP, 
GGT, TBL, PT/INR, 
albumin, CK, and GLDH 
in 48-72 hours. 
• 
Follow-up for symptoms. 
• 
Initiate close monitoring 
and workup for 
competing etiologies. 
• 
Study treatment can be 
restarted only if another 
etiology is identiﬁed and 
liver enzymes return to 
baseline. 
• 
If no cause can be 
identified to explain the 
elevation in liver 
enzymes, then study 
treatment must be 
discontinued. 
If elevated at baseline: 
ALT or AST > 3 x baseline 
for more than two weeks 
If normal at baseline: 
ALT or AST > 8.0 x ULN 
Normal 
None 
ALT or AST increase with TBL increase: 
If normal at baseline: 
ALT or AST > 3.0 x ULN 
TBL > 2.0 x ULN (or 
INR > 1.5) 
For participants with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT or AST > 2 x baseline 
If normal at baseline: 
ALT or AST > 3.0 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper quadrant 
pain 
If elevated at baseline: 
ALT or AST > 2 x baseline 


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Table 16-3 
Follow-up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia or elevated ALP 
Criteria 
Actions required 
Follow-up monitoring 
Elevated TBL (isolated) 
> 1.5 – 3.0 x ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 hours 
Monitor LFTs weekly until resolution 
to ≤ Grade 1 (≤ 1.5 x ULN) or to 
baseline 
> 3.0 - 10.0 x 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. concomitant 
medications, medical history, 
lab) in the appropriate eCRF 
Monitor LFTs weekly until resolution 
to ≤ Grade 1 (≤ 1.5 x ULN) or to 
baseline (ALT, AST, TBL, albumin, 
CK, GLDH, PT/INR, ALP and GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 10.0 x ULN 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. concomitant 
medications, medical history, 
lab) in the appropriate eCRF 
ALT, AST, TBL, albumin, CK, 
GLDH, PT/INR, ALP and GGT until 
resolution (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., concomitant 
medications, medical history, 
lab) in the appropriate eCRF 
Investigator discretion 
Elevated ALP (isolated) 
> 2.0 x ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 hours 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
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: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Refer to Section 10.2.2. 

SAP_001.pdf: 
Clinical Development 
KJX839/inclisiran/Leqvio® 
CKJX839D12304 / NCT05763875
A Double-blind, Randomized, Placebo- and Active-Comparator 
Controlled Study to Evaluate the Efficacy of Inclisiran as Monotherapy 
in Patients with Primary Hypercholesterolemia Not Receiving Lipid-
Lowering Therapy (VictORION-Mono)  
Statistical Analysis Plan (SAP)  
Document type: 
SAP Documentation 
Document status: 
Final Amendment 1 
Release date: 
21-Jun-2024
Number of pages: 
34 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 6.0, Effective from 23-Nov-2022 


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SAP Amendment 1 
 
Study No. CKJX839D12304 
 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
23-
Mar-
2023 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
NA 
21-
Jun-
2024 
Prior 
to 
DB 
lock 
Creation of 
amendment 
1 
Clarified the details about how the 
treatment group in SAF will be 
determined based on the study 
treatment actually received. 
Section 2.2  
Analysis sets 
 
 
 
Updated the subgroup definitions and 
the scope of subgroup analyses. 
Section 2.2.1 
Subgroup of interest 
 
 
 
Clarified that for subjects who 
discontinued 
study 
treatment 
prematurely, the compliance will 
only be summarized up to last p.o. 
treatment date + 1 day. Added details 
about 
handling 
of 
missing 
compliance 
data 
in 
cumulative 
compliance calculation.  
Section 2.4.1 
Study 
treatment 
/ 
compliance 
 
 
 
Specified that the exposure to p.o. and 
s.c. 
study 
treatment 
will 
be 
summarized separately. 
Section 2.4.1 
Study 
treatment 
/ 
compliance 
 
 
 
Updated the missing value imputation 
method 
for 
Treatment-policy 
Estimand. 
Section 2.5.3 
Handling 
of 
intercurrent events 
 
 
 
Added the details about tipping point 
analyses. 
Section 2.5.5 
Sensitivity analyses 
 
 
 
Instead 
of 
using 
models 
with 
interaction terms with subgroup 
variables, subgroup analyses will be 
Section 2.5.6 
Supplementary 
analyses 


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Study No. CKJX839D12304 
 
 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
performed by running the primary 
analysis model within each subgroup.  
 
 
 
Sensitivity analysis will be conducted 
for the primary endpoint only. 
Section 2.6 
Analysis 
supporting 
secondary objectives  
 
 
 
eGFR 
will 
be 
summarized 
by 
categories: 
Severe, 
Moderate, 
Normal or Mild. 
Section 2.7.3 
Laboratory data 
 
 
 
Added summary of COVID-related 
AEs 
Section 2.8 
Impact of COVID-19 
 
 
 
Added derivation rule of last p.o. 
treatment date for subjects with 
missing end date in the last dosing 
record. 
Appendix 5.1.1 
Study treatment 
 
 
 
Added implementation details of 
MCP 
Appendix 5.4 
Implementation 
of 
MCP 
 
 
 


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SAP Amendment 1 
 
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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................................ 9 
1.2 
Study objectives, endpoints and estimands ........................................................... 11 
1.2.1 
Primary estimand(s) .............................................................................. 11 
1.2.2 
Secondary estimand(s) .......................................................................... 13 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 15 
2.2.1 
Subgroup of interest .............................................................................. 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 17 
2.3.1 
Patient disposition ................................................................................. 17 
2.3.2 
Demographics and other baseline characteristics ................................. 17 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 19 
2.4.1 
Study treatment / compliance ................................................................ 19 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.5 
Analysis supporting primary objective(s) .............................................................. 21 
2.5.1 
Primary endpoint(s) ............................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of intercurrent events ............................................................. 22 
2.5.4 
Handling of missing values not related to intercurrent event ............... 23 
2.5.5 
Sensitivity analyses ............................................................................... 24 
2.5.6 
Supplementary analyses ........................................................................ 24 
2.6 
Analysis supporting secondary objectives ............................................................. 25 
2.6.1 
Secondary endpoint(s) ........................................................................... 25 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 25 
2.6.3 
Handling of intercurrent events ............................................................. 26 


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2.6.4 
Handling of missing values not related to intercurrent event ............... 26 
2.7 
Safety analyses....................................................................................................... 27 
2.7.1 
Adverse events (AEs) ............................................................................ 27 
2.7.2 
Deaths .................................................................................................... 29 
2.7.3 
Laboratory data ..................................................................................... 29 
2.7.4 
Other safety data ................................................................................... 31 
2.8 
Impact of COVID-19 ............................................................................................. 31 
2.9 
Pharmacokinetic endpoints .................................................................................... 31 
2.10 
PD and PK/PD analyses ........................................................................................ 31 
2.11 
Patient-reported outcomes ..................................................................................... 31 
 
 ............................................................................................................. 31 
 
.................................................................................... 31 
2.14 
Interim analysis ...................................................................................................... 32 
3 
Sample size calculation ..................................................................................................... 32 
3.1 
Primary endpoints .................................................................................................. 32 
3.2 
Secondary endpoints .............................................................................................. 32 
4 
Change to protocol specified analyses .............................................................................. 32 
5 
Appendix ........................................................................................................................... 32 
5.1 
Imputation rules ..................................................................................................... 32 
5.1.1 
Study treatment ..................................................................................... 32 
5.1.2 
AE date imputation ............................................................................... 32 
5.1.3 
Concomitant medication date imputation ............................................. 33 
5.2 
AEs coding/grading ............................................................................................... 33 
5.3 
Laboratory parameters derivations ........................................................................ 33 
5.4 
Implementation of MCP ........................................................................................ 33 
6 
Reference ........................................................................................................................... 34 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 11 
Table 2-1 
Specification of subgroups .................................................................... 16 
Table 2-2 
Notable liver function test criteria ......................................................... 30 
 


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List of figures 
Figure 1-1 
Study Design ......................................................................................... 10 
Figure 2-1 
Testing procedure for primary and secondary endpoints ...................... 26 
 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AGB 
ADaM Governance Board 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
Apo A-1 
Apolipoprotein A-1 
Apo B 
Apolipoprotein B 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification system 
BILI 
Total Bilirubin 
BMI 
Body Mass Index 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CRS 
Case Retrieval Strategy 
CSR 
Clinical Study Report 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HbA1c 
Glycated hemoglobin (hemoglobin A1c) 
HDL-C 
High-Density Lipoprotein Cholesterol 
IA 
Interim Analyses 
ICF 
Informed Consent Form 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LFT 
Liver Function Test  
LLQ 
Lower Limit of Quantification 
LLT 
Lipid Lowering Therapy 
Lp(a) 
Lipoprotein (a) 
MAR 
Missing-at-Random 
MCP 
Multiple Comparison Procedure 


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MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
non-HDL-C 
non-High-Density Lipoprotein Cholesterol 
NYHA 
New York Heart Association 
PCE 
Pooled Cohort Equations 
PCSK9 
Proprotein Convertase Subtilisin/Kexin type 9 
PD 
Pharmacodynamics 
PDS 
Programming Datasets Specifications 
PK 
Pharmacokinetics 
p.o. 
oral(ly) 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
RAS 
Randomized Analysis Set 
RDO 
Retrieved Dropout 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
s.c. 
subcutaneous(ly) 
SCR 
Screened Set 
SD 
Standard Deviation 
SOC 
System Organ Class 
TC 
Total Cholesterol 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
ULN 
Upper Limit of Normal 


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1 
Introduction 
This document contains a detailed statistical analysis plan that will be performed to support the 
completion of the Clinical Study Report (CSR) for the CKJX839D12304 study protocol (version 
01 – amended protocol) dated 08-Feb-2023. 
1.1 
Study design 
CKJX839D12304 (VictORION-Mono) is a randomized, double-blind, placebo- and active 
comparator-controlled, multicenter study in adult participants with primary hypercholesterolemia 
not receiving any lipid-lowering therapy (LLT) and who have a 10-year Atherosclerotic 
Cardiovascular Disease (ASCVD) risk of less than 7.5%, estimated using the pooled cohort 
equations (PCE) (Grundy et al 2019). This study will evaluate the efficacy and safety of inclisiran 
sodium 300 mg, administered as a monotherapy in comparison to ezetimibe and placebo.  
As depicted in Figure 1-1, the study consists of: 
• A screening period up to 14 days 
• A double-blind treatment period of 150 ± 5 days based on the Day 1 randomization date; 
and 
• A Safety Follow-up / End of Study (EOS) visit (Day 180) conducted 30 +5 days after the 
Day 150 visit 
At screening, participants will sign the Informed Consent Form (ICF) and their eligibility will be 
assessed through the review of study inclusion/exclusion criteria. If at the time of ICF signature the 
participant is not fasting, he/she will have to return for the blood draw in a fasting state. Key 
inclusion criteria assessed at the screening visit include:  
• Adults ≥ 18 to ≤ 75 years of age 
• Fasting low-density lipoprotein cholesterol (LDL-C) value of ≥ 100 mg/dL (equivalent to 
2.59 mmol/L) but < 190 mg/dL (equivalent to 4.92 mmol/L) 
• Fasting triglycerides ≤ 400 mg/dL (equivalent to 4.52 mmol/L) 
• With a 10-year ASCVD risk score of less than 7.5%, estimated using the PCE 
• Have not been on any lipid-lowering therapy within 90 days 
The detailed inclusion/exclusion criteria are in Section 5 of the protocol. The screening period can 
be up to 14 days to allow adequate time for the completion of all qualifying screening and eligibility 
evaluations. 
 


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Figure 1-1 
Study Design 
 
Approximately 300 participants fulfilling the eligibility criteria will be randomized at the Baseline 
(Day 1) visit in a 2:1:1 double-blind fashion to one of three treatment arms: 
• subcutaneous (s.c.) inclisiran and oral (p.o.) placebo (inclisiran arm) 
• s.c. placebo and p.o. ezetimibe (ezetimibe arm) 
• s.c. placebo and p.o. placebo (placebo arm). 
Randomization of the participants will be stratified in interactive response technology (IRT) by 
their screening LDL-C result (LDL-C ≤ 130 mg/dL vs. LDL-C > 130 mg/dL). Following 
randomization, the participant will receive inclisiran sodium 300 mg or placebo by subcutaneous 
injection at Day 1 by a healthcare professional at the study site. The participant will also be 
dispensed one bottle of oral ezetimibe or placebo, and will be asked to take 1 capsule once a day, 
starting with the day of the Baseline visit (Day 1). 
After the Baseline visit, participants will have study visits on Day 30, Day 90, and Day 150. The 
participant will receive a second subcutaneous injection of 300 mg inclisiran sodium or placebo on 
Day 90, administered by a healthcare professional at the study site. Treatment compliance to oral 
ezetimibe or placebo from Day 1 through the day before the Day 30 visit will be assessed at the 
Day 30 visit.  The participant will also be dispensed two bottles of additional oral ezetimibe or 
placebo on Day 30 and Day 90 and will be asked to continue to take 1 capsule once a day through 


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the day before the Day 150 visit.  Treatment compliance will be assessed again at the Day 90 and 
Day 150 visits. 
The overall study duration is approximately 190 days but can vary depending on individual 
screening and the visit windows allowed for the treatment period and EOS visit. 
The primary endpoint of the study is the percentage change from baseline to Day 150 in  
LDL-C. No formal interim analysis will be performed in this study. 
1.2 
Study objectives, endpoints and estimands  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● To demonstrate the superiority of inclisiran as 
monotherapy, compared with placebo, in reducing 
LDL-C as measured by percentage change from 
baseline to Day 150 
● Percentage change in LDL-C from baseline to  
Day 150 
● To demonstrate the superiority of inclisiran as 
monotherapy, compared with ezetimibe, in 
reducing LDL-C as measured by percentage 
change from baseline to Day 150 
● Percentage change in LDL-C from baseline to  
Day 150 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To assess the efficacy of inclisiran as 
monotherapy, compared to ezetimibe and 
placebo, on absolute change in LDL-C, 
percentage change in PCSK9, non-HDL-C, 
TC/HDL-C ratio, Apo B, Apo B/Apo A-1 ratio and 
Lp (a) from baseline to Day 150 
● Absolute change in LDL-C, percentage change 
in PCSK9, non-HDL-C, TC/HDL-C ratio, Apo B,  
Apo B/Apo A-1 ratio and Lp (a) from baseline to  
Day 150 
● To assess the safety and tolerability of inclisiran 
as monotherapy, compared to placebo and 
ezetimibe 
● Incidence of TEAEs and SAEs, safety laboratory 
values at each visit 
 
1.2.1 
Primary estimand(s) 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results (e.g., 
premature discontinuation of treatment). 
There will be two estimands of interest in comparing efficacy of inclisiran as monotherapy against 
that of placebo or ezetimibe: a “Monotherapy Estimand” and a “Treatment-policy Estimand”. 
For the “Monotherapy Estimand,” the clinical question of primary interest is: what is the reduction 
in LDL-C, quantified by difference of mean percentage changes from baseline to Day 150, in trial 


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participants with primary hypercholesterolemia and a 10-year ASCVD risk of less than 7.5% who 
are not on any LLT, and receive inclisiran as monotherapy, compared to the reduction in those who 
are on placebo or ezetimibe, if participants had not died or discontinued study treatments, and if 
other lipid-lowering therapy were not available. 
The justification for the Monotherapy Estimand is that it will capture the effect of inclisiran as 
monotherapy in reducing LDL-C, in line with the study purpose of assessing the treatment effects 
of inclisiran in the absence of confounding factors such as concomitant treatment with other LLTs. 
The Monotherapy Estimand is described by the following attributes: 
Population: Participants with primary hypercholesterolemia and a 10-year ASCVD risk of less than 
7.5%, who are not on any LLT. ASCVD risk will be estimated using the Pooled Cohort Equations 
(PCE) (Grundy et al 2019). 
Endpoint: Percentage change from baseline to Day 150 in LDL-C. 
Treatments of interest: Inclisiran as monotherapy compared to the use of comparator (placebo or 
ezetimibe). 
Handling of intercurrent events: 
• Information following permanent discontinuation of study treatment will be handled with a 
hypothetical scenario of what would happen if the participants had not prematurely 
discontinued any study treatment (hypothetical strategy). 
• Participants who died will be handled in a hypothetical scenario of what would have happened 
had they not died (hypothetical strategy). 
• Use of other LLT will be treated in a hypothetical scenario of what would happen if other LLT 
were not available (hypothetical strategy). 
Summary measure: The summary measure to be used is the difference of mean percentage changes. 
In addition, for regulatory purposes, the “Treatment-policy Estimand” was added in parallel as a 
primary estimand. This estimand shares the same population, endpoint, and summary measure as 
the Monotherapy Estimand but considers different treatments of interest and adopts alternative 
strategies for handling intercurrent events: 
Treatments of interest: Inclisiran as monotherapy compared to the use of comparator (placebo or 
ezetimibe) with or without other LLTs added during the study. 
Handling of intercurrent events: 
• Permanent discontinuation of study treatment will be ignored (treatment-policy strategy). 
• Death will be handled as an unfavorable outcome using a composite variable strategy. 
• Use of other LLTs will be ignored (treatment-policy strategy). 


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The Treatment-policy Estimand answers the clinical question regarding inclisiran efficacy in LDL-
C lowering as compared to placebo or ezetimibe irrespective of adherence to study treatment or 
addition of other LLTs, with death being an unfavorable outcome. 
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 2.5.   
1.2.2 
Secondary estimand(s) 
The secondary estimands address the same clinical question as the primary estimands, albeit for 
different endpoints. For each of the secondary efficacy endpoints, the Treatment-policy Estimand 
and the Monotherapy Estimand will be defined in a similar way as for the primary endpoint. They 
share the same population, strategies for handling intercurrent events, summary measure, as well 
as the same treatments of interest as the primary estimands. They differ by the definition of the 
endpoints, these being: 
• Absolute change in LDL-C from baseline to Day 150 
• Percentage change in PCSK9, non-HDL-C, TC/HDL-C ratio, Apo B, Apo B/Apo A-1 ratio and 
Lp(a) from baseline to Day 150 
The statistical methods and inference approaches are described in Section 2.6. 
2 
Statistical methods 
The following sections contain important information on detailed statistical methodologies to be 
used in the analyses for the final CSR. 
2.1 
Data analysis general information 
All analyses will be performed by Novartis using SAS version 9.4 (or above) and/or R version 4.1 
(or above). 
Study-collected data will be summarized by the treatment groups (Inclisiran, Ezetimibe, Placebo) 
using descriptive statistics, graphs, and/or raw data listings. Categorical variables will be 
summarized using counts and percentages. Continuous variables, including changes from baseline, 
will be summarized using descriptive statistics (n (number of non-missing observations), mean, 
standard deviation (SD), median, first and third quartiles (Q1 and Q3), minimum and maximum). 
Absolute change and percent change from baseline will be calculated as follows: 
• Absolute change from baseline to Day X =Value at Day X – Baseline value. 
• Percent change from baseline to Day X = (Absolute change/Baseline value)*100%. 
For laboratory measurements below the lower limit of quantification (LLQ), LLQ/2 will be used 
as the numeric value for the measurement. For example, if numeric result is missing in the database 
and character result is “< 3”, the numeric result should be treated as 3/2 = 1.5 during analysis. 


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Analyses for the final CSR will be conducted after the final database lock (DBL) of the study. The 
final DBL will be performed after all participants either complete the study or discontinued early.  
The stratification factor (screening LDL-C result ≤ 130 mg/dL vs. > 130 mg/dL) will be included 
as a covariate in the efficacy analysis models.  
2.1.1 
General definitions  
Study treatment 
Throughout this document, the term “study treatment” refers to: 
• s.c. inclisiran and p.o. placebo (for participants in the inclisiran arm) 
• s.c. placebo and p.o. ezetimibe (for participants in the ezetimibe arm) 
• s.c. placebo and p.o. placebo (for participants in the placebo arm) 
where s.c. inclisiran refers to inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL 
solution for subcutaneous injection in prefilled syringe, and s.c. placebo refers to its matching 
placebo; p.o. ezetimibe refers to the 10 mg oral ezetimibe capsule and p.o. placebo refers to its 
matching placebo. The term “s.c. study treatment” refers to the s.c. part of the study treatment (s.c. 
inclisiran or s.c. placebo) and “p.o. study treatment” refers to the p.o. part of the study treatment 
(p.o. ezetimibe or p.o. placebo). 
Date of first administration of study treatment 
The term “date of first administration of study treatment” refers to the first date of administration 
of the s.c. or the p.o. study treatment, whichever is earlier.  
Study day 
Day 1 is defined as the date of first administration of study treatment. For participants who were 
randomized but not treated, if any, Day 1 will be defined as the randomization date. 
The term “study day” of any assessment refers to the assessment date relative to Day 1. 
For a particular assessment date, its study day will be calculated as follows: 
For dates on or after Day 1, 
 
Study day = Assessment date – Date of Day 1 + 1; 
For dates prior to Day 1, 
 
Study day = Assessment date – Date of Day 1. 


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Baseline 
The term “baseline” is defined as the last available non-missing record on or prior to Day 1, 
unless otherwise specified.  
Last contact/participation date 
The last contact/participation date for a participant is the last available date across all the data 
collected for that participant. For a participant with a death event, the date of death will be used. 
Unscheduled visit 
Only for selected analyses of safety laboratory assessments will unscheduled measurements be 
considered. For efficacy analyses and by-visit safety analyses, measurements from unscheduled 
visits will generally not be used, unless otherwise specified. 
Reflexive LDL-C 
The endpoints involving LDL-C will use a reflexive LDL-C approach. When both calculated and 
beta-quantified LDL-C are available for a sample, calculated LDL-C will be used unless 
triglycerides are greater than 400 mg/dL or calculated LDL-C is less than 70 mg/dL. When only 
calculated LDL-C or beta-quantified LDL-C is available for a sample but not both, the available 
one will be used. 
2.2 
Analysis sets  
The following analysis sets will be used for statistical analyses: 
The Screened Set (SCR) consists of all participants who signed the informed consent. The SCR 
includes only unique screened participants, i.e., in the case of re-screened participants only the 
chronologically last screening data is counted. 
The Randomized Analysis Set (RAS) consists of all participants who received a randomization 
number, regardless of receiving trial medication. 
The Full Analysis Set (FAS) comprises all randomized participants with the exception of those 
participants who have not been qualified for randomization and have not received study treatment 
but have been inadvertently randomized into the study. Following the intent-to-treat (ITT) principle, 
participants will be analyzed according to the treatment they have been assigned to at 
randomization. Efficacy variables will be analyzed based on the FAS. 
The Safety Analysis Set (SAF) includes all participants who received at least one dose of study 
treatment. Participants will be analyzed according to the study treatment actually received. 
Participants who received at least one dose of inclisiran will be considered in the inclisiran arm of 
SAF. Participants who received at least one dose of ezetimibe but never received any inclisiran will 
be considered in the ezetimibe arm of SAF. Participants who never received any dose of inclisiran 


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or ezetimibe will be considered in the placebo arm of SAF. The SAF will be used for the analyses 
of safety variables. 
Note: The last part of the definition of the FAS is what is often referred to as misrandomized 
participants; i.e. participants for whom IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the participant’s final randomization eligibility and double-
blind medication was not administered to the participant. These participants would subsequently 
not continue to take part in the study or be followed-up. Misrandomized participants will not be 
included in the FAS, but they will be included in the RAS. Further exclusions from the FAS may 
only be justified in exceptional circumstances (e.g., serious GCP violations). 
2.2.1 
Subgroup of interest 
Subgroup analyses will be performed to explore the consistency of treatment effects and safety 
profiling on selected parameters between the subgroups and the overall population. In general, 
subgroups will be defined based on baseline information. In Table 2-1, subgroups defined for this 
study and the ways to derive them have been listed. Additional subgroups may be included later as 
needed. 
Table 2-1 
Specification of subgroups 
Subgroup 
Method of 
derivation 
Demographics 
and baseline 
characteristics 
Efficacy 
Selected 
Safety 
Age group 
(< Median, >= Median) 
Screening 
X 
X 
X 
Sex (Male, Female) 
Screening 
X 
X 
X 
Race 
(White, Black or African 
American, Other or multiracial) 
Screening 
X 
X 
X   
Region* 
Screening 
X 
X 
X 
Hypertension (Yes, No) 
Screening  
 
X 
 
ASCVD risk score (<5%, ≥5%) 
estimated using PCE 
Screening 
 
X 
 
Screening LDL-C [mg/dL]  
(<= 130mg/dL, > 130mg/dL) 
Screening 
 
X 
 
Baseline PCSK9 [ug/L]  
(< Median, >= Median) 
Randomization 
 
X 
 
Baseline Lp(a) [nmol/L]  
(< Median, >= Median) 
Randomization 
 
X 
 
* The regions are: USA, Europe (Germany, Hungary), Latin America (Colombia, Mexico) 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The following participant disposition at screening and randomization will be summarized by 
treatment group and overall, for the SCR: 
• Screened (Screened Set) 
o Completed screening 
o Did not complete screening 
 Reasons for not completing screening 
• Randomized (Randomized Analysis Set) 
• Included in the Full Analysis Set 
• Treated (Safety Analysis Set) 
The following study treatment disposition will be summarized by treatment group and overall, for 
the SAF: 
• Completed study treatment 
• Discontinued study treatment prematurely 
o Primary reason for early discontinuation of study treatment 
The following study disposition will be summarized by treatment group and overall, for the RAS: 
• Completed study 
• Discontinued prior to study completion 
o Primary reason for discontinuing study 
The duration of study (number of days from Day 1 to the date of last contact/participation date) 
will be summarized using descriptive statistics by treatment group and overall, for the FAS. 
The frequency (%) of participants with protocol deviations will be presented for the RAS. Finally, 
the number of randomized participants by region (Latin America, Europe, USA) and country will 
be presented descriptively for the RAS. 
2.3.2 
Demographics and other baseline characteristics 
The FAS will be used for the analyses in this section. 
The following demographics and baseline characteristics will be summarized descriptively by 
treatment group and overall: 


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• Age [years] 
• Age group 1 (< 55, ≥ 55 to < 65, and ≥ 65 years) 
• Age group 2 (< Median, >= Median) 
• Sex 
• Race 
• Race group (White, Black or African American, Other or multiracial) 
• Ethnicity 
• Region (Latin America, Europe, USA)  
• Height [cm] 
• Weight [kg] 
• Body mass index (BMI) [kg/m2] calculated as weight [kg] / height2 [m2] 
• Baseline BMI groups (< 30, ≥ 30 to < 35, and ≥ 35 kg/m2) 
• Pulse 
• Systolic and diastolic blood pressure (SBP and DBP) [mmHg] 
• Alcohol history 
• Smoking and vaping history 
• Baseline estimated glomerular filtration rate (eGFR) groups (< 30, ≥ 30 to < 60, and ≥ 60 
mL/min/1.73m2) 
• Baseline HbA1c [%] 
• Baseline plasma glucose [mg/dL, mmol/L] 
• Screening LDL-C stratum (≤ 130, > 130 mg/dL) 
• Baseline lipid profile 
o LDL-C [mg/dL; mmol/L] 
o High-density lipoprotein cholesterol (HDL-C) [mg/dL; mmol/L] 
o Non-HDL-C [mg/dL; mmol/L] 
o Total cholesterol (TC) [mg/dL; mmol/L] 
o TC/HDL-C ratio 
o Apolipoprotein (Apo) A-1 [mg/dL] 


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o Apo B [mg/dL] 
o Apo B/Apo A-1 ratio 
o Lipoprotein A (Lp(a)) [nmol/L; mg/dL] 
o Triglycerides [mg/dL; mmol/L] 
• Baseline PCSK9 [ug/L] 
The number and percentage of participants with protocol solicited medical history, such as primary 
hypercholesterolemia, hypertension, NYHA class I and II, will be presented by treatment group 
and overall. 
Other relevant medical histories will be summarized by primary system organ class (SOC) and 
preferred term (PT), for each treatment group and overall. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The SAF will be used for the analyses in this section. 
2.4.1 
Study treatment / compliance 
The number and percentage of participants receiving the s.c. injection, the injection site location, 
and the reason for not receiving the injection will be summarized for each study visit, by treatment 
group and overall. The total number of s.c. injections will also be summarized. 
Compliance [%] to the p.o. treatment will be summarized for the period from Day 1 to Day 30 visit, 
from Day 30 to Day 90 visit, and from Day 90 to Day 150 visit, by treatment group and overall. 
Cumulative compliance will also be summarized. For participants who completed the planned 
duration of study treatment, the cumulative compliance will be calculated from Day 1 to Day 150 
visit. For participants who discontinued study treatment prematurely, both the by-visit compliance 
summary and the cumulative compliance will only consider the compliance data up to the treatment 
disposition date + 1 day (or last p.o. treatment date + 1 day, if the treatment disposition date is 
missing). For example, consider a subject who discontinued study treatment early and had the 
treatment disposition date on Day 123 and had the Day 150 visit on Day 152. Because 152 > 123 
+ 1, only the subject’s Day 30 and Day 90 compliance data will contribute to the by-visit summary, 
and the cumulative compliance for that subject will also be calculated from Day 1 to Day 90 visit 
instead of from Day 1 to Day 150 visit. The formulae to calculate cumulative compliance are 
• Cumulative compliance from Day 1 to Day 90 visit = [Compliance from Day 1 to Day 30 
visit * (Day 30 date – Day 1 date) + Compliance from Day 30 visit to Day 90 visit * (Day 
90 date – Day 30 date)] / [Day 90 date – Day 1 date]  
• Cumulative compliance from Day 1 to Day 150 visit = [Compliance from Day 1 to Day 30 
visit * (Day 30 date – Day 1 date) + Compliance from Day 30 visit to Day 90 visit * (Day 


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90 date – Day 30 date) + Compliance from Day 90 visit to Day 150 visit * (Day 150 date – 
Day 90 date)] / [Day 150 date – Day 1 date] 
The calculations above are essentially the weighted average of treatment compliance at each visit 
interval (for subjects who discontinued treatment early, only consider visits no later than one day 
after treatment disposition date), where the weights are proportional to the duration of the interval. 
If there is any visit interval for which the treatment compliance is missing, the interval with missing 
treatment compliance will be excluded from the calculation of cumulative compliance. For example, 
if a subject who completed study treatment missed a compliance assessment at Day 90 for the 
interval from Day 30 visit to Day 90 visit, this subject’s cumulative compliance will be the 
weighted average of Day 30 and Day 150 visit compliance assessments.  
The duration of exposure to s.c. study treatment (inclisiran or its matching placebo) will be 
computed as the time from the first administration of s.c. study treatment to the first of the following 
two events to occur: 
• The last administration of s.c. injection plus 180 days, or 
• The participant’s last contact/participation date. For subjects who died, the death date will be 
considered. 
The duration of exposure to p.o. study treatment (ezetimibe or its matching placebo) will be 
computed as the time from the first administration of p.o. study treatment to the first of the 
following two events to occur: 
• The last administration of p.o. study treatment plus 1 day, or 
• The participant’s last contact/participation date. For subjects who died, the death date will be 
considered. 
These algorithms reflect the planned treatment schedule and the exposure attributable period of the 
s.c. and p.o. study treatments respectively. The duration of exposure to s.c. and p.o. study treatment 
(in days) will be summarized separately by treatment group and overall using descriptive statistics. 
The total participant years of exposure will be computed as the sum of duration of exposure (in 
days) across all participants, then divided by 365.25. 
2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medications will be summarized by the treatment group and overall, in 
separate tabulations based on the coding dictionary used. Medications will be presented using the 
preferred drug names and grouped by anatomical main group. Tables will show the number and 
percentage of participants receiving at least one drug of a particular preferred drug name and at 
least one drug in a particular anatomical main group. Significant non-drug therapies will be 
summarized in a similar way, using the PTs and grouped by primary SOC.  
Prior medications and significant non-drug therapies are defined as any medications and significant 
non-drug therapies taken and stopped prior to the first administration of study treatment (Day 1). 
Concomitant medications and significant non-drug therapies are defined as those used during the 


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double-blind period, including those that started before or on Day 1 and are either ongoing or 
stopped on Day 1 or later, as well as those that started after Day 1. 
In addition, LLTs added after Day 1 will be presented using the preferred drug names and 
summarized by the treatment group and overall. LLTs added after Day 1 are defined as concomitant 
medications with 2nd level ATC classification being C10 (lipid modifying agents) and start date 
after Day 1 date. 
2.5 
Analysis supporting primary objective(s) 
The primary aim of the study is to demonstrate the superiority of inclisiran to either placebo or 
ezetimibe in reducing LDL-C. 
The FAS will be used for the primary efficacy analysis. 
2.5.1 
Primary endpoint(s) 
The primary endpoint of the study is the percentage change from baseline to Day 150 in LDL-C. . 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The primary objectives are to demonstrate the superiority of inclisiran as monotherapy compared 
to the use of placebo or ezetimibe separately, in reducing LDL-C as measured by percentage change 
from baseline to Day 150. To this end, the Monotherapy Estimand assesses the treatment effect of 
inclisiran alone in the absence of confounding factors such as additional LLT. 
As described in Section 1.2.1, in addition to the primary Monotherapy Estimand, the Treatment-
policy Estimand was added for regulatory purposes. Both estimands will be considered in parallel 
as primary analysis. 
The primary statistical hypotheses to be tested are: 
• HIP0: μi - μp ≥ 0 vs. HIPa: μi - μp < 0 
• HIE0: μi - μe ≥ 0 vs. HIEa: μi - μe < 0 
where μi, μp and μe are the mean percentage changes in LDL-C from baseline to Day 150 in the 
inclisiran group, placebo group, and ezetimibe group respectively. The study can be claimed a 
success if at least one of the above two individual hypotheses is rejected. 
The primary efficacy endpoint will be analyzed using an Analysis of Covariance (ANCOVA) 
model with treatment, stratification factor, and baseline value as fixed effects. Due to probable 
heterogeneity of variances between treatment groups, an ANCOVA model that assumes unequal 
variances between treatment groups will be used. The two primary endpoint hypotheses will be 
tested using an equally weighted Dunnett test (Dunnett 1955). 
A multiple comparison procedure (MCP) will be used in statistical hypothesis testing for primary 
and secondary endpoints to control the overall type I error rate at 0.025 (one-sided test). For each 
of the secondary efficacy endpoints, the Treatment-policy Estimand and the Monotherapy 


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Estimand will be defined in a similar way as for the primary endpoint, and the MCP will be applied 
to Monotherapy Estimands and Treatment-policy Estimands separately, to control the overall type 
I error rate within each set of estimands. Since the Treatment-policy Estimands are intended for 
regulatory purposes, while the Monotherapy Estimands are intended for all other purposes, no 
multiplicity adjustment will be made across those two sets of estimands. The testing procedure to 
be followed is graphically presented in Figure 2-1, and outlined in the following steps: 
• First, a weighted Dunnett test with equal weights assigned to each of the two individual 
primary hypotheses (HIP0 and HIE0) is performed. This test will exploit the correlation of the 
primary endpoint between the two comparisons, with the test statistics derived from the 
ANCOVA model described as above. 
• If one primary hypothesis is rejected, a fraction of its significance level will be passed to the 
other primary hypothesis while the remaining alpha will be propagated to the family of 
secondary hypotheses under the same treatment comparison, according to the pre-specified 
weights as indicated in the graph. The choice of weights for passing alpha to the other 
primary hypothesis (0.4 and 0.6 respectively) reflects the importance of demonstrating 
efficacy in the comparison between inclisiran and placebo. 
• Within a family of secondary hypotheses (HIPk or HIEk), the hierarchical testing procedure will 
be used. Refer to Section 2.6.2 for details. 
• If one secondary hypothesis in the comparison between inclisiran and placebo HIPk is rejected, 
a fraction of its significance level will be passed to the next hierarchy of secondary 
hypotheses under the same treatment comparison, while the remaining alpha will be 
propagated to the primary hypothesis comparing inclisiran and ezetimibe. If there is no next 
hierarchy of secondary hypotheses, then the whole alpha will be propagated to the primary 
hypothesis comparing inclisiran and ezetimibe. Vice versa for the alpha passing from HIEk. 
The nodes HIP and HIPk represent the null hypotheses related to the primary and secondary 
endpoints compared between inclisiran and placebo, while the nodes HIE and HIEk represent the 
null hypotheses related to the primary and secondary endpoints compared between inclisiran and 
ezetimibe. The correlations between endpoints and between the two comparisons for each endpoint 
will also be considered. 
The least squares means for the difference between inclisiran and two comparators and 
corresponding unadjusted two-sided confidence intervals (CI) will be provided separately. The raw 
p-value for testing the individual hypothesis will also be provided. The superiority of inclisiran to 
a comparator can be claimed when the corresponding individual null hypothesis is rejected or the 
raw p-value is statistically significant at corresponding alpha level of current stage. 
Details of MCP implementation are described in SAP Appendix 5.4. 
 
2.5.3 
Handling of intercurrent events  
The Monotherapy Estimand will account for different intercurrent events as explained in the 
following: 


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• Discontinuation of study treatment: Discontinuation of study treatments will be treated in a 
hypothetical scenario of what would happen if the participants had not discontinued study 
treatments (hypothetical strategy). 
• Death: Participants who die will be treated in a hypothetical scenario of what would happen 
if participants had not died (hypothetical strategy).  
• Use of lipid-lowering therapy: Use of LLT will be treated in a hypothetical scenario of what 
would happen if other LLT were not available (hypothetical strategy).  
The efficacy endpoints after the intercurrent events will be multiply imputed under the missing-at-
random (MAR) assumption. In other words, it is assumed that a subject who experienced 
intercurrent events would have had similar efficacy compared to subjects with the same observed 
covariates in the same treatment group but did not experience any intercurrent event, in a 
hypothetical scenario that the subject had not experienced any intercurrent event. The imputation 
model will include stratification factor, baseline value, and available post-baseline values as 
covariates. 
The Treatment-policy Estimand will account for intercurrent events as follows: 
• Discontinuation of study treatment: Retrieved dropout (RDO) data collected after 
discontinuation from study treatments will be used for the analysis (treatment-policy 
strategy). Missing data after discontinuation from study treatments will be multiply imputed 
based on RDO data, and when there are no sufficient RDO data, a placebo-based Pattern-
Mixture Model (PMM) will be used for multiple imputation, which includes stratification 
factor, baseline value, and available post-baseline values as covariates. 
• Death: A composite variable strategy will be utilized to handle the intercurrent event of 
death, and efficacy parameter measurements after death will be imputed using the 
participant’s baseline values. 
• Use of lipid-lowering therapy: The data collected after use of other LLTs will be used for 
analyses (treatment-policy strategy). Missing data will be multiply imputed using a placebo-
based PMM, which includes stratification factor, baseline value, and available post-baseline 
values as covariates. 
The primary analysis will be conducted on each multiply imputed dataset, and the treatment effects 
estimated from each of those imputed datasets will be combined using Rubin’s method 
(Rubin 1987).  
2.5.4 
Handling of missing values not related to intercurrent event 
In the Monotherapy Estimand, missing values not related to intercurrent events will be multiply 
imputed under the MAR assumption. The imputation model will include stratification factor, 
baseline value, and available post-baseline values as covariates.  


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In the Treatment-policy Estimand, missing values not related to intercurrent events will be multiply 
imputed using a placebo-based PMM, which includes stratification factor, baseline value, and 
available post-baseline values as covariates.  
The primary analysis will be conducted on each multiply imputed dataset, and the treatment effects 
estimated from each of those imputed datasets will be combined using Rubin’s method 
(Rubin 1987). 
2.5.5 
Sensitivity analyses  
The following sensitivity analyses will be conducted to assess the robustness of the inferences to 
various assumptions about the missing data: 
• Conduct the primary analyses under the alternative missing value imputation model where 
the post-baseline (Day 30 and Day 90 visit) measurements are not included as covariates.  
• Tipping point analyses: a tipping point analysis will be performed to search for the tipping 
point that reverses the study conclusion regarding the primary endpoint. In the tipping point 
analysis, scale-adjustments will be applied to the imputed values in the inclisiran arm. The 
multiplicity adjustment between the inclisiran vs. placebo and inclisiran vs. ezetimibe 
comparisons will be performed using the same graphical approach as outlined in Section 
2.5.2, but the graph in Figure 2-1 is reduced using Algorithm 1 in Bretz et al 2011 to only 
include the two hypotheses regarding the primary endpoint. In the reduced graph, the initial 
weights are 1/2 for each of the two hypotheses, with transition weight = 1 between them.  
2.5.6 
Supplementary analyses 
Subgroup analyses 
Subgroup analyses to assess the homogeneity of the treatment effect across demographic and 
baseline characteristics will be performed. The subgroup variables are defined in Table 2-1.  
The subgroup analyses will be based on the multiply imputed datasets created for the primary 
analysis. Within each subgroup, the same ANCOVA model as described in Section 2.5.2 will be 
used. For the analysis of subgroups which are also stratification factors, the corresponding 
stratification factor term will be removed from the model. The least squares means for the 
difference between inclisiran and two comparators and corresponding unadjusted two-sided 
confidence intervals (CI) will be provided separately. The unadjusted p-value for testing the 
individual hypothesis will also be provided. No adjustment for multiple comparisons will be made. 
Forest plot will be provided for subgroup analyses. If the model did not converge for a subgroup, 
the results for that subgroup will be left blank or indicated as not estimable. 


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2.6 
Analysis supporting secondary objectives  
2.6.1 
Secondary endpoint(s) 
There are seven secondary efficacy endpoints defined, and fourteen secondary hypotheses to be 
tested for these seven secondary endpoints in the comparison between inclisiran and each 
comparator (placebo or ezetimibe) respectively: 
1. Percentage change in PCSK9 from baseline to Day 150 
2. Absolute change in LDL-C from baseline to Day 150 
3. Percentage change in non-HDL-C from baseline to Day 150 
4. Percentage change in TC/HDL-C ratio from baseline to Day 150 
5. Percentage change in Apo B from baseline to Day 150 
6. Percentage change in Apo B/Apo A-1 ratio from baseline to Day 150 
7. Percentage change in Lp (a) from baseline to Day 150 
2.6.2 
Statistical hypothesis, model, and method of analysis 
For each of the secondary efficacy endpoints, the Treatment-policy Estimand and the Monotherapy 
Estimand will be defined in a similar way as for the primary endpoint. All secondary efficacy 
endpoints will be analyzed on FAS using the same ANCOVA model as for the primary efficacy 
endpoint as described in Section 2.5.2. Lipoprotein (a) will be log-transformed before modeling. 
The model will include treatment, stratification factor, and baseline value as fixed effects, and 
assume unequal variances between treatment groups. The least squares means for the difference 
between inclisiran and two comparators and corresponding unadjusted two-sided CIs will be 
provided separately. 
As stated in Section 2.5.2, the two families of secondary hypotheses HIPk and HIEk (k = 1, 2, ..., 7, 
following the order of the seven secondary endpoints as above) are included in the multiple testing 
procedure as presented in Figure 2-1. The hierarchical testing procedure will be used to test the 
seven secondary hypotheses within each family of the secondary endpoints (HIPk or HIEk). If one 
secondary hypothesis in the comparison between inclisiran and placebo HIPk is rejected, a fraction 
of its significance level will be passed to the next hierarchy of secondary hypotheses under the 
same treatment comparison, while the remaining alpha will be propagated to the primary hypothesis 
comparing inclisiran and ezetimibe, according to the pre-specified weights as indicated in the graph. 
If there is no next hierarchy of secondary hypotheses, then the whole alpha will be propagated to 
the primary hypothesis comparing inclisiran and ezetimibe. Vice versa for the alpha passing from 
HIEk. 


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Figure 2-1 
Testing procedure for primary and secondary endpoints 
 
The intercurrent events and missing values will be handled following the same approach as 
described for the primary endpoint. 
2.6.3 
Handling of intercurrent events  
Intercurrent events will be handled using the strategies described in Section 2.5.3. 
2.6.4 
Handling of missing values not related to intercurrent event 
Missing values not related to intercurrent events will be imputed as described in Section 2.5.4. 


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2.7 
Safety analyses 
For all safety analyses, the SAF will be used. All tables and listings will be presented by treatment 
group and overall. 
2.7.1 
Adverse events (AEs) 
The most recent version of MedDRA before DBL will be used for coding AEs. An AE will be 
counted as a treatment emergent AE (TEAE) if the AE started on or after Day 1 or the AE was 
present prior to Day 1 but increased in severity on or after Day 1. Since the investigators are 
required to enter any worsened AE as a separate record, implementation-wise an AE is a TEAE as 
long as its start date is on or after Day 1.  
The following summaries will be presented for TEAEs using number and percentage of participants 
with the event: 
• Overall Summary of TEAEs 
• TEAEs by primary SOC and PT 
• TEAEs by primary SOC 
• TEAEs by PT 
• TEAEs by primary SOC, PT, and maximum severity 
• TEAEs possibly related to inclisiran/placebo by primary SOC and PT 
• TEAEs possibly related to ezetimibe/placebo by primary SOC and PT 
• TEAEs possibly related to inclisiran/placebo by PT 
• TEAEs possibly related to ezetimibe/placebo by PT 
• Treatment Emergent Serious AEs (TESAEs) by primary SOC and PT 
• TESAEs by primary SOC 
• TESAEs by PT 
• TESAEs possibly related to inclisiran/placebo by primary SOC and PT 
• TESAEs possibly related to ezetimibe/placebo by primary SOC and PT 
• TEAEs leading to discontinuation of inclisiran/placebo by primary SOC and PT 
• TEAEs leading to discontinuation of ezetimibe/placebo by primary SOC and PT 
• TEAEs leading to discontinuation of inclisiran/placebo by PT 
• TEAEs leading to discontinuation of ezetimibe/placebo by PT 


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• TEAEs with a fatal outcome by primary SOC and PT 
If more than one event occurred with the same SOC/PT for the same participant, the participant 
will be counted only once for that SOC/PT. 
Participant data listings will be presented for AEs with a fatal outcome, SAEs, AEs leading to 
discontinuation of inclisiran/placebo, and AEs leading to discontinuation of ezetimibe/placebo. 
Those listings will include all AEs in database, regardless of whether they are TEAE. 
Additional Analysis of Adverse Events for ClinicalTrials.gov and EudraCT: 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than certain 
percentage in any treatment group and on treatment emergent serious adverse events and SAE 
suspected to be related to study treatment will be provided by SOC and PT on the SAF. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, seriousness 
and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the preceding 
AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study treatment 
/ non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at least one SAE 
is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Case Retrieval Strategy (CRS) will be used to determine the MedDRA search criteria to be used to 
identify adverse events of special interest (AESI). The number and percentage of participants with 
treatment emergent AESIs will be presented by treatment group, for each topic of AESI. The AESIs 
in this study are specified as follows: 
• New Onset Diabetes Mellitus 
• Hepatotoxicity 
The following summary tables will be generated for the AESIs: 
• Overall Summary of TEAEs 
• TEAEs by PT 
• TEAEs possibly related to inclisiran/placebo by PT 


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• TEAEs possibly related to ezetimibe/placebo by PT 
• TEAEs by primary SOC, PT, and maximum severity 
• TESAEs by PT 
• TEAEs leading to discontinuation of inclisiran/placebo by PT 
• TEAEs leading to discontinuation of ezetimibe/placebo by PT 
Participant data listings will be provided for each topic of AESI, which will include all AEs in the 
database, regardless of whether they are TEAE. The CRS definitions for the AESIs will also be 
provided in a listing. 
2.7.2 
Deaths 
As stated in Section 2.7.1, TEAEs with fatal outcome will be summarized by primary SOC and PT. 
All deaths (regardless of treatment emergent or not) will be listed at the individual participant level 
as well.  
2.7.3 
Laboratory data 
Observed value, absolute change, and percent change from baseline in safety laboratory parameters 
will be summarized descriptively at baseline (for observed value only) and at each post-baseline 
visit. eGFR will be summarized by categories (< 30, ≥ 30 to < 60, and ≥ 60 mL/min/1.73m2) at 
baseline and at each post-baseline visit. For each parameter, only the visits at which the parameter 
is scheduled to be assessed per protocol will be presented for such visit-based summary.  
For glucose, only measurements taken in a fasting state will be used. Baseline glucose is defined 
as the average of the last two non-missing fasting glucose values on or prior to Day 1. If only one 
non-missing fasting glucose value is available on or prior to Day 1, the available value will be used 
as baseline. 
In addition, shift tables using the low, normal, or high classification based on the standard ranges 
for each laboratory parameter will be used to present incidence of transitions from baseline to the 
worst post-baseline value. For eGFR, HbA1c, and fasting glucose, the following ranges will be 
used: 
• For eGFR, the categories will be Severe: < 30 mL/min/1.73m2; Moderate: ≥ 30 to < 60 
mL/min/1.73m2; Normal or Mild: ≥ 60 mL/min/1.73m2. 
• For HbA1c, the categories will be < 5.7%, ≥ 5.7% to < 6.5%, and ≥ 6.5%. 
• For fasting glucose, the categories will be < 100 mg/dL, ≥ 100 mg/dL to < 126 mg/dL, and 
≥ 126 mg/dL 
The number and percentage of participants with abnormalities in liver function tests (LFT) will 
also be summarized, according to the criteria defined in Table 2-2. 


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The shift tables and the analyses of abnormalities in LFT will use all the available post-baseline 
laboratory assessments, including unscheduled visits and early exit. 
 
Table 2-2 
Notable liver function test criteria 
Peak post-baseline value 
ALT >3x ULN 
ALT >5x ULN 
ALT >10x ULN 
ALT >20x ULN 
AST >3x ULN 
AST >5x ULN 
AST >10x ULN 
AST >20x ULN 
ALT or AST >3x ULN 
ALT or AST >5x ULN 
ALT or AST >8x ULN 
ALT or AST >10x ULN 
ALT or AST >20x ULN 
ALP > 2x ULN 
Total bilirubin (BILI) >2x ULN 
Total bilirubin (BILI) >3x ULN 
Combined elevations post-baseline 
For participants with AST and ALT =< ULN at baseline   
    Elevated ALT or AST ($) & BILI >2x ULN 
    Elevated ALT or AST ($) & BILI >2x ULN & ALP >=2x ULN 
    Elevated ALT or AST ($) & BILI >2x ULN & ALP <2x ULN 
For participants with ALT or AST > ULN at baseline 
    Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) 
    Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP >=2x ULN 
    Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP <2x ULN 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
Combined elevations based on the peak post-baseline values (considering all post-baseline data 
from scheduled, unscheduled and premature discontinuation visit) for each parameter for each 
participant. 
* Elevated AST or ALT for participants with > ULN at baseline is defined as >3x Baseline or 8x 
ULN. 
$ Elevated AST or ALT for participants with =< ULN at baseline is defined as >3x ULN. 
 




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2.14 
Interim analysis 
No formal interim analysis will be performed in this study. 
3 
Sample size calculation 
3.1 
Primary endpoints 
The sample size calculation was based on a two sample t-test for the hypothesis that inclisiran is 
superior to either placebo or ezetimibe in terms of mean percentage change from baseline to Day 
150 in LDL-C, at a one-sided significance level of 0.0125 (assuming a more conservative 
Bonferroni alpha split between the two primary hypotheses). 
The sample size of 280 completers in total (with randomization ratio of 2:1:1 to inclisiran, placebo, 
and ezetimibe arms) will provide at least 99% power to detect a 40% difference between inclisiran 
and placebo or a 20% difference between inclisiran and ezetimibe at significance level of 0.0125 
(one-sided test) assuming 30% for the standard deviation. Adjusted for 6% potential dropouts, 
approximately 300 participants in total will be randomized with a 2:1:1 ratio, i.e., 150 participants 
in the inclisiran arm, and 75 participants in both the placebo and ezetimibe arm. 
3.2 
Secondary endpoints 
Statistical power will not be assessed for secondary endpoints. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study treatment 
For subjects whose end date of last dosing summary record with p.o. study treatment dose > 0 is 
missing, the date of last p.o. study treatment will be derived as the start date of that dosing summary 
record or the last IRT date of p.o. study treatment dispensing record, whichever is later. 
5.1.2 
AE date imputation 
The partially missing AE start/end date will be imputed using the Novartis ADaM Governance 
Board (AGB) global standard approach. Details will be provided in the study programming datasets 
specifications (PDS). 


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5.1.3 
Concomitant medication date imputation 
The partially missing concomitant medication start/end date will be imputed using the Novartis 
ADaM Governance Board (AGB) global standard approach. Details will be provided in the study 
PDS. 
5.2 
AEs coding/grading 
Coding of AE will be done per MedDRA dictionary. 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Implementation of MCP 
The graphical MCP outlined in Section 2.5.2 and Section 2.6.2 will be implemented using a closed 
test procedure. Let U = {IP, IE, IP1, IE1, …, IP7, IE7} denote the index set for the 16 hypotheses 
HIP, HIE, HIP1, HIE1, …, HIP7, HIE7 that correspond to the nodes in Figure 2-1. The closed test 
procedure rejects Hi, i ∈ U, at overall significance level alpha, if all non-empty intersection 
hypotheses containing Hi, i.e. HJ = ∩j∈J Hj, i ∈ J ⊆ U, are rejected by their corresponding alpha-
level tests.  The weights wj(J) assigned to each individual hypothesis j ∈ J for each non-empty 
intersection hypothesis HJ, J ⊆ U, are derived by Algorithm 1 in Bretz et al 2011 based on the graph 
in Figure 2-1. Because of the hierarchical structure of the graph, 216 – 1 non-empty intersection 
hypotheses can be categorized into two types based on the number of intersected individual 
hypotheses that are given positive weights: 
Type 1: Only one individual hypothesis has positive weight wj(J) = 1, j ∈ J. All the other 
individual hypotheses (if any) included in the intersection have zero weight. 
Type 2: Exactly two individual hypotheses Hi, Hj, i and j ∈ J, i ≠ j have positive weights 
wi(J) and wj(J) that sum up to one. All the other individual hypotheses (if any) included in 
the intersection have zero weight. 
Type 2 can be further categorized based on whether the two positive-weight individual hypotheses 
are for the same endpoint (i.e. a pair of nodes in the same layer in Figure 2-1): 
Type 2-1: The two hypotheses are for different endpoints. 
Type 2-2: The two hypotheses are for the same endpoint. 
A Type 1 intersection hypothesis will be rejected at level alpha if the only positive-weight 
individual hypothesis is rejected at local level alpha. A Type 2-1 intersection hypothesis will be 
tested using a weighted Bonferroni test, i.e. the intersection hypothesis is rejected if pi ≤ wi(J) * 
alpha or pj ≤ wj(J) * alpha, where pi and pj are the unadjusted p-values for the two positive-weight 
individual hypotheses. 


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Although the Type 2-2 intersection hypotheses can also possibly be tested using a weighted 
Bonferroni test, a weighted Dunnett test will be used to benefit from the correlation between the 
inclisiran-placebo and inclisiran-ezetimibe comparisons for the same endpoint. The correlation will 
be based on the total covariance matrix derived by combining within-imputation covariance matrix 
and between-imputation covariance matrix using Rubin’s method (Rubin 1987). Within-
imputation covariance matrix is the average of the covariance matrices of least squares means, each 
estimated from the ANCOVA model applied to a multiply imputed dataset. Between-imputation 
covariance matrix is the sample covariance matrix of least squares means across multiply imputed 
datasets. Let Φ-1 denote the inverse cumulative distribution function (a.k.a. quantile function) of 
standard univariate normal distribution, and (Z1, Z2) denote a bivariate normal random vector with 
marginal variance = 1 and correlation as estimated above. The weighted Dunnett test rejects a Type 
2-2 intersection hypothesis if pi ≤ cJ * wi(J) * alpha or pj ≤ cJ * wj(J) * alpha, where cJ is a constant 
between 1 and 2 that satisfies Prob [Z1 ≥ Φ-1(1- cJ * wi(J) * alpha) or Z2 ≥ Φ-1(1- cJ * wj(J) * alpha)] 
= alpha.  
 
6 
Reference 
Bretz, F., Posch, M., Glimm, E., Klinglmueller, F., Maurer, W., & Rohmeyer, K. (2011). 
Graphical approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical journal. Biometrische Zeitschrift, 53(6), 894–913. 
Dunnett, CW (1955) A multiple comparison procedure for comparing several treatments with a 
control. Journal of the American Statistical Association, 50(272):1096-121. 
Grundy SM, Stone NJ, Bailey AL, et al (2019) 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on 
the Management of Blood Cholesterol: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll 
Cardiol; 73(24):e285-e350. 
Rubin, DB (1987) Underlying Bayesian Theory. In: Multiple Imputation for Nonresponse in 
Surveys. John Wiley & Sons Inc, p. 75-112.